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emdn_eudamed_nomenclature_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 1 The European Medical Device Nomenclature (EMDN) The European Medical Device Nomenclature (EMDN) will be the nomenclature of use by manufacturers when registering their medical devices in the EUDAMED database. Founded on pre-established criteria and requirements1 and based on orientations provided by the Medical Device Coordination Group (MDCG) , the European Commission decided in favour of the use of the ‘Classificazione Nazionale Dispositivi medici (CND)’2 as the basis for the EMDN . Currently, a n extrao rdinary revision of the CND is ongoing so that to release the first version of the EMDN, which will be i ntegrated in EUDAMED for use by operators. The EMDN will be fully available and accessible to any operators and will be copyright free. To the extent possible, t he Commission will map the EMDN to the G lobal Medical Device Nomenclature (GMDN) . This task has been undertaken with th e hopes of possibly facilitating EMDN code search by operators current ly using GMDN . The correspondence between the nomenclatures is intended to be visible to operators and incorporated in the future database in the form of a searching tool. Therefore, and in cooperation with GMDN, t he mapping exercise is currently ongoing . The level of quality and reliability of this mapping is dependent on the commitment of all relevant parties to work together in ma pping and validating the result s. A sub -group of the MDCG on nomenclature which includes experts from National Competent Authorities and stakeholders has been established to oversee regulatory activities linked to nomenclature . The sub -group will aim to define the rules and processes related to the creation, update , maintenance and use of the European Medical Device Nomenclature. Additionally, t he Commission is currently collaborating with the World Health Organisation (WHO ) in the context of their work and activities on a future international medic al device nomenclature. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements 2 CND is currently used in Italy, Portugal and Greece.

FAQ_MDR_180117_V1.0-1.pdf.txt

Page 1 of 13 CAMD Transition Sub Group FAQ – MDR Transitional provisions Disclaimer : The information presented in this document is for the purpose of general information only and is not intended to represent legal advice to any individual or entity. It reflects the outcome of discussions within the Transition Sub Group (TSG) of the CAMD (established in May 2017) to establish recommendations on the interpretation of transition -related provisions. It is not intended to be a guidance document . We recommend that you should obtain your own legal advice before taking any action based on information given here. The content of this FAQ table will be updated cont inuously. While we strive to provide the following information in as timely and accurate a manner as possible , this document does not make any claims or guarantees about the accuracy, completeness or sufficiency of its contents. Participants of the Transit ion Sub Group, authors and reviewers of this document expressly disclaim liability for any errors and omissions in the contents. Page 2 of 13 Glossary: • AIMDD/MDD compliant device = device that is compliant with Directive 90/385/EEC/ Directive 93/42/EEC • AIMDD/MDD certificates = certificates in accordance with Directive 90/385/EEC/ Directive 93/42/EEC • DoA = date of application of the MDR • MDR = Medical Device Regulation (EU) 2017/745 • MDR compliant de vice = device that is compliant with the MDR • MDCG = Medical Device Coordination Group • MFR = manufacturer • PRRC = person responsible for regulatory compliance • NB = notified body • “old” NB = NB that has issued an AIMDD/MDD certificate • The Directives = Directives 90/385/EEC, 93/42/EEC Document History Version Publication Note V1.0 17/01/18 Original publication Conten ts: I - Issue: Transition in general ................................ ................................ ................................ ................................ ................................ .............................. 3 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) ................................ ................................ ............. 4 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) ................................ ................. 7 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR ................................ ................................ ................................ ................................ .. 11 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) .... 12 Page 3 of 13 I - Issue: Transition in general 1 Question: When does the Medical Devices Regulation (EU) 2017/745 (= MDR) apply? Answer: The MDR shall apply from 26 May 2020 (= date of application (DOA)) , see Art. 123 para 2 MDR . There are however exceptions to that general rule. Some provisions apply earlier (e.g. regarding notified bodies or the Medical Device Coordination Group), some later (e.g. regarding UDI labelling). For the exceptions, see Art. 123 para 3 MDR (earlier application: a -c, i; p ostponed application: d –h). 2 Question: When do the Directives 90/385/EEC , and 93/42/EEC [= the Directives] cease to apply ? Answer: In general the Directives 90/385/EEC and 93/42/EEC are repealed with effect from 26 May 2020 (= DoA), see Art. 122 MDR . However there are some exceptions , e.g. • in order to deal with devices that are compliant with the Directives or • to serve as a “back up” in case EUDAMED is not fully functional at DoA (see Art. 122 MDR). 3 Question: What is the applicable legislation until 26 May 2020 (= DoA )? Answer: Laws and regulations adopted by Member States in accordance with the Directives (= Directives regime). There are however exceptions (see for example Art. 123 para 3 a – c, i MDR and Art. 120 para 5 and 6 MDR ). Page 4 of 13 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) 4 Question: Is it possible to place a device, which is compliant with the MDR (= MDR compliant device ), on the market prior to 26 May 2020 (= DoA) ? Answer: Yes, see Art. 120 para 5 MDR. Manufacturer s (= MFR ) are – until 26 May 2020 (= DoA) normally required to place devices on the market that comply with the Directives (= AIMDD/MDD compliant devices) , however Art. 120 para 5 MDR offers the option to place MDR compliant devices on the market before DoA. 5 Question: Is it possible for all types of devices (for all different risk classes I – III) compliant with the MDR (= MDR compliant device) to be placed on the market prior to 26 May 2020 (according to Art. 120 para 5 MDR )? Answer: Yes, all types of devices - regardless of their risk class – may be placed on the market according to Art. 120 para 5 MDR. This includes for example custom made devices (Art. 2 para 3 MDR ) and system s and procedure packs (Art. 2 para 10 and para 11 MDR). However , devices being subject to the “clinical evaluation consultation procedure” according to Art. 54 MDR (= certain class III and class IIb devices) may not be placed on the market in ac cordance with Article 120 para 5 MDR before the Medical Device Coordination Group ( MDCG ) and the expert panels have been established (see Art. 120 para 7 MDR) . Depending on the risk class of the device, conformity assessment may requir e the involvement of a NB designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). In this c ase, such devices cannot complete a conformity assessment, and therefore may not be placed on the market, before NBs have been designated and notified under the MDR. Page 5 of 13 6 Question: As a MFR , which obligations of the MDR do I need to fulfil in order to place a MDR compliant device on the market before the DoA according to Art. 120 para 5 MDR? Answer: As many obligations as are possible , while taking into account that • EUDAMED is not fully functional and • the MDR is not fully applicable at that point in time . Generally speaking, that is to say that: • first, the device as such needs to be MDR compliant (see Annex I) and • second, the MFR has to comply with the MDR. In particular, the MFR shall undertake an assessment of the conformity of that device in accordance with the applicable conformity assessment procedures set out in Art. 52 MDR . This may, depending on the risk class of the devic e, necessitate the involvement of a notified body designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). The following requirements of the MDR need to be fulfilled by t he MFR (non -exhaustive list) : • clinical evaluation • risk management • QMS • Post-market surveillance • Technical documentation and other reports • Liability for defective devices Page 6 of 13 However, exceptions /adaptations are possible /necessary , particularly due to the fact that EUDAMED may not be fully functional before the DoA . For example : • in the absence of a fully functional EUDAMED some requirements of the Directives shall – where necessary - apply in place of the relevant provisions of the Regulation (e.g. registration of d evices and economic operators). • A person responsi ble for regulatory compliance (PRRC, Art. 15 MDR) needs to be available but not necessarily registered until EUDAMED is available . . • The assignment of an UDI (Art. 27 para 3 MDR) is not possible as long as there are - no issuing entities designated by the Commission according to Art. 27 para 2 MDR or - as long as the legal fiction according to Art. 120 para 12 does not apply (it shall apply from 26 May 2019 , see Art. 123 para 3 i MDR ). It is of no significant use as long as there is no UDI database . • An implant card and the information according to Art. 18 MDR need to be provided, however without the UDI related content (as the requirement to place the UDI carrier on the devices will be stepwise introduced after the DoA). 7 Question: Are MDR compliant devices placed on the market according to Art . 120 para 5 MDR subject to the so called “sell off” provision in Art. 120 para 4 MDR (see below)? Answer No, the possibility of their being made available/put into service is not time-limited. Page 7 of 13 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) 8 Question: Do certificates issued by notified bodies in accordance with the Directives (= AIMDD/MDD certificates ) prior to 25 May 2020 remain valid after the DoA? Answer: Yes, as specified in Art. 120 para 2 MDR. In general , they remain valid until the end of the period indicated on the certificate. Certain AIMDD/MDD certificates (Annex 4/IV, refer to Art. 120 para 2 first sentence MDR) become void at the latest on 27 May 2022, others (refer to Art. 120 para 2 second sentence MDR) on 27 May 2024 at the latest. In other words, after 27 May 2024 there will be no more valid AIMDD/MDD certificates. 9 Question: What kind of certificates remain valid according to Art. 120 para 2 MDR? Answer: All certificates which are commonly issued by Notified Bodies with reference to the Council Directives MDD and AIMDD. That is [see for example NBOG BPG 2010 -3, similar NB-MED/2.5. 1Rec 4]:  EC Design -Examination Certificate (Annex II section 4 MDD, Annex 2, section 4 AIMD)  Certificate of Conformity (Annex IV MDD, Annex 4 AIMD)  EC Type Examination Certificate (Annex III MDD; Annex 3 AIMD)  EC Certificate Full Quality Assurance System (Annex II excluding section 4 MDD; Annex 2 section 2 AIMD)  EC Certificate Production Qualit y Assurance (Annex V MDD, Annex 5 AIMD) Page 8 of 13  EC Certificate Product Quality Assurance System (Annex VI MDD) 10 Question: May a “ declaration of conformity ” be considered as a “certificate” according Art.120 para 2 MDR? Answer: No, since it is not a certificate issued by a NB. 11 Question: Is it possible for a MFR to have valid MDR and valid AIMDD/MDD certificates in parallel until the 27 May 2024 expiry date? Answer: Yes. 12 Question: May devices, that are compliant with the Directives (= MDD/AIMDD compliant devices ), be placed on the market/put into service after 26 May 2020 (= DoA) ? Answer: Yes, under certain conditions (see answer on question 1 7) as specified in Art. 120 para 3 MDR. In general , after 26 M ay 2020 , devices need to comply with the MDR in order to be placed on the market/put into service (see Art. 5 MDR) . However , for a limited time (depending on the validity of the MDD/AIMDD certificates) there is the option to continue to place devices on the market that are compliant with the Directives. Making use of this option may postpone the immediate need for a new certificate under the MDR. 13 Question: May MFR s of class I devices , that are compliant with the Directives , make use of the derogation in Art. 120 para 3 MDR (= be placed on the market after the DoA)? Answer: No, they must comply with the MDR , unless the device concerned is a class I device with measurement function or in sterile condition covered by a valid MDD certificate . Page 9 of 13 14 Question: May devices that are excluded from the scope of the MDR (e.g. via Art. 1 para 6 lit h) nonetheless benefit from Art. 120 para 3 MDR ? Answer: No, these devices do not fall under the MDR, thus Art. 120 para 3 MDR is not applicable. 15 Question: May MDD/AIMDD compliant devices , which under the MDR will be subject to an “upgrade” in risk class (“up- classification”) , e.g. formerly class IIa -> then class III , benefit from Art. 120 para 3 MDR ? Answer: Yes, under the conditions specified in Art. 120 para 3 MDR (e.g. valid AIMDD/MDD certificate ). Devices which are in a different respectively higher risk class in MDR than under the Directives are not as such excluded from the scope of Art. 120 para 3 MDR . 16 Question: If, according to Art. 120 para 3 MDR, a MFR intend s to place a MDD/ AIMDD compliant device on the market after the DoA, that , under the MDR , will be subject to an “upgrade” in risk class (“up-classification”) , what is the relevant risk class with regard to the applicable MDR requirements listed in Article 120 para 3 MDR (e.g. PSUR)? Answer: The risk class under MDD/AIMDD . 17 Question: What are the requirements for the placing on the market/putting into service of MDD/AIMDD compliant devices according to Art. 120 para 3 MDR after DoA? Answer: See Art. 120 para 3 MDR. In short: 1. A valid AIMDD/MDD certificate according to Art. 120 para 2 MDR [All certificates necessary for the placing on the market of the device in question need to be valid , e.g. a class III device needs to have a valid QMS as well as product specific certificate .] 2. Continuous compliance of the device with the Directives Page 10 of 13 3. No signif icant changes in the design and intended purpose [If there is a significant change in either the design or the intended purpose , Art. 120 para 3 MDR cannot be claimed . Qualification of a change as “significant ” according to Art. 120 para 3 MDR shall be determined on a case by case basis. However, - limitations of the intended purpose - design changes related to corrective actions assessed and accepted by the Competent Authority are not considered “ significant ” in the sense of Art. 120 para 3 MDR. . 4. Appl ication of MDR requirements in place of the corresponding requirements of the Directives with regard to: a. Registration of economic operators and of devices (see Art. 31 MDR and Art. 29 MDR) b. Post market surveillance (PMS) (see Art. 83 -86, 92 MDR including Annex III but without the PMS having to be an integral part of the QMS) c. Market surveillance (see Art. 93 – 100 MDR, but device s tandards to be met = Directives ) d. Vigilance (see Art - 87-92 MDR) However exceptions are possible in the case that EUDAMED is no t fully functional in time (then see Art. 123 para 3 d and e MDR). Moreover, the “old” NB which issued the AIMDD/MDD certificate shall continue to be responsible for the appropriate surveillance of all the applicable requirements relating to the devices it has certified. This should be agreed on between the “old” NB and the MFR on a contractual basis . Page 11 of 13 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR 18 Question: What is the so called “sell off” provision (Art. 120 para 4 MDR) about? Answer: It is intended to limit the time during which AIMDD/MDD compliant devices, that have already been placed on the market (either before the DoA or by virtue of Art. 120 para 3 after the DoA) , may be made available e.g. by a distributor . After May 27, 2025 these devices may not be made available/put into service (= deadline) . If such devices are still within the supply chain by this date - i.e. have not reached the final user as being ready for use (e.g. the hospital) - they are not “marketable” any more. This provision is thus primarily dealing with the “making available” of AIMD/MDD compliant devices once they have been placed on the market , e.g. within the supply chain . It does not apply to the “placing on the market” of these devices by the MFR . Please also note, that this provision is not intended to apply to second hand sales (see recital 3). This means , once a device has been made available to the final use r (e.g. the hospital) as being ready for use, the further making available of this device is not subject to/covered by the MDR. 19 Question: Does Art. 120 para 4 MDR enable MFRs to place MDD/AIMDD compliant devices on the market until May 27, 2025? Answer: No. Art. 120 para 4 MDR is not applicable to the “placing on the marke t” of MDD/AIMDD compliant devices (see question 18). The only way to place MDD/AIMDD compliant devices on the market after DoA is Art. 120 para 3 MDR (see question s 12-17). Given th at MDD/AIMDD certificate s will no longer be valid after May 27 2024 , this option ceases to exist from that date onwards . Page 12 of 13 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) 20 Question: Do all devices have to be registered according to Art. 29 para 4 MDR by the DoA? Answer: No. Even if EUDAMED is fully functional at the DoA there will be a n 18-month “interim phase ” (= EUDAMED fully functional but Art. 29 para 4 MDR not yet applicable) during which the different devices to be placed on the market may be registered “step by step” in EUDAMED accordin g to Art. 29 para 4 MDR instead of nationally according to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR) . However , at the end of this “interim phase ” it must be ensured that all devices of a MFR’s portfolio have been registered in EUDAMED. If EUDAMED is not fully functional until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). 21 Question: Must NBs have entered all the certificate related information of all devices according to Art. 56 para 5 MDR into EUDAMED by the DoA ? Answer: No. Even if EUDAMED is fully functional at the DoA there will be an 18-month “interim phase” (= EUDAMED fully functional but Art. 56 para 5 MDR not yet applicable) during which the relevant information according to Art. 56 para 5 MDR may be registered in EUDAMED “step by step = certificate by certificate” instead of nationally acco rding to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR). However , at the end of this “interim phase” it must be ensured that all the relevant data regarding all certificates have been registered in EUDAMED. If EUDAMED is not fully functio nal until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). Page 13 of 13 22 Question: What happens if EUDAMED is not fully functional at the DoA? How does this affect the application of obligations and requirements of the MDR that relate to EUDAMED ? Answer: The relevant provisions to refer to are mainly Art. 123 para 3 d and e . Art. 123 para 3 d MDR: The different Articles listed in Art. 123 para 3 d (= dealing with e.g. the registration of devices and economic operators, clinical investigations, notified bodies, vigilance, post -market surveillance, market surveillance) are not fully postponed with regard to their applicati on but generally remain applicable from the DoA. However , their application is postponed as far as the obligations and requirements within these Articles relate to EUDAMED (which is not fully functional yet). To that extent they shall apply from the date c orresponding to 6 months after the date of notice of full functionality . Meanwhile ( until EUDAMED is fully functional ) the corresponding provisions of the Directives regarding exchange of information continue to apply . The principle is that the derogation applies to the electronic exchange of information/upload to EUDAMED. If the derogation is applicable this does not necessarily mean that the information itself does not need to be prepared/exchanged. This exchange of in formation e.g. reports will have to be done by other means in lieu of exchange via EUDAMED (Directives regime ). The underlying idea behind this paragraph was to ensure compliance with the new obligations and requirements via the “old” systems as far as pos sible. The actual practical implication of this concept with regard to the different Articles listed in Art. 123 para 3 d MDR needs a closer look and further guidance , which is in progress. Art. 123 para 3 e MDR : For the application of Art. 29 para 4 MDR and Art. 56 para 5 MDR in the case that EUDAMED is not fully functional in time, see question 20 and 2 1.

ivd_mfr_stepbystep.pdf.txt

MEDICAL DEVICES CHANGE OF LEGISLATION Internal market, Industry, Entrepreneurship and SMEs1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the IVDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (IVDR Classes A–D) and confirm conformity assess - ment routes for existing and future products. Check the requirement for involving the Notified Bodies Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 56) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market performance follow-up plan (PMPF, Annex XIII Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for IVDs under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know!Implementation Model for In-Vitro Diagnostic Medical Devices Regulation Step by Step Guide Ref. Ares(2018)3873813 - 20/07/20182Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs related to the new risk classification system and the need of involving a Notified Body and costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the IVDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, re - source requirements and a steering group, and ensure overall responsibility for IVDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transi - tional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through IVDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (performance evaluation, technical documentation, relations with other economic operators, Unique Device Identifica - tion, labelling, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for IVDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the IVDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the IVDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89124-3 DOI: 10.2873/41862 ET-04-18-659-EN-N

scheer_o_015.pdf.txt

Final Version Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices Scientific Committee on Health, Environmental and Emerging Risks SCHEER GUIDELINES on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties The SCHEER adopted this document at plenary meeting on 18 June 2019 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 2 ABSTRACT The SCHEER was requested to provide Guidelines on the benefit -risk assessment (BRA) of the presence, in the medical devices specified in the regulation , of phthalates , which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction (CMR) or endocrine -disrupt ing (ED), according to the criteria outlined in the legal obligation section from the mandate. Phthalates are widely used in industry as plastici sers of polymers, in a variety of applications such as coated fabrics and roofing membranes, as well as in me dical devices, adhesives, paints, inks and enteric -coated tablets. Di -(2-(ethylhexyl) phthalate (DEHP) is the most widely used phthalate in medical devices. Dimethyl phthalate (DMP) and diethyl phthalate (DEP) are not used as plasticis ers but e.g. as addit ives in cosmetics, medical devices, and household products. The interaction of phthalates with the polymers they are embedded in is weak, so they may be released from the plastic product into the environment and into the human body if the product is in con tact with it. The Medical Device Regula tion, Regulation (EU) 2017/745 allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w. when a proper justification can be provided (Annex I, Chapter II Section 10.4). Fo r such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the risk associated with such alternatives should be weighed against the risk of the u se of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1 . However, the risk by itself is not the only parameter to consider: also the impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device shall be evaluated. These Guidelines describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices and/or or parts or materials used therein at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alternatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. The approach of these Guidelines may also be used for a BRA of other CMR/ED substances present in medical devices. During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices, SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data needed for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices. Pending on new scientific evidence, it is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Keywords: Guidelines, benefit -risk assessment , CMR/ED phthalates, medical devices, SCHEER . Guidelines to be cited as: SCHEER (Scientific Committee on Health, Environmental and Emerging Risks), Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are ca rcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties, final version adopted at SCHEER plenary on 18 June 2019. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 3 ACKNOWLEDGMENTS Members of the Working Group are acknowledged for their valuable contribution to this opinion. The members of the Working Group are: SCHEER members: Teresa Borges Rodica Mariana Ion Wim H. de Jong (Chair and Rapporteur) Demosthenes Panagiotakos Emanuela Testai Theo Vermeire SCCS members: Ulrike Bernauer Christophe Rousselle External experts: Stéphane Bégué (Etablissement Français du Sang, EFS, Paris, France) Hilde B. M. Kopperud (Nordic Institute of Dental Materials, Oslo, Norway) Maria Rosaria Milana (Istituto Superiore di Sanità, Dip. Ambiente e Salute, Roma, Italy) Tanja Schmidt (Ansbach University of Applied Science, Ansbach, Germany) Experts from EU Agencies : Francesco Pignatti (European Medicines Agency ) Evgenia Stoyanova (European Chemicals Agency ) Katarina Volk (European Food & Safety Authority ) All Declarations of Working Group members are available at the following webpage: http://ec.europa.eu/health/scientific_committees/experts/declarations/scheer_wg_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 4About the Scientific Committees (2016 -2021) Two independent non -food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commissio n's attention to the new or emerging problems which may pose an actual or potential threat . They are: the Scientific Committee on Consumer Safety (SCCS) and the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER). The Scientific Comm ittees review and evaluate relevant scientific data and assess potential risks. Each Committee has top independent scientists from all over the world who are committed to work in the public interest. In addition, the Commission relies upon the work of other Union bodies, such as the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCHEER This Committee, on request of Commission services, provides Opinions on questions concerning health, environmental and emerging risks. The Committees addresses questions on: -health and environmental risks related to pollutants in the environmental media and other biological and physical factors in relation to air quality, water, waste and soils. -complex or multidisciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health, for example antimicrobial resistance, n anotechnologies, medical devices and physical hazards such as noise and electromagnetic fields. SCHEER members Roberto Bertollini, Teresa Borges, Wim de Jong, Pim de Voogt, Raquel Duarte -Davidson, Peter Hoet, Rodica Mariana Ion, Renate Kraetke, Demosthen es Panagiotakos, Ana Proykova, Theo Samaras, Marian Scott , Remy Slama, Emanuela Testai, Theo Vermeire, Marco Vighi, Sergey Zacharov Contact European Commission DG Health and Food Safety Directorate C: Public Health, Country Knowledge, Crisis management Unit C2 – Country Knowledge and Scientific Committees Office: HTC 03/073 L -2920 Luxembourg SANTE- C2-SCHEER@ec.europa.eu ISBN 978-92-76-15387-0© European Union, 2020 ISSN 2467-4559 doi: 10.2875/784367 EW-CA-20-001-EN-N The Opinions of the Scientific Committees present the views of the independent scientists who are members of the committees. They do not necessarily reflect the views of the European Commission. The Opinions are published by the European Commission in their original language only. http://ec.europa.eu/health/scientific_committees/policy/index_en.htm Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 5 TABLE OF CONTENTS ACKNOWLEDGMENTS ................................ ................................ ................................ ........... 3 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine -disrupting phthalates used in medical devices ................................ ................................ .............................. 6 1. Introduction ................................ ................................ ................................ .............. 7 2. Framework for Benefit -Risk Assessment ................................ ................................ ..... 10 3. Assessment of the presence of phthalates in a medical device ................................ ....... 15 4. Assessment of possible alternative substances, materials, designs or medical treatments . 18 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates ................................ ................................ ........ 23 6. Justification for the use of CMR/ED phthalate ................................ .............................. 25 7. Benefit assessment ................................ ................................ ................................ .. 27 7.1 Material benefit ................................ ................................ ................................ ....... 28 7.2 Clinical benefits ................................ ................................ ................................ ....... 28 8. Methodologies for Benefit –Risk Assessment ................................ ............................... 29 9. Uncertainty analysis ................................ ................................ ................................ . 30 10. Conclusions ................................ ................................ ................................ ............. 34 11. Consideration of the responses received during the public consultation process ............... 35 B. REFERENCES ................................ ................................ ................................ ........... 36 C. ANNEXES ................................ ................................ ................................ ................ 40 Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates ........... 40 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances ......... 44 Annex 3: Definitions/descriptions – References - Glossary ................................ ....................... 45 Annex 4: CMR and/or ED substances ................................ ................................ .................... 51 Annex 5: Legislation on CMR and/or ED phthalates ................................ ................................ . 53 Annex 6: Use of phthalates in medical devices ................................ ................................ ....... 57 Annex 7: Approaches for Benefit -Risk Assessment ................................ ................................ .. 60 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 6 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine - disrupting phthalates used in medical devices Scope The Regulation (EU) 2017/745 on m edical devices (MDR), Annex I “General Safety and Performance Requirements”, Chapter II “Requirements regarding design and manufacture”, Section 10.4 deals with the presence of substances that may be released from a medical device. Annex I Chapter II Section 10.4.1 state s that substances that are carcinogenic, mutagenic, or reprotoxic (CMR) of category 1A and 1B, or substances having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans, shall only be present in device s, or parts thereof or those materials used therein , above 0.1% weight by weight (w/w) when justified according to a set of criteria listed under Section 10.4.2. These Guidelines1 describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alt ernatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. These Guidelines apply to those medical devices and components thereof indicated in Annex I section 10.4.1.of the MDR . They do not provide information for the BRA of the use of a medical device itself . However, the BRA as described can be integrated within the risk management system for individual medical devices. For the BRA of medical devices in general, stakeholders are referred to section A7.2. of MEDDEV 2.7/1, revision 4. Additional information may be found elsewhere, for example in the following documents FDA 2 016, 2018, EN ISO 14971, ISO/TR 24971. It should be noted that the acceptability of any risk is evaluated in relation to the benefit of the use of the medical device. When the word “patient” is used in these Guidelines, this also covers professional users and other persons (e.g. donors in case of blood donation) exposed to the medical device as well. Annex 1 to these Guidelines describes the mandate, Annex 2 describes Annex I Chapter II Section 10.4. of the MDR regarding the use of substances that could be released from the medical device and pose a risk to patients, and Annex 3 describes the definitions used in these Guidelines. 1 It should be noted that, in accordance with Regulation (EC) 2017/745, Annex I, Chapter II Section 10.4.3. and 10.4.4., updates of these Guidelines might be available in the future. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 7 1. Introduction Placing medical devices on the market, making them available on the market and putting them into service are all activities governed by Regulation (EU) 2017/745 that replaces Directive s 90/385/EEC and 93/42/EEC . Medical devices are defined in the MDR as presented in the text box below: For the purposes of this Regulation, the following definitions apply (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes : — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anat omy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended a ction by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conce ption; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. As a general requirement , the medical device shall perform acc ording to its intended purpose and be safe for professional users and patients , or where applicable other persons (e.g. donor s) on which the device is used. The conformity of medical devices shall be evaluated against the requirements of the Regulation (EU) 2017/745. They shall be presumed to be in conformity with this Regulation if they are in conformity with EU - harmonised standa rds or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union. Although not mandatory, these standards provide a route to comply with the MDR. For medical devices the horizontal standards EN ISO 14971 and EN ISO 10993 -1 are especially relevant. EN ISO 14971 describes the application of a risk management process for medical devices, whereas EN ISO 10993 -1 deals with the biological evaluation and t esting of medical devices within a risk management process. According to EN ISO 10993 -1, evaluation of the biological safety of a medical device should be a strategy Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 8 planned on a case -by-case basis to identify the hazards and estimate the risks of known hazards. In Annex A of EN ISO 10993 -1, a series of endpoints is indicated from which a selection can be made for the biological evaluation of a medical device. The selection is based on the nature of the device's contact with the body (device category: surfa ce device, external communicating device, or implant device; type of contact: skin, mucosal membrane, compromised surface, blood, tissues, organs; duration of the contact: limited ≤24 h, prolonged >24 h to 30 days, permanent >30 days). A systematic literat ure review is part of the biological evaluation of a medical device in order to avoid unnecessary testing (EN ISO 10993 -1). This systemic literature review should also be performed for a CMR/ED phthalate or potential relevant alternatives identified for a given in a medical device. In addition to EN ISO 10993 -1, a series of EN ISO 10993 standards has been published describing various assays and approaches for the evaluation of the endpoints identified in EN ISO 10993 -1 for the biological evaluation of medic al devices. Assays described in the various standards include cytotoxicity, sensitisation, irritation, systemic toxicity, implantation, haemocompatibility, genotoxicity, and carcinogenicity endpoints. Additionally immunotoxicity and organ -specific toxiciti es need to be considered, if appropriate. In addition, reproductive and developmental toxicity should be addressed for novel materials, materials containing substances with a known reproductive or developmental toxicity, medical devices with relevant targe t populations (e.g. pregnant women), and/or medical devices where there is the potential for local presence of device materials in the reproductive organs (EN ISO 10993 -1:2018). For the risk assessment EN ISO 10993 -17 describes determination of allowable l imits for leachable substances, whereas EN ISO 10993 -18 describes methods for chemical characterization of materials used in medical devices. In addition to the horizontal standards, vertical i.e. device specific standards and standards for clinical investigation are available ( e.g. EN ISO 14155). Furthermore, the EU also provides guidance in MEDDEV documents (e.g. MEDDEV 2.7/1 rev.4 for clinical evaluation of medical devices). The MDR states that substances that are classified as carcinogenic, muta genic, or toxic to reproduction (CMR) of category 1A or 1B, or substances identified at EU level as having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans (CMR/ED substances, in this text) , shall only be present in a device s or parts thereof or those materials used therein above 0.1% weight by weight (w/w) when justified. Annex 4 provides further information on the classification of CMR and on identification of ED substances. The justificatio n for the use of CMR/ED substances in a medical device above 0.1% w/w, shall be based on an analysis of potential patient and user exposure, availability of possible alternatives, an argumentation why possible alternatives are appropriate or inappropriate, and on the most recent Guidelines of this Scientific Committee. Phthalates are a group of substances widely used in medical devices. When used as plastici sers they may comprise a substantial part of the medical device. A typical concentration of Bis(2 -ethylhexyl) phthalate (DEHP; CAS 117 -81-7) in plastici sed polyvinyl chloride (PVC) can be 30% based on weight (ECB 2008, SCENIHR 201 5). For many years the reproductive toxicity and the possible endocrine disrupting activity of certain phthalates has been a source for debate. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 9 Phthalates currently classified as reproductive toxicants category 1B under the Classification, Labelling and Pa ckaging (CLP) regulation (EC 1272/2008) and identified as substances of very high concern (SVHC) under Article 57 (c) of REACH Regulation (EC) 1907/2006 are listed in Annex 5 of this document . This list may be updated, so it is recommended to consult the An nex VI of the CLP Regulation. In addition, the Commission Implementing Decision (EU) 2017/1210 and Commission Implementing Decision (EU) 2018/636 identified some phthalates as substances of very high concern (SVHC) according to Article 57(f) of REACH Regu lation (EC) 1907/2006, due to their endocrine disrupting properties with probabl e serious effects to humans, namely Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) , Diisobutyl phthalate (DIBP) , and Dicyclohexylphthalate (DCHP) . Bis(2- ethylhexyl) phthalate (DEHP), was also identified in 2014 as a substance of very high concern in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) because it is a substance with endocrine disrupting prop erties for which there is scientific evidence of probable serious effects to the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) of Article 57 REACH. https://echa.europa.eu/documents/10162/21837b30 -0318-8b45-92db-9e8c39f89dee SCENIHR adopted an Opinion on the safety of medical devices containing DEHP - plasticised PVC in 2008, and a revision of this Opinion in 201 5 (SCENIHR 2008, 201 5). The main source for DEHP exposure of the general population was determined to be food. In addition, the use of medical devices can increase the exposure considerably in the course of specific medical treatments, for e xample during massive blood transfusions, haemodialysis, and in neonatal intensive care units (NICU) for prematurely born neonates (SCENIHR 201 5). Although quite a number of alternative substances were available for DEHP, for some of them serious data gaps were observed regarding hazard identification and exposure estimation (Bui et al., 2016, SCENIHR 201 5). The Danish EPA assessed different alternatives and concluded that to various degrees some substances can be considered to be relevant alternatives to DEHP in terms of human health hazards, especially regarding the endpoints reproductive and developmental toxicity (Nielsen et al. 2014). However, for a number of possible alternatives the data set was limited. Some alternatives showed a low migration rate and some of them are already used as substitutes in medical devices for traditional DEHP -applications. For example, four additional plasticisers for PVC (BTHC, DEHT, DINCH, and TOTM) used in medical devices have recently been included in th e updated chapters of the European Pharmacopoeia (Council of Europe, EDQM 2018). Phthalates classified as CMR of category 1A or 1B according to the procedure described in Annex 4 are listed in Annex VI of the CLP regulation (CLP -Regulation (EC) No 1272/200 8, OJ L353). According to article 57 (f) of REACH (Regulation (EC) 1907/2006) or the Biocides Regulation ( Regulation (EC) 528/2012) phthalates can be identified as having ED-properties when there is scientific evidence of probable serious effects to human health . These Guidelines provide a framework of how to perform a BRA for the presence of such CMR and/or ED phthalates in medical devices or parts or materials used therein at percentages above 0.1% weight by weight (w/w) , and shall be used by all relevant stakeholders, e.g. manufacturers and notified bodies, and regulatory bodies for the justification of the presence of CMR/ED phthalates . The evaluation according to the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 10 Guidelines should be performed by a multidisciplinary team including amongst others e.g. a material scientist, medical device specialist, toxicologist and clinician. A justification for the use of a CMR/ED phthalate can also be based on an already availabl e justification relating to a medical device for which equivalence with the device in question can be demonstrated according to the MDR Annex XIV Section 3. The existing justification can be used as a reference, and the data used for this justification sho uld be available . The approach of these Guidelines can also be u sed for a BRA of other CMR/ED substances present in medical devices. Other descriptions for BRA may be “benefit -risk analysis” or “benefit -risk determination” as defined in the MDR. As Annex I Section 10.4.3 indicates a benefit -risk assessment this terminology is used in these Guidelines. 2. Framework for Benefit -Risk A ssessment The MDR allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w when a proper justification can be provided ( MDR Annex I, Chapter II Section 10.4). For such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the r isk associated with such alternatives shall be weighed against the risk of the use of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1. However, the risk is not the only parameter to consider . The impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device should also be evaluated. The justification for the presence of CMR 1A or 1B and/or ED phthalates for which there is scientific evidence of probable serious effects on humans should be based on a number of considerations as described below and in Figure 1 . In order to perform the BRA as indicated above , it is important to describe the terminology to compare the risk s of the presence of the phthalates to be evaluated (see text box below). Annex 3 provides a selection of definitions as present in the MDR and/or the OECD Substitution and Alternatives Assessment Toolbox. (http://www.oecdsaatoolbox.org/ ) For the purpose of these Guidelines the following definition for "alternatives" is used: “alternatives are defined as substances, materials, designs and medical treatments that can be used to replace the use of CMR and/or ED substances in medical devices” The alternative therefore is not limited to a possible substitute substance or material but could also be another device design (e.g. coating/production process/ techniques /lower concentration of substances) or medical treatment (e.g. procedure, device) or a combination of technical and substance alternatives that can substitute or eliminate the use of the CMR/ED phthalate (modified from the ECHA REACH guidance on the preparation of an application for authori sation). The functionality and performance of the alternative should be comparable to the extent that there would be no clinical ly relevant difference foreseen in the performance of the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 11 device or in the outcome of the alternative medical procedure. Conside rations of functionality and performance shall be based on proper scientific justification. In order to justify the use of a CMR 1A or 1B and/or ED phthalate, the manufacturer shall clearly demonstrate that the identified alternative(s) are not appropriate to maintain the functionality, performance and benefit -risk ratios of the medical device. A number of aspects need to be considered for the justification of the presence of a phthalate classified as CMR category 1A or 1B and/or identified as ED above content > 0.1% w/w in a medical device , or parts thereof or those materials used therein, as intended to be used. In summary, these aspects can be considered by a stepwise approach given below and presented in Figure 1. Further details and examples on the steps used in the Guidelines are given in the following chapters. Assessment of the CMR/ED phthalate (CMR/ED scenario) Step 1: Description and characterisation of the composition of the medical device (or parts or materials thereof) . Identif ication of the presence and concentration of CMR/ED phthalate (s) in weight by weight percentage (% w/w) . Step 2: Description of the use and function of the CMR/ED phthalate used in medical device. 2a. Description of functionality/performance provided by the presence of the CMR/ED phthalate. 2b. Description of the benefit (material and/or clinical) of the presence of CMR/ED phthalate in the medical device. Step 3: Assessment of the risks of the CMR/ED phthalate. 3a. Determin ation of the patient exposure based on realistic worst -case2 use scenario in the intended use . 3b. Identif ication of biocompatibility, general toxicological and specific CMR/ED hazards associated with the phthalate. 3c. Determin ation of the maxim um tolerable/ acceptable exposure for the patient, based on pre -clinical and clinical information (if available). 3d. Determination of the risks for various intended use scenarios and patient groups. Assessment of possible alternative (s) (non CMR/ED phthalate scenario) Step 4: Inventory of possible alternative (s). 4a. Substances. 4b. Materials. 2 Realistic worst case is the situation where the exposure is estimated us ing a range of factors (i.e. duration, amount, exposure controls), where applicable, the ones that would be expected to lead to maximum amount of exposure (e.g. exposure might be assessed under realistic simulated -use scenarios by EN ISO 10993 -12 and EN IS O 10993 -18 or a non-volatile residue test (USP <661>)). The realistic worst case does not include deliberate misuse. (EU Biocides Regulation 528/2012). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 12 4c. Designs and/or medical treatments3. Step 5: Identification of the potential relevant candidates for assessment as alternatives to CMR/ED phthalates and justification for the selection and exclusion of possible alternatives. This also includes assessment of the availability of the potential alternative (s). Step 6: Description of identified potential relevant alternative(s). 6a. Description of functionality and performance of the potential alternative(s). 6b. Description of the benefit (material and/or clinical) of the use o f the potential alternative(s). Step 7: Assessment of the risk of identified potential relevant alternative (s). 7a. Determination of patient exposure o f the alternative based on a realistic worst -case use scenario in the intended use. 7b. Identification, where available, of biocompatibility, toxicological and CMR/ED hazards associated with the alternative. 7c. Determination of maximum tolerable/acceptabl e exposure of the alternative for patient (if available). 7d. Determination of risk of potential alternatives for various use scenarios and patient groups. Assessment of potential relevant alternative (s) versus CMR/ED phthalate Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Step 9: Comparison of hazard (s) of original CMR/ED phthalate as used in the medical device with hazard (s) of identified potential relevant alternative (s). Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. In addition to patients, the same approach shall be used for the justification of the presence of CMR/ED phthalate in medical devices to evaluate the risk for professional users and for other persons (e.g. donors) exposed to the CMR/ED phthalates. When alternative designs or medical treat ments were identified as potential alternatives in step 5, adequately adopted endpoints for risks and benefits shall be chosen. It should be noted that scientific developments may be available after the initial assessment regarding the use of alternatives for CMR/ED phthalates . Therefore, a 3 It should be noted that for alternative designs and/or medical treatments, appropriate endpoints for r isks and benefits shall be selected. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 13 revision of the BRA of the presence of the CMR and/or ED phthalate may be necessary. Revisions of the above indicated BRA shall occur as indicated in the relevant sections of MDR for the general risk assessment of the me dical device. Figure 1 illustrates the BRA and is based on Eliason and Morose (2011), EMA (2014), FDA (2016) and a critical selection from the OECD Substitution and Alternatives Assessment Toolbox ( http://www.oecdsaatoolbox.org ). It presents the stepwise approach described above including a general description of factors to consider when performing a BRA. Figure 1 presents a use scenario in which the CMR/ED is used in a medical device versus a non -use scenario in which a proper potential alternative is evaluated. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 14 Figure 1 . BRA for evaluation of presence of CMR/ED phthalates and their potential alternatives in medical devices (relevant sections between brackets) . Step 3 (3) Use scenario Assessment of the risks of phthalate 3a. Exposure assessment patient 3b. Biocompatibility, hazard assessment 3c. Maximum tolerable /acceptable dose 3d. Risk characterisation Step 4 (4) Inventory of possible alternatives 4a. Substitute substances 4b. Substitute materials 4c. Alternative designs/treatmentsDefine aim and scope Step 1 (3) Description and characterisation of composition of medical device, IdentifIcation of presence and amount of CMR/ED phthalate Step 2 Description of phthalate 2a. Use, functionality and performance of phthalate (3) 2b. Benefit (7)Step 5 (4) Identification of potential candidates for alternatives and justification for the selection and exclusion Step 6 Description of identified potential relevant alternatives 6a. Functionality, performance (4) 6b. Material and clinical benefit of the use (7) Step 7 (4) Assessment of the risks of Identified potential relevant alternative(s) 7a. Exposure assessment patient or user 7b. Biocompatibility, hazard assessment 7c. Maximum tolerable /acceptable dose 7d. Risk characterisation Step 8 (5) ComparIson of functionality, performance of use and non- use scenario Overall summary report Justification for continued use of CMR/ED phthalate (6)Step 9 (5) Comparison of hazard(s) of use and non-use scenario Step 10 (5,7, 8) Comparison of benefit and risk of use and non-use scenario Uncertainty analysis (9)Non-CMR/ED phthalate scenarioCMR/ED phthalate scenario Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 15 3. Assessment of the presence of phthalates in a medical device4 It is already necessary to provide most of the information as indicated for the use of CMR/ED phthalates in order to prove compliance with the general safety and performance requirements for the phthalate containing medical device. When more than one CMR/ED phthalate is used simultaneously in the medical device, a justification shall be provided for each of the phthalates and their combination. Some risk assessment data regarding the combinat ion of phthalates are available, as EFSA has recently proposed a Group TDI for some of them, having a similar Mode of Action (MOA) in vivo (EFSA 2019, see Annex 5). Information on assessment of combined exposures to phthalates can be found for example at the report by the National Research Council Committee on the Health Risk of Phthalates (2008) and the ECHA website on the restriction of f our phthalates ( https://echa.europa.eu/registry -of-restriction -intentions/ - /dislist/details/0b0236e180d73895 ) and EFSA guidance on cumulative expos ure (EFSA, 2019 https://doi.org/10.2903/j.efsa.2019.5634 ) Step 1: Description and characterisation of the composition of the medical device. Provide a description of the medical device and its composition including identification and the concentration of each CMR/ED phthalate in the device , and the type of chemical /physical binding of the phthalate in the formulation/device, when there is an impact on leakage. Use available chemical information for identifying target phthalates (e.g. CAS Nº; EINECS Nº; IUPAC name). The chemical composition of a medical device can be evaluated by using e.g. EN ISO 10993 -18 (FDIS published in 2019) . Step 2: Use and function of CMR/ED phthalates in the medical dev ice. Characterise the function and use of the CMR/ED phthalates in the medical device and the properties it imparts to the device. Provide a description of the intended use, functionality and performance of the medical device containing the CMR/ED phthala te and how the use of the phthalate is critical for its functionality and performance . For example, for PVC consider, with regard to the performance of the medical device, maintenance, flexibility, durability and for the phthalate viscosity and PVC compatibility. Provide a description of the patients targeted (e.g. with respect to sex, age, probable vulnerable groups5). Provide a description of use types of the medical device for which it is intended (e.g. single vs repeated exposure ). Other aspects that can be relevant include the critical properties (e.g., flexibility), the conditions of use, critical quality criteria, process/treatment and performance constraints (e.g., sterilization, device/drug interactions), regulatory or clinical or other requi rements that the CMR/ED phthalates and the phthalate -containing device need to deliver. Key criteria for the function, 4 The analysis presented in section 3 (steps 1 -3) describes the current use scenario of the CMR/ED phthalate, i.e., the scenario that would continue in the future if no additional action (other than, e.g., a planned regulatory action entering into force) is taken to limit, substitute or eliminate the presence of the CMR/ED phthalate in the medical device. The current scenario can also be referred to as baseline, business as usual or continued use scenario. 5 Vulnerabl e Groups (in these Guidelines): vulnerable groups of the population such as children and individuals with increased susceptibility due to pre -existing disease, medication, compromised immunity, pregnancy or breastfeeding, women and men in reproductive age. These vulnerable groups also include infants, elderly people or people with poor health conditions. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 16 performance and overall use should be outlined and applied as the basis for an identification and screening of possible alternatives and a more detailed assessment of potential alternatives. Justification for the selection of these criteria should be provided. Benefits of the device with CMR/ED phthalates should also be considered e.g. treatment of specific patients groups due to tuning of flexibility of the medical device . Present an inventory of the benefits of the CMR/ED phthalates in the medical device for the patients (separately for vulnerable groups). More detailed information on the benefit assessment is presented in section 7. Step 3: Assessment of the risks of the CMR/ED phthalate. Perform a risk assessment of the CMR/ED phthalate present in the medical device. The risk assessment should contain a description of the potential phthalate exposure of various patient groups for which the medical device is intended (e.g. single vs repeated exposure ). This should separately include vulnerable groups. EN ISO 10993 -1 provides information on use type in terms of exposure potential (e.g. limited ( ≤24h), prolonged (>24h to 30d) and permanen t (>30d)) that slightly differs from the duration of use as defined in the MDR (Annex VIII, 1, transient <60 minutes, short term 60 minutes to 30 days, long term >30 days). Exposure estimation Provide information , preferably based on data from direct measurement or, when not available, an estimation based on worst -case scenario or from scientific literature , on the release of the CMR/ED phthalate from the medical device when used in various clinical modalities. For data generation , analytical contact conditions for the evaluation of leaching of substances from medical device s, should consider fo r example temperature, contact duration and frequency, polarity of contact liquids, flow rates, contact surface, and volume of contact liquids (EN ISO 10993 -1, EN ISO 10993 -12, EN ISO 10993 -18, USP 661). The contact conditions should be set to represent realistic worst -case conditions taking into account the intended use of the medical device. Estimate exposure to the phtha late(s) considering data on the release of the substance from the device. Consider repeated use scenarios (e.g. dialysis, apheresis donation, chronic treatment) and different population groups. The combined exposure to different CMR/ED phthalates also needs to be considered when present in a medical device. More details on the use of phthalates in medical devices are presented in Annex 6. Risk management measures in place and their effectiveness should be described and taken into account in the assessme nt (EN ISO 14971, EN ISO 10993 -1). In addition, data from biomonitoring programs may become available that could also provide information on exposure levels of phthalates in the general population and more specifically during medical treatment. Hazard id entification Describe hazards associated with the CMR/ED phthalate by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity. EN ISO 10993 -1 provides information on hazard endpoints to be considered depending on the exposure and use category of a medical device, whereas allowable limits can be determined according to EN ISO 10993 -17. Possible hazardous effects of combined exposure should Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 17 also be assessed. Identify an adequate point of departure (PoD) for risk ass essment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no-observed - adverse -effect -level (NOAEL ) or lowest -observ ed-adverse -effect -levels (LOAEL ), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non -threshold effects (e.g. in the case of genotoxic carcinogens or for certain substances acting via an ED -mediated MoA), such a dose descriptor could be a T256 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the analysis could refer to these derived figures without referring to detailed assessment how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). However, as some of these data may have been derived in the past, relevant up -to-date scientific evidence (based upon a systematic li terature review) and up -to-date risk assessment methodology for all relevant toxicological endpoints needs to be considered . If such DNEL/DMELs are not used in the assessment, a justification should be presented (e.g. new information /studies). Some of thes e other legislations are defined under Annex 4. In addition, information can also be obtained in the SCENIHR 201 5 Opinion on DEHP. The ED property of the phthalate can be described according to the recently published EFSA/ECHA guidance document . https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2018.5311 This includes impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental effects, and other effects associated with the CMR/ED phthalates. Describe risk (risk characterisation) The risk can be described by comparing exposure levels that are considered safe with the expected exposure (worst -case scenario) to obtain a risk characterisation ratio (RCR). Starting points (points of departure, PoD) for exposure levels that are considered safe could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) for threshold substances. For non -threshold substances, a T25 value or the benchmark dose associated with a 10% response (BMD10) could be used. From these PoDs, acceptable expo sure values can be derived such as “Der ived No -Effect Level ” (DNEL), “Derived Minimum Effect Level” (DMEL) or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE). As such data are often obtained in rat studies, th e use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited p eriod of time. EN ISO 10993 -17:2002 7 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, acceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors . Specifically for ED effects additional assessment factors might be considered as proposed recently (Hass et al., 2019). 6 Animal dose -descriptor; chronic dose rate that will give 25% of the animal's tumours at a specific tissue site after correction for spontaneous incidenc e (Dybing et al., 1997) 7 EN ISO 10993 -17:2002 is currently under revision. It is discussed to replace in the updated version TE by TI. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 18 The risks can also be described by calculation of the Margin of Safety (MoS), which is the ratio between the lowest PoD and the expected exposure (worst case scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18). Perform this evaluation for e very group (patients/donors) for which the device is intended to be used. Determine and describe in which situation the risk can be acceptable for the use of the CMR/ED phthalate in the medical device. The benefit -risk assessment for the use of the CMR/ED phthalate can be performed using for example MEDDEV 2.7/1rev4 and EN ISO 14971 (see also Section 8). The MDR considers a risk acceptable when outweighed by the benefit of using the device in patients (Chapter I of MDR , Chapter VI Article 62 ). In addition to potential CMR/ED effects, discuss any other potential hazards associated with the composition of the device (e.g. by using the EN ISO 10993 series of standards). Evaluate if such effects are associated with the use of the CMR/ED phthalates i n the device. Note: It should be noted that for some genotoxic carcinogens a no effect level is assumed not to exist. Similarly, a scientific debate is ongoing about whether this also applies to ED activity. The assessment of the risk should be accompan ied by an estimation of the impact of uncertainties in the described outcomes (see section 9). 4. Assessment of possible alternative substances, materials, designs or medical treatments8 In general a similar risk assessment as presented in step 3 above has to be performed for the alternative (substance s, material s, designs or medical treatment ). An inventory should be prepared in order to be able to evaluate possible alternative s. An alternative could be another substance/material or device design modifi cation or it could be a clinical procedure (e.g. a process, technique, treatment or modification) or a combination of technical and substance alternatives. Step 4: Inventory of possible alternatives Prepare a list of possible alternatives ( such as substances, materials, designs or medical treatments)9. A description of the alternative scenario (CMR/ED phthalate "non -use scenario”) needs to be presented including identification of alternative substances , materials, designs or medical treatment , e.g. by includ ing consideration of all available information, such as alternative medical devices available on the market, information about independent research, published peer-reviewed studies, systematic literature reviews, risk assessment reports or scient ific opinions from relevant scientific committees and the results of in - 8 The analysis presented in section 4 constitutes the non -use scenario or the scenario that would transpire if the CMR/ED phthalates would no longer be used in the medical device. 9 Information source for alternatives might be the European Pharmacopoeia. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 19 house research and development. The identif ication of possible alternatives should be properly documented. Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates The MDR indicates that an analysis of all possible alternatives shall be performed. However, when many alternatives are available it would not be feasible to do an extensive evaluation of all alternatives. It is therefo re recommended to select a number of potential relevant alternatives based on screening against key criteria for function, performance, toxicity, and overall use in the medical device in question (see below). In addition, analysis of availability and technical feasibility might affect choices for alternatives as well. A preliminary analysis of possible alternative substances, materials or designs or medical treatments should be performed . This preliminary analysis should include a description of their possible use as alternative substance , material , designs or medical treatment s. Justification on how and why alternatives are rejected for further assessment by defining inclusion and exclusion criteria should be provided. Information/data on functionalit y (e.g. level of flexibility in tubes) as well as performance and/or chemical safety assessment (e.g. hazard profile) may be used for rejection of the less likely alternatives (see below ) and no further risk assessment for the alternative is required. The rejection of the less likely alternatives requires justification and documentation. The chemical safety assessment should be done after assessment of the functionality and performance. In addition to the comparison in terms of functionality, technical per formance and risks to patients and users, which are critical elements for the benefit -risk assessment, Annex I Section 10.4.2 of the MDR states that the justification for the presence of CMR/ED substances should also be based on an analysis of the availabi lity of possible alternatives. Availability has several aspects, including for example the availability of necessary quantity (volumes) of the alternative on the market within a required timeframe and the ability to gain access to alternatives that may be proprietary (e.g., via licensing). If potential alternatives can be identified, a shortlist of the potential alternatives can be established for further detailed assessment with regard to technical feasibility, health benefits, comparison of risks, exist ing legal requirements, availability (e.g. sufficient availability or accessible to the manufacturer), and technical performance. In the event that no alternative is identified, i nformation should be presented on the actions undertaken to identify alternat ives. A compilation of resources and elements in support of chemical substitution and an assessment of alternatives can be found on the OECD webpage : http://www.oecdsaatoolbox.org/ Step 6: Description of identified potential relevant alternative(s) and conclusion on their technical feasibility CMR/ED phthalates are present in medical devices for a specific purpose depending on the intended use of the medical device. For example, phthalates offer the possibility for fine tuning the flexibility (e.g. optimal flexibility without kinking) of a PVC -based medical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 20 device. In addition, DEHP has a stabilising effect on red blood cells in blood bags (SCENIHR 201 5). Technical feasibility of an alternative is based on the alternative fulfilling the function of the CMR/ED phthalate. Therefore, the assessment of the functional properties in relation to the intended use of the medical device is essential. Besides functionality, performance under intended use conditi ons should also be considered. Argumentation shall be provided for justifying why possible substances and/or material substitutes, if available, or design or medical treatment changes, if feasible, are inappropriate in relation to main taining the functionality and/or performance of the medical device. For example, it might be the case that replacement is possible for one specific functional use whereas for another functionality the use of the CMR/ED phthalate remains necessary . Also oth er aspects related to performance of the alternatives need to be considered like material processing conditions (Crespo et al., 2007), material quality after sterilisation (Burgos and Jiménez 2009), and possible interaction with drugs in therapeutic infusi on systems (Treleano et al. , 2009, Salloum et al. , 2015, Tortolano et al., 2018). The benefit(s) should also be considered. An inventory of the benefit(s) of the potential alternative substances, materials, designs or medical treatments for patient populations (separately for vulnerable patient groups) should be presented (see section 7 ). The evaluation of the identified potential relevant alternatives can be done in a tiered way to avoid full assessments for each candidate alternative. For example, based on the outcome of the functionality evaluation, the choice of the potential relev ant candidates might be reconsidered and some might be discarded before performing the risk assessment (see Step 7). The ECHA guidance on the preparation of an application for authorisation and ECHA formats for Analysis of Alternatives provide more detailed information on how to conduct an initial screening of possible alternatives and to assess the technical feasibility of potential alternatives. Submitted applications for authorisations contain a number of examples (https://echa.europa.eu/applying -for-authorisation/preparing -applications -for- authorisation ) of technical feasibility assessment for uses of substances of very high concern. Step 7: Assessment of the risk of identified potential relevant alternatives The risk assessment of alternatives is comparative in nature. Its aim is to assist in the conclusion in section 5 whether the transition to the alternatives would lead to lower benefit and/or risk to human health for patients when compared to the current u se of the CMR/ED phthalates in the medical device. Th e methodology of the assessment in this step is similar to that in step 3 as performed for the phthalate to be evaluated with reference to the alternative. If potential relevant alternative s were identified under Steps 1 -6, a risk assessment of these potential relevant alternative substance/material or designs or medical treatments should be performed. The risk assessment should contain a description of the potential substance/material (alternative medical procedure) exposure of various person groups (e.g. including patients, donors, professional users) for which the medical device is intended to be used (considering single or repeated use). This should include separately Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 21 vulnerable groups . For each subgroup a different level of risk may be accepted based on the potential benefit of the medical device for that particular group . Risk management measures (EN ISO 14971, EN ISO 10993 -1) and their effectiveness to reduce exposure should be described and t aken into account in the assessment. Exposure estimation Estimate the potential release of the alternative substance(s) when used in various treatment modalities. Consider also the rate of leaching to estimate the potential exposure to the alternative substance. Multiple use scenarios (including various types of possible contact) should be considered for the exposure estimation of the alternative substance (e.g. frequent use of dialyzer) and different population groups. Hazard identification Identify hazards based on literature, supplier documentation and other information (such as risk assessments performed by regulatory bodies). Describe hazards associated with the alternative substance/material by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity including human data. Identify an adequate point of departure (PoD) for risk assessment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non - threshold effects (e.g. in the case of genotoxic carcinogens or for substances acting via an ED -mediated MoA), such a dose descriptor could be a T25 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Hazards should preferably be evaluated by a relevant exposure route for the intended use of the assessed medical device. For the hazard identification special attention should be on the determination of any potential CMR and/or ED property of the alternative substance used . For further information purposes, a procedure is described in ECHA Guidance on the application of the CLP criteria https://echa.europa.eu/documents/10162/23036412/clp_en.pdf/58b5dc6d -ac2a-4910- 9702-e9e1f5051cc5 or by searching Annex VI of CLP regulation. ED propert ies of the alternative substance/material can be described according to the recently published EFSA/ECHA guidance document . https://echa.europa.eu/documents/10162/23036412/bpr_guidance_identif_ed_en.pdf/1a 4d2811 -3faa-fe61-1de2-3cbce8fd4d95 These effects include impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental eff ects, and other potential toxic effects associated with phthalates with ED properties and reprotoxic effects category 1A/B. It needs also to be considered that the potential alternative (substances, materials, designs or medical treatments) could also have other hazards than those of the CMR/ED activity. These other hazards and their possible associated risks should be discussed for example by using the EN ISO 14971 and the EN ISO 10993 series. See also Table 1. Descri ption of risk (risk characteri sation) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 22 The risk can be described by comparing exposure levels that are considered safe with the expected exposure (realistic worst case use scenario). Exposure levels that are considered safe could be “Derived No Effect-Levels” (DNEL s) for threshold substances, “Derived Minim um Effect Levels” (DMEL s) for non -threshold substances or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE ). As such data are often obtained in rat studies, the use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited period of time. EN ISO 10993 -17:2002 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, a cceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors. For medical devices allowable limits of their chemical constituents can be determined by EN ISO 10993 -17. The risks can also be described by calculation of the Margin of Exposure (MoE) or the Margin of Safety (MoS) due to the substances present in a medical device , which is the ratio between the lowest PoD and the expected exposure (e.g. realistic worst case use scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18 ). Perform this evaluation for every patient group for which the device is intended to be used. Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the assessment could refer to these derived figures without referring to a detailed assessment of how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). Data on the relevant exposure route of the medical device application (e.g. intravenously) are preferred (see also Table 1A, EN ISO 10993 -1). The risk can be described by the so -called risk characterisation ratio (RCR), being a ratio between the exposure and the DNEL /DMEL . If such DNEL/DMELs are not used in the assessment, a justification should be stated (e.g. new information /studies). Determine and describe acceptability of the risk for the use of the potential alternative s. Risks may be acceptable when they are outweighed by the benefits for the patient. Consider any known adverse events associated with the operation of the device using the phthalate, and whether the potential alternatives might affect these adverse event s. These considerations can be based upon a systematic literature review (see MEDDEV 2.7/1rev4) . This exercise has to be performed for each potential relevant alternative substance and/or materials . A large number of phthalates exist and some may be potential relevant alternatives for the CMR/ED phthalate used in the medical device. However, a number of these phthalates are also classified as CMR and/or designated ED (see above and Table 1 Annex 5 ). Such phthalates might be identified as alternatives when the CMR/ED risk is reduced compared to the phthalate intended to be used. In addition, different substances , have also been proposed as alternative plastici sers. In 201 5 SCENIHR published an updated Opinion of potential alternative plastici sers for DEHP (SCENIHR Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 23 2015). Although many alternatives were potentially available, it was also observed that for many of them the information on potential risks and the necessary risk assessment was rather limited precluding their use as alternative s. For DEHP an extensive amount of literature is available, allowing a very careful evaluation of the risk associated to its use . In the event that the risk assessment of a potential relevant alternative cannot be performed due to lack of information, document ation should be presented on the actions undertaken to obtain information to characterise the risk, including the outcome (for example, QSAR /read across could be performed). Note shall be taken that alternative designs or medical treatments might lead to adaptation of endpoints for the benefit -risk assessme nt when compared to the toxicological endpoints of CMR/ED phthalates. The assessment of the risk should be accompanied by an estimation of the uncertainties in the described outcomes which might be qua ntitative (e.g. confidence interval, standard deviation) or qualitative (see section 9). Conclude the analysis of the potential relevant alternative(s) with a summary describing the possible scenario(s) ( see Fig ure 1). 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates Based on the information obtained above a decision can be made on the appropriateness of potential relevant alternative s (substance, material , design or medical treatment ). In this evaluation several factors need to be included such as weighing of technical feasibility, benefits and risks . And, if possible, quantification of benefits and risks. These steps entail a comparison of the CMR/ED phthalate “use-scenario” (summarised in step 3) with the “Non-use scenario ” (summarised in step 4) as shown in Figure 1. Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Compare the functionality and performance of CMR/ED phthalate in the medical device and the potential relevant alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 8 for each candidate identified as the potential relevant alternative in section 4. If several potential relevant alternatives have a similar functionality and hazard profile, exposure conditions and possibilities for Risk Management Measures (RMM) res ulting in risk reduction should be considered (see below). Risk management is described in EN ISO 14971. In this comparison also additional issues not directly related to the functionality and performance of the alternative itself, like technical possibili ties, sterilisation effects and Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 24 interactions with infusion liquids, are important for the application of the alternative and the comparison with the CMR/ED phthalates, and thus should be considered. Step 9: Comparison of risk(s) of CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives. Compare the risk of both CMR/ED phthalate and alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 9 for each potential relevant alternative. There may be difficulties in comparing the risks of a substance e.g. a phthalate, and the risks of a technical alternative such as medical design or medical treatment. For example, there may be risks as sociated with alternative technologies but these may not be of the same nature of the risk of the phthalate. However, the potential relevant alternative must represent a reduction in the overall risks to human health (Step 10) . Therefore, a comparison of risks must be conducted and the applicant will need to consider how these different risks might be compared in terms of risks to human health. Note that an alternative medical design or medical treatment may also result in expo sure to other risks previously not present in the treatment modality. Possible risks of these substances will also need to be considered in the assessment. The comparison with technological alternatives such as a medical design or medical treatment can nor mally not be fully quantitative (i.e. with directly comparable numeric values), as the hazards and associated risks will not be expressed in similar terms, but will in most cases be qualitative or semi -quantitative. Nevertheless, a clear and transparent de scription can give a good basis to conclude whether overall risks are reduced or not (Step 10) . Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Present summary/overvi ew of comparison of benefit and risk of CMR/ED phthalate used in the medical device with the potential relevant alternatives, including uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters presented. The summary should contain various aspects of functionality, performance, risk and benefit of the use of the original CMR/ED phthalate used in the medical devic e and the potential relevant alternative (s). In section 6 below the justification of the use of a CMR/ED phthalate is described based on the summary table comparing an alternative with the CMR/ED phthalate. Perform step 10 for every potential relevant alternative. Each of the assessments performed in steps 1 to 1 0 is associated with uncertainties. Certain uncertainties can be described by the use of measures like the standard deviation or confidence interval. For other uncertainties , a description may be necessary to explain the extent of the uncertainty and its impact on the final outcome . Benefit and risks should be described and weighted against each other in the use of the potential alternative substance /material in the medical device (or designs or medical treatments by choosing adequate endpoints) similar to the procedure for the CMR/ED phthalate (see step 2). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 25 6. Justification for the u se of CMR/ED phthalate Based on the comparison of functionality, performance, availability, risk and benefit, an argumentation can be built as to why a possible substance and/or material alternative, if available, or changes in designs or medical treatment, if feasible, are inap propriate in relation to maintaining the functionality, performance and the benefit -risk ratio or profile (quantitative/semi -quantitative or qualitative) of the medical device containing a CMR/ED phthalate. Explain the importance of any difference in ter ms of benefits and risks between the CMR/ED phthalate to be used in the medical device and potential relevant alternatives using value judg ements and explain how the use of the CMR/ED phthalate can be justified over the alternatives by describing the accep tability of trade -offs in the achievement of some criteria against others. Any advantage in benefits needs to be weighed against possible disadvantages in terms of functionality and risks. Both differences in benefits and risks need to be considered jointly. In building the argumentation for the use of a CMR/ED phthalate, note can be taken of the Memorandum on weight of evidence and uncertainties of SCHEER (SCHEER 2018). This Memorandum describes a methodology that classifies the strength of evidenc e in the human health risk assessment based on integration of different lines of evidence into strong, moderate, weak, uncertain and inconclusive (no suitable evidence available). Any weight of evidence evaluation needs to show the overall confidence in t he assessment. The argumentation should specifically take into account the intended use of such devices. This should include consideration and discussion of possible high risk groups such as children or pregnant or breastfeeding women, and other patient groups considered particularly vulnerable to such substances and/or materials. In addition, where applicable and available, any future update of these Guidelines shall be considered. A Table with the most relevant information and values should be used to p resent an overview of the performed assessment comparing the CMR/ED phthalate with potential alternative(s). A non-exhaustive example of such Table is presented below. The Table should be extended depending on the number of criteria evaluated and the numbe r of potential alternatives identified. Table 1: Example for a comparison of CMR/ED phthalate with potential relevant alternative(s). Assessment criteria Description (examples) Reference phthalate Alternative I Alternative II etc. Identification of substances/material etc Name and CAS number Chemical information CAS 117-81-7 Functionality/performance Used as plasticiser e.g. DEHP Clinical benefit/performance Treatment possibility e.g. Flexibility of tubing / red blood Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 26 cells storage Material benefit Concentration (% w/w) Leaching from medical device for relevant conditions e.g. media, temperature, etc (mg per hour/day) Exposure estimation (realistic worst case use scenario ) for relevant route of exposure Hazard identification Local and systemic acute and repeat -dose toxicity, ED - properties, organ toxicity, CMR properties, biocompatibili ty, and others Identification of a point of departure for risk assessment ( LOAEL, NOAEL, BMD, T25, BMD10) Identification of dose levels associated with minimal or negligible risk (e.g. DNEL, DMEL, TDI , TE, TI) Risk characterisation (MoE, MoS, RCR) Confidence estimation (see Table 2) Technical feasibility Other This Table shall be completed for every component of the medical device that contains CMR/ED phthalate(s ) above the 0.1% w/w level. For some medical devices used as a system (e.g. blood bag system) the whole system might be evaluated. Note that in case of alternative designs or medical treatments adequate endpoints for the comparison shall be chosen. These endpoints may represent risks that may be of a different nature than that of the risk of the phthalate. When the outcome of the comp arison shows that the alternative fulfils a comparable or better intended functionality as well as performance and shows a reduced risk, the use of a CMR/ED phthalate is not possible. The risk assessment should also indicate whether there would be a reduce d hazard concerning CMR and/or ED properties, and/or reduced exposure overall resulting in reduced risk. In this evaluation, other toxicities (e.g. for any Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 27 other organ or system ) of the potential relevant alternatives shall also be considered. So, the full toxicological profile of the potential relevant alternatives shall be taken into account. A balanced weighing of the benefit versus the risk has to be performed . For example it is possible to use a combination of a CMR/ED phthalate and PVC/material with h igh intrinsic toxicological hazards, thus accepting a risk from a toxicological perspective, in case the clinical benefit is very high . In contrast, a minor loss in medical functionality might be acceptable if there is a large reduction or even absence of risk. Each comparison of a potential alternative for the use of a phthalate should be based on the combination of functionality , risk and benefits for patients. In this final evaluation , the assessment of uncertainties associated with the alternatives (e.g. on the nature of the risks; assumptions made) should also be considered (see Table 2 below section 9). Therefore, where possible, quantitative results should be collected and compared (e.g. NOAEL, estimated exposure in mg/kg) and their uncertainties should be reported. Also a qualitative description of the uncertainties may be useful (see Table 2 below sec tion 9). Their impact on the conclusions should also be discussed. Although not the main subject of these Guidelines, it should be realised that availability and accessibility on the market might be a limitation for the introduction of an alternative subst ance/material. Some chemicals proposed as alternatives are widely available (e.g. BTHC, DEHT, DINCH, and TOTM) however, this may not be the case for other alternatives identified . The lack of the availability of a potential alternative for a medical device might result in the conclusion that replacement is not feasible and that the use of a phthalate with CMR and/or ED property continues in order to keep the device available for pat ients. So, besides technical feasibility in terms of functionality and risk reduction (risk assessment of the phthalate versus the alternative), also availability and accessibility on the market needs to be considered. The BRA of the CMR/ED phthalate shoul d be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated. A plan to perform an update of the relevant part of the technical file of the device needs to be submitted during the certification process (post -market surveillance plan referred to in Article 84, the requirements are set out in Section 1.1 of Annex III MDR) and this should also cover upd ates needed on the justification for the presence of CMR/ED phthalates . 7. Benefit assessment These Guidelines do not provide information for the benefit -risk assessment of the use of a medical device itself but are limited to the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates in a medical device above 0.1% (w/w). The evaluation of the overall benefit -risk assessment of a medical device is presented in other documents (e.g. MEDDEV 2.7/1 rev4, EN ISO 14971). The benefits of the CMR/ED phthalate use in a medical device need to be compared to the benefits of the potential relevant alternatives, with the focus of the analysis being on Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 28 the net or incremental benefits of use of the CMR/ED phthalate in comparison to the alternatives. These benefits may include material or clinical benefits. Uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters need to b e presented. 7.1 Material benefit A medical device does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but may be assisted in its function by such means. For the use of phthalates in medical devices, additional functionalit ies need to be considered. One of the functionalit ies is the fine -tuning of the flexibility of PVC when used as plasticiser s e.g. in intubation devices. For blood bag materials other requirements are , for example, resistance to heat and chemicals, especially during sterili sation, and permeability of gases to assure that pH and oxygen levels remain stable . In addition, DEHP has an additional property namely the stabilising effect on red blood cells (RBCs) (SCENIHR 2015). A number of alternatives were evaluated as alternative for DEHP in blood bags (Simmchen et al., 2012, SCHENIR 2015). Platelets are extremely sensitive to changes in the pH of the medium in which they are suspended, so sufficient gas permeability to O2 and CO 2 has to be assured in the containers devoted to their storage (Simmchen et al. , 2012). For this reason, DEHP has been almost fully replaced with BTHC, DINCH, and/or Trioctyltrimellitate (TOTM or Tri( 2 - ethyl hexyl)trimellitate (TEHTM) ) (Simmchen et al. 2012, Prowse et al. 2014). A better gas exchange has been found in bags plasticised with these chemicals . Also other materials, like polyolefins, are currently used for platelet storage bags (Prowse et al. 2014). This potentially will allow the stor age of platelet concentrates for up to 7 days, if measures to prevent bacterial contamination can be safely implemented. It should be noted that the benefit of phthalates in terms of material functionality and performance may differ from device to device. An alternative may be available for one application while this may not be available for another in view of added or specific demands on the functionality of the p hthalate . 7.2 Clinical benefits Clinical benefit of medical devices is defined in the MDR as follows: ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnos is, or a positive impact on patient management or public health; (Regulation (EU)2017/745: Article 2 Definitions: (53)): This “clinical benefit” has to be substantiated by the manufacturers in the “clinical evaluation” of the medical device, which includes a number of considerations. These include a discussion and overall conclusions covering safety and performance results, assessment of risks and clinic al benefits, discussion of clinical relevance in accordance Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 29 with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device and limitations of the investigation. A ”clinical benefit ” could include any meaningful, measurable, patient -relevant outcome as presented below. SCHEER identified the following examples that may be relevant for the use of phthalates (list not exclusive):  Improved survival rates  Improved length of hospital stay  Improved time of intervention  Improved time of placing ( among others in tubes and catheters)  Improved product quality/ clinical performance ( among others in tubes and catheters) in terms of: o Improved leakage rates o Improved breakage rates o Improved knotting rates o Improved blockage rates o Improved bending performance rates o Improved release rates of toxic substances o Improved release rates of (nano -)particles  Improved displacement rates  Improved possibilities for sterili sation  Reduction of diameters in relation to performance  Possibility to produce “multiple -purpose” devices, (e.g. inclusion of additional sensors), and therefore reduction of over -all patient -stress and patient -impact  Improved observability (safety) in terms of translucence, printability, radiopaque lines included, identifiab ility, traceability, etc. ( among others in tubes and catheters)  Fewer adverse events , e.g. r educed mucosal or endothelial irritation or injury rates ( among others in tubes and catheters)  Fewer serious adve rse events and serious incidents The benefit of the use of the CMR/ED phthalate should always be judged with respect to the “intended use” of the medical device and the exposed patient -group to the medical device and weighed in its clinical impact (“clinically relevant difference”). These aspects should be judged by clinical experts. Quantitative information on the benefits should be provided where possible or at a minimum qualitative description of their magnitude. Information on the probability of the benefit to occur and/or the duration of the benefit should also be included. 8. Methodologies for Benefit –Risk A ssessment In general, a Benefit - Risk A ssessment (BRA) aims to evaluate the desired effects of therapeutic mean s, medicine s or device s, against their undesired effects, i.e., risks for human health. An appropriate BRA can contribute to a more objective analysis and help conformity verification bodies and authorities towards a more objective and transparent decision -making process. Weighi ng the benefits and risks can be a complex task. It may involve the evaluation of a large amount of data that should be as accurate as possible , Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 30 without methodological weaknesses and biases. There is always some uncertainty around the actual benefits and r isks, because they can only be determined by looking at the information that is available at a given point in time which may contain various sources of uncertainty. For the BRA of medical devices in general, guidance is available in section A7.2. of MEDDEV 2.7/1, revision 4 “Clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC” . EN ISO 14971 (FDIS published in 2019) and the accompanying ISO/TR 24971 provide information on the risk benefit analys is to be performed within a risk management process. Additional information may be found elsewhere, for example in the documents of the FDA 2016, 2018,. It should be noted that the acceptability of any risk is weighted against the benefit of the use of the medical device. Several methodologies for BRA have been proposed (Guo et al, 2010 , Mt-Isa et al. 2014), of which most methodologies are so far , mainly used for pharmaceutical products. However, it should be underlined that f or medical devices the quantitative determination of a benefit -risk ratio may be rather difficult to be made and expressed in a figure. In such cases a qualitative approach of weighing the benefit based on expert judgement might be used. One methodology, namely the multi criteria decision analysis (MCDA), can be generally applied to various areas of BRA. Therefore, this methodology might also be suitable for performing the BRA of medical devices (see Annex 7). The MCDA methodology has its origins in decisi on theory aiming to evaluate multiple conflicting criteria in decision making. These criteria can include the benefits and risks of the use of a medical device on human health. The final BRA of both the used CMR/ED phthalate and potential relevant alterna tives should contain all aspects as indicated in the framework above. A quantitative or semi - quantitative description of the risks (e.g. MoS, RCR) and of the benefits of a medical device containing a CMR/ED phthalate or alternative should be the basis for a BRA. However, a lthough quantitative approaches for a BRA are preferable, a qualitative description of the value judgements about the balance of benefits and risks might also be an acceptable approach when justified (see step 10). 9. Uncertainty analysis Uncertainty plays an important role in medical decision making. It is widely accepted that, despite the methodological and technological improvements that were achieved in the past decades, there is never absolute certainty regarding the safety, effective ness, or performance of a medical treatment or use of a device. Therefore, the degree of certainty and thus uncertainty of the benefits and risks of a medical device is a factor that should always be considered when making BRA. There are various sources of uncertainty in bio -medical studies; a major source of uncertainty is the biological differences among individuals. Another source of uncertainty is the intra - and inter - variability of the laboratories, with respect to equipmen t, reagents, and methods used. It is also accepted that diagnostic tools which evaluate benefit and risk share several limitations , giving false negative and false positive results in a variety of cases. Observer variation occurs quite often and should alw ays be taken Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 31 into account. Other factors that may influence the degree of uncertainty include: the type of clinical information available (e.g., clinical investigation data, observational studies, evidence derived from registries or use experience), the re presentativeness of the information (e.g., sample size, relevance of the sample to the referent population exposed to the device), as well as the statistical inferences derived from the information. A number of techniques for uncertainty analysis are descr ibed in t he Guidance for Socio - Economic Analysis of ECHA (ECHA 2011). The aim is to determine whether uncertainties in the estimation of impacts could affect the overall conclusions. More accurately , the techniques shown can be used to either reduce the va riability of estimates, or to help test whether uncertainties affect the conclusions drawn. The only way to actually reduce uncertainty is through better data, better understanding and knowledge of the uncertainties and through further analysis. However, i n most cases residual uncertainties will remain. Recently EFSA published a guidance on uncertainty analysis (EFSA 2018 a) and a description of the principles and methods behind the guidance for uncertainty analysis (EFSA 2018 b). The EFSA Guidance recogni ses that the form and extent of uncertainty analysis, and how the conclusions should be reported, vary widely depending on the nature and context of each analysis and the degree of uncertainty that is present. Therefore it is important to identify appropriat e options for each BRA. The EFSA documents provide a flexible framework for uncertainty analysis within which different methods may be selected, according to the needs of each BRA. It seems likely that also for medical devices a similar flexibility is need ed in view of the broad range of medical devices used. EFSA describes a number of main elements of uncertainty that need to be considered in the uncertainty analysis: EFSA: Main elements of uncertainty analysis  Identifying uncertainties affecting the assessment. This is necessary in every assessment and should be done in a structured way to minimise the chance of overlooking relevant uncertainties. In assessments that follow standardised procedures, it is only necessary to identify nonstandard uncertai nties.  Prioritising uncertainties within the assessment plays an important role in planning the uncertainty analysis, enabling the assessor to focus detailed analysis on the most important uncertainties and address others collectively when evaluating overa ll uncertainty. Often prioritisation will be done by expert judgement during the planning process, but in more complex assessments it may be done explicitly using influence analysis or sensitivity analysis.  Dividing the uncertainty analysis into parts. In some assessments, it may be sufficient to characterise overall uncertainty for the whole assessment directly, by expert judgement. In other cases, it may be preferable to evaluate uncertainty for some or all parts of the assessment separately and then comb ine them, either by calculation or expert judgement.  Ensuring the questions or quantities of interest are well -defined. Each question or quantity of interest must be well -defined so that the true answer or value could be determined, at least in principle. This is necessary to make the question or quantity a proper subject for scientific assessment, and to make it possible to express uncertainty about the true answer or value clearly and unambiguously. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 32 Some assessments follow standardised procedures, within which the questions and/or quantities of interest should be predefined. In other assessments, the assessors will need to identify and define the questions and/or quantities of interest case by case.  Characterising uncertainty for parts of the uncertainty analysis. This is needed for assessments where assessors choose to divide the uncertainty analysis into parts but may only be done for some of the parts, with the other parts being considered when characterising overall uncertainty.  Combining uncertainty f rom different parts of the uncertainty analysis. This is needed for assessments where the assessors quantify uncertainty separately for two or more parts of the uncertainty analysis.  Characterising overall uncertainty. Expressing quantitatively the overall impact of as many as possible of the identified uncertainties, and describing qualitatively any that remain unquantified. This is necessary in all assessments except those standardised assessments where only standard uncertainties are identified (e.g. inter-and intra -species uncertainty factors).  Prioritising uncertainties for future investigation. This is implicit or explicit in any assessment where recommendations are made for future data collection or research, and may be informed by influence or sensit ivity analysis.  Reporting uncertainty analysis. Required for all assessments, but extremely brief in standardised assessments where only standard uncertainties are identified. A number of methods that can be used in the uncertainty analysis include:  Sensitivity analysis  Scenario analysis  Expert judgement  Monte Carlo Simulations Some of these techniques can be used in combination (e.g. scenario analysis together with expert judgement to establish ranges for key variables) but also together with less commonly used techniques such as risk -risk analysis, Delphi techniques and portfolio analysis, which can be used to help reduce the variability of estimates but are not discussed in these Guidelines. After performing the uncertainty analysis , the observed overall confidence associated with a BRA can be expressed as a probability score. This score gives the risk assessor an indication what the uncertainty is in the BRA. In situations where sufficient data are available, a quantitative categori sation of probability levels is preferred. If this is not possible, the manufacturer should give a qualitative description. A good qualitative description is preferable to an inaccurate quantitative description ( EN ISO 14971). EFSA (EFSA, 2018 b) and SCHEER (2018) use a rather detailed probability scale of 9 and 7 probab ility levels, respectively. EFSA stresses that this scale may be used as an aid to support the development of judgements and that other ranges or qualitative descriptions can be used as well. EFSA (2018 b) also argues that presenting the numerical probabilities alongside verbal expressions of probability, e.g. ‘Likely (> 66% probability)’, increases the consistency of interpretation. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 33 A detailed scale does not seem to be applicable for the uncertainties that can be obtained during a BRA evaluation of medical devices. For medical devices, a probability scale as indicated in Table 2 may b e used EN ISO showing a 5-level scale recommended by ISO for semi -quantitative assessments ( EN ISO 14971, Table D4 ). Table 2 further show s the verbal terms and subjective probability ranges that are based on a simplification of the EFSA/SCHEER scales. Table 2: Probability scale for (semi -)quantitative description of the overall confidence ISO probabil ity term Subjective probability range Probability term Frequent Probable Occasional Remote Improbable > 90% 66-90% 33-66% 10-33% <10% very l ikely likely as likely as not unlikely very unlikely Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 34 10. Conclusions These G uidelines are intended to be used for a BRA of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties . The Guidelines can be used for the justification of the use of CMR/ED phthalates in a medical device according to the Regulation (EU) 2017/745 on medical devices. They also provide a framework on how to assess and compare possible alternative substances, materials , designs or medic al treatments to the use of CMR/ED phthalates in medical devices. Major aspects include the functionality of phthalates, the performance of the medical device using the phthalate or the potential relevant alternative for the phthalate, as well as the risk assessment of the phthalate or the alternative s. In the end , the benefit (s) shall be weighed against the possible risk s of the use of the CMR/ED phthalate and of the alternative substance, materials , desig ns or medical treatments . This overall analysis will determine whether it is justified or not to use a CMR/ED phthalat e in a medical device. In view of the concern of the CMR/ED properties of phthalates, further research to possibilities to replace these p hthalates in medical devices is highly encouraged by the SCHEER . During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices , SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices . As the BRA of the presence of phthalates may have an impact on the conclusions of the "overall" benefit -risk determination of the medical device, a periodic update of the BRA of the medical device may be needed. The BRA of the presence of the CMR/ ED phtha late should be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated . A plan to perform an update of the general BRA for the medical device should be included in the dossier before marketing the device, and this should also include a plan regarding the necessary updates on the evaluation of alternatives for CMR/ED phthalate s. Pending on new scientific evidence, i t is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 35 11. Consideration of the responses received during the public consultation process A public consultation on these Guidelines was opened on the website of the non -food scientific committees from 18 March to 29 April 2019 . Information about the public consultation was broadly communicated to national authorities, international organisation s and other stakeholders. A to tal of 197 submissions from 19 contributors (providing 378 comments and additional references ) provided input to different chapters and subchapters of the document. The vast majority of comments came from industry and were requesting clarifications . Each submission was carefully considered by the SCHEER and the scientific opinion has been revised to take account of relevant comments. The literature has been accordingly updated with relevant publications. The SCHEE R expresses their thanks to all contributors for their comments and for the literature references provided during the public consultation. The text of the comments received and the response provided by the SCHEER is available at: https://ec.europa.eu/health/scientific_committees/consultations/public_consultations/sch eer_consultation_08_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 36 B. REFERENCES  Bui TT, Giovanoulis G, Cousins AP, Magnér J, Cousins IT, de Wit CA. Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ. 2016 Jan 15;541:451 -467. do i: 10.1016/j.scitotenv.2015.09.036 .  Burgos N, Jiménez A.Degradation of poly(vinyl chloride) plasticized with non - phthalate plasticizers under sterilization conditions. Polymer Degradation and Stability 94 (2009) 1473 –1478.  Crespo JR, Balart R, Sanchez L, López J. 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EFSA Journal 2018;16(1):5123, 39 pp. (https://doi.org/10.2903/j.efsa.2018.5123 .)  EFSA Scientific Committee, Benford D, Halldorsson T, Jeger MJ, Knutsen HK,More S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V, Solecki R, Turck D, Younes M, Craig P, Hart A, Von Goetz N, Koutsoumanis K, Mortensen A, Ossend orp B, Germini A, Martino L, Merten C, Mosbach -Schulz O, Smith A and Hardy A, 2018. Scientific Opinion on the principles and methods Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 37 behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. 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Benefit -Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics. Guidance for Industry and Food and Drug Administration Staff. September 25, 2018. Washington , USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM404773.pdf  FDA. US Food and Drug Administration. Factors to Consider Regarding Benefit - Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions. Guidance for Industry and Food and Drug Administration Staff. December 27, 2016. Washington, USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM506679.pdf  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report of the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 38  Hass U, Christiansen S, Andersson A -M, Holbech H, Bjerregaard P. Report on interpretation of knowledge on endocr ine disrupting substances (EDs) – what is the risk? Danish Centre on Endocrine Disruptors, Denmark . (http://www.cend.dk/files/ED_Risk_report -final-2019.pdf)  Katsikantami I, Sifakis S, Tzatzarakis MN, Vakonaki E, Kalantzi OI, Tsatsakis AM, Rizos AK. A global assessment of phthalates burden and related links to health effects. Environ Int. 2016;97:212 -236. doi: 10.1016/j.envint.2016.09.013  Mariana M, Feiteiro J, Verde I, Cairrao E. The effects of phthalates in the cardiovascular and reproductive systems: A review. Environ Int. 2016;94:758 - 776. doi: 10.1016 /j.envint.2016.07.004.  Mt-Isa S, Hallgreen C.E., Wang N., Callréus T., Genov G., Hirsch I., Hobbiger S., Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki I., Micaleff A., Ashby D. , IMI-PROTECT benefit -risk participants. Balancing benefit and risk of medicines a systematic review and clas sification of available methodologies, Pharmacoepidemiol Drug Saf. 23(7):667 -78, 2014. doi: 10.1002/pds.3636.  Nielsen BS, Andersen BN, Giovalle E, Bjergstrom M, Larsen PB. Alternatives to classified phthalates in medical devices. The Danish Environmental Protection Agency 2014, Copenhagen, Denmark  Prowse CV, de Korte D, Hess JR, van der Meer PF; Biomedical Excellence for Safer Transfusion (BEST) Collaborative.Commercially available blood storage containers. Vox Sang. 106(1):1 -13, 2014. doi: 10.1111/vox.12 084.  Salloum HA, Saunier J, Aymes -Chodur C, Barakat H, Yagoubi N. Impact of the nature and concentration of plasticizers on the ability of PVC to sorb drug. International Journal of Pharmaceutics 496, 664 –675, 2015.  SCHEER 2018 Memorandum on weight of evidence and uncertainties. Revision 2018. https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/s cheer_o_014.pdf  SCENIHR Opinion on The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). 2015 https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_047. pdf  Simmchen J , Ventura R , Segura J . Progress in the removal of di -[2-ethylhexyl] - phthalate as plasticizer in blood bags. Transfus Med Rev. 2012; 26(1):27 -37. doi: 10.1016/j.tmrv.2011.06.001. Epub 2011 Aug 5.  Tortolano L, Matmati H, Bourhis M,Manerlax K, Lemare F, Saunier J,Yagoubi N. DinCH and ESBO actual migration from PVC infusion tubings used in an oncopediatric unit. J. Appl. Polym. Sci. 135, 46649, 2018. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 39  Treleano A,Wolz G,Brandsch R, Welle F. Investigation into the sorption of nitroglycerin and diazepam intoPVC tubes and alternative tube materials during application . Intl JPharmac 369, 30 –37, 2009.  Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008 ; 118(4):1479 -90. doi: 10.1172/JCI34241. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 40 C. ANNEXES Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates 1. Background What are phthalates? Phthalates are the esters of 1,2 -benzenedicarboxylic acid (o -phthalic acid) and their chemical structure consists of one benzene ring and two ester functional groups linked with two consecutive carbons on the ring10. The hydrocarbon chains of the ester groups are either straight or branching; they give each substance its name and they are responsible for the different properties amo ng phthalates. Phthalate esters (PEs) may be categori sed into three distinct groups according to the length of their carbon chain. High molecular weight (HMW) phthalates include those with 7 –13 carbon atoms in their carbon chain and low molecular weight (L MW) those with 3 –6 carbon atoms in their backbone. DEHP is classified as a LMW phthalate. A third group includes dimethyl phthalate (DMP) and diethyl phthalate (DEP)11. What are they used for? Phthalates are widely used in industry as plastici sers of polym ers such as polyvinyl chloride (PVC). HMW phthalates are used in a variety of applications such as coated fabrics and roofing membranes. LMW phthalates are used in medical devices, adhesives, paints, inks and enteric -coated tablets. DEHP is the most widel y used phthalate in medical devices. DMP and DEP are not used as plastici sers but e.g. as additives in cosmetics, medical devices, and household products. Potential CMR or endocrine -disrupting properties The interaction of phthalates with the polymers the y are embedded in is weak, so they may migrate from the plastic product into the environment and into the human body if the product is in contact with it. Correlation between exposure to a range of phthalates and adverse health effects has been documented in animals and humans (see for example tables in Mariana et al. 2016 and Katsikantami et al. 2016). A number of phthalates are suspected of and/or have been classified or identified as having CMR or endocrine -disrupting properties. 10 A global assessment of phthalates burden and related links to health effects. Katsikantami et al., Environ Int. 2016 Dec;97:212 -236. https://www.ncbi.nlm.nih.gov/pubmed/?term=katsikantami 11 Footnote added by SCHEER. It should be noted that there are hundreds of phthalates of which only a limited number is used as plasticiser in polymers. Phthalates can be categorised according to the length of the carbon chain and one of these categorisations is mentioned in the mandate of DG GROW. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 41 Previous work of Commission Scientific Committees on phthalates Previous opinions on the most commonly used phthalate DEHP [di -(2-(ethylhexyl) phthalate] in medical devices were issued by EU Scientific Committees in 2002 (SCMPMD), 2008 and 2015 (SCENIHR). The 2008 Opinion concluded that "So far, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans", but noted that "newborn and pre -term born male infants are of special concern" . In the 2015 Opinion, SCENIHR additi onally identified that "patients subject to haemodialysis procedure may be at risk of DEHP induced effects" . The Committee noted that "Food is the primary source of exposure to DEHP for the general population." In both opinions, the Committee emphasised th at "the benefit of the medical devices must also be considered" and in the 2008 Opinion the Committee states that "each alternative to DEHP, however, must also be evaluated with regard to their functionality in respect to medical devices. The risk and bene fits of using alternative plasti cizers should be evaluated case by case." In the 2015 opinion, the Committee states that “The potential for replacement of DEHP in these products should be considered against their efficiency in the treatment, as well as the toxicological profile and leaching properties of the alternative materials.” The legal obligation Article 5 paragraph 2 of the Regulation 2017/745 on medical devices stipulates: "A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose." Accordingly, Section 10.4 of Annex I, which deals with substances in medical devices, states that "Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device." Particular substances of concern are those which (a) are carcinogenic, mutagenic or toxic to reproduction (CMR), of category 1A or 1B,12 or (b) have endocrine -disrupting properties (ED)13. The Regulation states that: "Devices, or those parts thereof or those materials used therein that:  are invasive and come into direct contact with the human body,  (re)administer medicines, body liquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body" 12 in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 13 identified as such in accordance with the relevant provisions of Regulation (EC) No 1907/2006 or respectively of Regulation (EU) No 528/2012 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 42 shall only contain any such substance ab ove the concentration of 0.1% weight by weight where justified pursuant to Section 10.4.2. The justification shall be based on several elements, including the latest relevant scientific committee guidelines on benefit -risk assessment of the presence of suc h substance in devices. According to Section 10.4.3, the Commission shall provide a mandate to the relevant scientific committee to prepare such guidelines for phthalates which are subject to these provisions. These guidelines are explicitly requested by t he Regulation to be available at the latest on the date of application of the Regulation, and are to be updated whenever appropriate on the basis of the latest scientific evidence, or at least every five years. 2. Terms of reference The Scientific Committee is requested to provide guidelines on the benefit -risk assessment of the presence, in the medical devices specified below, of phthalates which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction or endocrine -disrup ting, according to the criteria outlined in the previous section. The devices covered, or those parts thereof of those materials used therein, are those which:  are invasive and come into direct contact with the human body,  (re)administer medicines, body l iquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body. The guidelines shall include guidance on how, for an individual device, to:  analyse and estimate potential patient or user exposure to the substance,  analyse possible alternative substances, materials, designs, or medical treatments,  to justify why possible substance and/or material substitutes, if available, or design change s, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratios of the product, including taking into account if the intended use of such devices includes treatment of children or treatment of pregnan t or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials. In addition, the Scientific Committee is requested to :  identify any relevant knowledge gap , and  to give consideration to what extent of new evidence would be deemed appropriate to justify an update of these guidelines before the maximum period of five years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 43 In order to ensure the appropriateness of this guidance the Scientific Committee should inter alia :  involve at the appropriate level the notified bodies active in the field of medical devices, or other relevant stakeholders such as Competent Authorities, professional and patient associations, industry associations, while maintaining scientific independence ,  involve to the necessary extent the relevant EU Agencies and Scientific Committees. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 44 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances The requirement for justification of the presence of CMR 1A or 1B and/or ED hazardous substances is described in Annex I 10.4.2 as presented in the text box below. 10.4. Substances 10.4.1. Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as fa r as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine -disrupting properties for which there is scientific ev idence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been ad opted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established the rein. 10.4.2. Justification regarding the presence of CMR and/or endocrine -disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the subs tance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer -reviewed studies, scientific opinions from relevant scientific committees and an analysis of the avail ability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratio s of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances an d/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3 and 10.4.4. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 45 Annex 3: Definitions/descriptions – References - Glossary Definitions ( Regulation (EU) 2017/745 ) Benefit -risk determination: means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer. Performance: means the ability of a device to achieve its intended purpose as stated by the manufacturer. Clinical performance: means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteri stics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer. Clinical benefit: means the positive impact of a de vice on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health. Risk: means the combination of the probability of occurrence of harm and the severity of that harm. Adverse event: means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or othe r persons, in the context of a clinical investigation, whether or not related to the investigational device. Serious adverse event: means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subjec t, that resulted in any of the following: (i) life -threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitali sation or prolongation of patient hospitali sation, (iv) medical or surgical intervention to p revent life -threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) fetal distress, fetal death or a congenital physical or mental impairment or birth defect. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 46 Incident: means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use -error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesir able side -effect. Serious incident: means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a pati ent's, user's or other person's state of health, (c) a serious public health threat. Serious public health threat : means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time. Device deficiency: means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer. Regulation (EU) 2017/745 Annex XIV Clinical evaluation and post -market clinical follow -up. Part A “Clinical evaluation” Section 3 describes the characteristics that shall be considered for demonstration of equivalence . “A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. T he following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: Technical : the device is of similar design; is used under similar conditions of use; has similar specifications and pr operties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and cr itical performance requirements; Biological : the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including de gradation products and leachables; Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 47 Clinical : the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has simila r relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in or der to justify their claims of equivalence. ” Definitions on assessment of alternatives (OECD Toolbox Glossary) Note: The term "chemical" is used synonymously with "substance" Alternativ es assessment : A process for identifying and comparing potential chem ical and non -chemical alternatives that can be used as substitutes to replace chemicals or technologies of high concern1 Chemical substitution : The process of replacing a chemical of concern with a safer chemical, material or product, or technology/process that eliminates the need to use that chemical Cost/benefits and availability : The negative (cost) and positive (benefit) implications, direct and indirect, resulting from some actio n. This includes both financial and non - financial information. Availability refers to the production of an alternative and its market accessibility3 Functional use approach : This approach starts with identifying the function that is desired. The concept is applied in two ways: first and foremost, to characteri se the purpose a chemical or mixture serves, or the properties it imparts in a product or process (functional use), and second, to eva luate the function of the product and how its use may influence the assessment of alternatives4, 5 Material substitution : The process of replacing a material containing a chemical of concern with a safer chemical, material, product or technology/process that eliminates the need to use that chemical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 48 Mixture : A composition of at least two chemicals in which they do not react6 Technical feasibility : The determination as to whether the performance or functional requirements of a chemical, material or product could be fulfilled or replaced by eliminating or using an alternative chemical, material, product, process or technology, while considering any need for process adaptations and changes3 Process modification : Changes in manufacturing processes to eliminate, reduce or substitute chemicals of concern. Such changes may include synthesis pathways, waste reduction, and manufacturing procedures where chemicals are used. Product performance : The ability of a product to meet identified performance requirements. The boundaries of performance characteristics are defined by the user3 Product substitution : The process of replacing a product containing a chemical of concern with a chemical, material or product or technology/process that eliminates, reduces or substitutes the need to use that chemical. 1 Adapted from Alternatives Assessment Guide, version 1.0 . 2013. Interstate Chemicals Clearinghouse. 2 REACH. Title I, Chapter 2, Article 3. 3 Current Landscape of Alternatives Assessment Practice: A Meta -Review. Organisation for Economic Cooperation and Development. 2013. 4 U.S. EPA. 2006. National Pollution Prevention and Toxics Advisory Committee (NPPTAC) Recommendation to the EPA Administrat or and Deputy Administrator on Incorporating the Functional Use Approach into OPPT Activities. 5 Lavoie, E. T., et al. 2010. "Chemical Alternatives Assessment: Enabling Substitution to Safer Chemicals." Environmental Science & Technology 44(24): 9244 -9249. 6 Adapted from U.N. Global Harmonized System of Classification and Labelling of Chemicals . 2003. 7 ECHA, 2008. Guidance on Socio -Economic Analysis - Restrictions. 8 Adverse event means pre -clinical and clinical occurrences of an effect whereas incident indicates a clinical effect occurring during post -market surveillance. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 49 Reference s  ECHA (2011) Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  EFSA (2019) Draft update of the risk assessment of di -butylphthalate 1 (DBP), butyl-benzyl -phthalate (BBP), bis(2 -2 ethylhexyl)phthalate (DEHP), di - isononylphthalate (DINP) 3 and di -isodecylphthalate (DIDP) for use in food contact 4 materials http://www.efsa.europa.eu/en/consultations/call/190221 .  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report o f the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66. Glossary BBP Benzylbutylphthalate BMD Bench Mark Dose BRA Benefit -Risk Analysis BTHC Butyryl -tri-n-hexylcitrate CAS Chemical Abstracts Service CEN European Committee for Standardization CLP Classification Labelling and Packaging regulation (EC No 1272/2008) CMR Carcinogenic, Mutagenic, toxic to Reproduction (Reprotoxic) DBP DiButylphthalate, DCHP Dicyclohexylphthalate DEHP Diethylhexylphthalate DIBP Diisobutylphthalate DIDP Di isodecyl phthalate) DINCH 1,2- cyclohexan edicarboxylic acid, di isononyl ester) DINP Di isononyl phthalate) DIPP Diisopentylphthalate DMEP Bis(2-methoxyethyl)phthalate DNHP Dihexylphthalate DHNUP 1,2-Benzenedicarboxylic acid, di -C7-11-branched and linear alkyl esters DPP Dipentyl phthalate DMEL Derived Minimum Effect Level DNEL Derived No Effect Level EC European Commission ECB European Chemicals Bureau (now ECHA) ECHA European Chemicals Ag ency (formerly ECB) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 50 ED Endocrine Disruptor EEC European Economic Community EMA European Medicines Agency EFSA European Food Safety Authority EN-ISO CEN and ISO combined published document FDA Food and Drug Administration (USA) FDIS Final Draft International Standard ISO International Organization for Standardization LOAEL Lowest Observed Adverse Effect Level MCDA Multi Criteria Decision Analysis MDD Medical Device Directive (Council Directive 93/42/EEC) MDR Medical Device Regulation (EU 20 17/745) MoA Mode of Action MoE Margin of Exposure MoS Margin of Safety NICU Neonatal Intensive Care Unit NOAEL No Observed Adverse Effect Level OECD Organization for Economic Cooperation and Development PoD Point of departure PVC Polyvinyl chloride RBC Red Blood Cell RCR Risk Characterisation Ratio REACH Registration, Evaluation, Authorisation and restriction of CHemicals. SCHEER Scientific Committee on Health, Environmental and Emerging Risks SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks T25 25 % increase of the tumour rate over controls TDI Tolerable Daily Intake TE Tolerable Exposure (EN ISO 10993 -17:2002 in mg/day) TEHTM Tri( 2 -ethyl hexyl)trimellitate also TOTM Trioctyltrimellitate TI Tolerable Intake TOTM Trioctyltrimellitate also TEHTM Tri( 2 -ethyl hexyl)trimellitate TWI Tolerable Weekly Intake Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 51 Annex 4: CMR and/or ED substances CMR substances are substances identified and classified as carcinogenic, mutagenic or toxic for reproduction of different categories based on the intrinsic toxic properties of a substance for which categories 1A and 1B apply to these Guidelines. In Europe, classification for these endpoints is harmonised through harmonised classification and labelling (CLH). Details can be found at https://echa.europa.eu/regulations/clp/understanding -clp. For a specific substance to be classified as CMR 1A, 1B or 2 a dossier needs to be prepared and if the Commission finds that the proposed classification is appropriate, it submits a draft decision concerning the inclusion of that substance in Part 3 of Annex VI to the CL P Regulation (Regulation (EC) 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures).  Category 1A means that the substance is a known human carcinogen, mutagen or reproductive toxicant based on human evidence.  Category 1B means that the substance is a presumed human carcinogen, mutagen or reproductive toxicant based on animal studies.  Category 2 means that a substance is considered as suspected carcinogen, mutagen or reproductive toxicant based on limited evidence from ani mal studies or humans (not part of these Guidelines) . Documents on the classification are publicly available , and a tutorial to search entries is given here: http://www.chemsafetypro.com/Topics/EU/Annex_VI_to_CLP:_List_of_Harmonised_Class ification_and_Labelling_for_Certain_Hazardous_Substances.html Guidance for the identification of endocrine disrupto rs (ED) in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009 has been published on 7th June 2018 by ECHA and EFSA (doi: 10.2903/j.efsa.2018.5311; EFSA Journal 2018;16(6):5311) which can be accessed via: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2018.5311 This EFSA/ECHA Guidance describes when a substance shall be considered as having endocrine disrupting properties. “A substance shall be considered as having endocrine disrupting properties if it meets all of the following criteria: a) it shows an adverse effect in [an intact organism or its progeny]/[non -target organisms], which is a change in the morphology, physiology , growth, development, reproduction or life span of an organism, system or (sub)population6 that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other in fluences; b) it has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system; c) the adverse effect is a consequence of the endocrine mode of action. It should be highlighted that the ‘endocrine mode of action ’ as stated in point (b) should be interpreted as ‘endocrine activity ’ while the term ‘endocrine mode of Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 52 action’ in point (c) covers the link between the adverse effect and the endocrine activity identified in points a) and b), respectively. Keeping this in mind point (b) abo ve should be understood as (differences from above in italics ): it shows endocrine activity, i.e. it has the potential to alter the function(s) of the endocrine system; Consequently point (c) above should be understood as (differences from above in italics ): the substance has an endocrine disrupting mode of action, i.e. there is a biologically plausible link between the adverse effect and the endocrine activity. ” EDs identified with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 concern ing the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), will finally enter the REACH candidate list of substances of very high concern for potential inclusion in REACH Annex XIV. The information can be found in the respecti ve decision document accessible via : https://echa.europa.eu/candidate -list-table. For substances having endocrine -disrupting properties as indicated above, there is currently no information concer ning whether it is foreseen to publish them in central lists or annexed to a Regulation. EDs identified by the delegated act pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products, can be accessed through the Biocidal Products Committee opinions on active substance approval which can be accessed via ECHA’s website (https://echa.europa.eu/regulations/biocidal -products -regulation/approval -of-active - substances/bpc -opinions -on-active -substance -approval ). Substances undergoing an ED assessment under the REACH or Biocidal Products regulations that have been brought for discussion to ECHA’s ED Expert Group are included in ECHA’s endocrine disruptor (ED) assessment list: https://echa.europa.eu/ed - assessment . For each substance, the table shows the assessing or evaluating Member State (submitter), the outcome and the suggested follow -up for the assessment, and the date of the latest update to the list entry. Recently the Commission Implementing Decision (EU) 2017/1210 was published that identified some phthalates (Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) and Diisobutyl phthalate (DIBP)) as substances of very high concern due to their endocrine disrupting properties with probable serious effects to humans (European Commission 2017). https://publications.europa.eu/en/publication -detail/ -/publication/357b3d45 -620f-11e7- 9dbe-01aa75ed71a1/language -en/format -PDF For completeness, even if not relevant for the purpose of this guidelines, Bis(2 - ethylhexyl) phthalate (DEHP) was also identified in 2014 as a substance of very high concern due to its endocrine disrupting properties with probable serious effects to the environment. In addition, Commission Implementing Decision (EU) 2018/636 identified Dicyclohexylphthalate (DCHP) as subs tance of very high concern (SVHC) according to Article 57(f) of REACH Regulation (EC) 1907/2006, due to its endocrine disrupting Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 53 properties with probable serious effects to humans. https://eur -lex.europa.eu/legal - content/EN/TXT/PDF/?uri=CELEX:32018D0636&fr om=EN Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 54 Annex 5: Legislation on CMR and/or ED phthalates Due to their reprotoxic properties and additionally since 2014 for DEHP due to their endocrine disrupting properties for the environment and since 2017 for DEHP, BBP, DBP, and DIBP due to their endocrine disrupting properties for human health , a considerable number of phthalates have been identified as substances of very high concern (SVHC) and therefore included in the candidate list for the inclusion in Annex XIV of the REACH regulation (Annex XIV of REACH EC 1907/2006 , see https://echa.europa.eu/de/candidate -list-table for the most recent update of the candidate list). Eight phthalates are also listed on the Authorisation list (Annex XIV of REACH), namely DEHP, BBP, DIBP, DBP, DIPP (diisopentylphthalate), Bis(2 -methoxyethyl) phthalate, dipentyl phthalate, and N -pentyl -isopentylphthalate. Since February 2015 DEHP, BBP, DIBP, and DBP cannot be used within the European Union withou t authorisation. The same provision would apply to the remaining four phthalates on Annex XIV from July 2020. To date, applications for authorisation have been submitted for DEHP and DBP only. However, imported articles do not come under the authorisation requirement. For the purpose of evaluating applications for authorisation, the ECHA Committee for Risk Assessment (RAC) has developed reference DNELs for several substances, including DEHP, BBP, DBP, and DIPP. (See Evaluating Applications table/Ref erence D NELs on ECHA’s website: https://echa.europa.eu/applying -for-authorisation/evaluating -applications .) Risks to human health arising from the use of an Annex XIV substan ce in medical devices regulated by Directives 90/385/EEC, 93/42/EEC or 98/79/EC are exempted from authorisation requirements under Title VII of the REACH Regulation14. ECHA is currently preparing a recommendation on the inclusion of the ED properties for environment for DEHP in Annex XIV to REACH .15 If DEHP is included on Annex XIV for environmental hazards , applications for authorisations may need to be prepared for uses of the substance in medical devices in the future. REACH Annex XVII (entry 51) also restricts the placing on the market of articles containing DEHP, BBP, DBP, and DIBP in concentration greater than 0.1% weight by weight of the plasticised material, individually or in combination in a range of articles. These articles include toys16 and childcare articles, as well as other primarily consumer and professional use articles whic h lead to dermal or inhalation exposure. (For risk assessment conclusions, including derivation of a DNEL for DIBP, see Compiled RAC & SEAC opinion and background document on ECHA’s website: https://echa.europa.eu/previous -consultations -on-restriction -proposals/ -/substance - rev/13919/term .) 14 These Regulations will be replaced by:  Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC •Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU 15 https://echa.europa.eu/draft -recommendation -for-amendment -of-authorisation -list-entries -previous - consultation 16 The Toy Safety Directive (2009/48/EC) stipulates that chemicals that are susceptible to cause cancer, change genetic information, harm fertility or harm an unborn child (CMR substances) are no longer allowed in accessible parts of toys beyond the concentration limits set in the CLP Regulation ((EC) No 1272/2008). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 55 REACH Annex XVII (entry 52) restricts the placing on the market and the use of DINP, DIDP, and DNOP, as a substance or in mixture, in concentrations greater than 0.1% weight by weight of the plasticised material in toys and childcare articles which can be placed in the mouth of children. In 2010, the European Commission requested ECHA to review the scientific evidence on the risks posed by articles containing these phthalates with the view to conclude on the need or not for further actions under REACH. The report and RAC risk assessment conclusions (including information on the derivation of DNELs) can be foun d on ECHA’s website: https://echa.europa.eu/consultations -draft-review - report -previous -consultations/ -/substance -rev/1108/term . EFSA recently launched a consultation on its updated 2005 risk assessments of DBP, BBP, DEHP, DINP and DIDP which are authorised for use in plastic FCM, by using the same database as ECHA for its 2017 assessment of certain phthalates. The draft update of the ri sk assessment can be found here: http://www.efsa.europa.eu/en/consultations/call/190221 In addition to the REACH legislation, there is also product -specific legislation which regulates certain phthalates, i.e. the Cosmetic Products’ Regulation (EC/1223/2009) and the Regulation on materials and articles intended to come into contact with food ( Food Contact Materials, Regulation EC 1935/2004 , as general framework regulation and Regulation EU 10/2011 specific for plastic materials and articles destined to be in contact with foodstuffs , recently amended by Regulation 2018/831 ). Both in the MDD (93/42/EEC) and the more recent MDR (2017/745), phthalates are specifically mentioned for their use in medical devices. For a number of phthalates there is legislation available that might contain information relevant for the use of phthalates in medical devices. Of specific relevance for medical devices may be the Regulation EU 10/ 2011, which also incl udes provisions for the use of phthalates in food contact materials and articles with respect to migration limits. This may be a parallel with migration (and thus potential internal exposure) of phthalates as present in polymers used for medical device man ufacturing. In Annex I of the Regulation EU 10/2011 all substances are listed, which are authorised for the use as starting material or additive for plastic layers in plastic materials and articles. Each substance must not exceed its specific migration lim it (SML). The following phthalates and other plastici sers17 are authorised for use as additives: DBP (SML) = 0.3 mg/kg food only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical supp ort agent in polyolefins in concentrations up to 0.05% in the final product BBP, SML = 30 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles; 17 Not exhausti ve examples for other than phthalates Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 56 (b) plasticiser in single -use materials and articles in contact with non -fatty foods, not for contact with infant formulae and follow -on formulae (Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Direc tive 2006/125/EC); (c) technical support agent in concentrations up to 0.1% in the final product. DEHP, SML = 1.5 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical su pport agent in concentrations up to 0.1% in the final product. DINP SML = 9 mg/kg food (cumulative with DIDP) only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Di rective 2006/125/EC) (c) technical support agent in concentrations up to 0.1% in the final product. DIDP, SML = 9 mg/kg food ( cumulative with DINP) Only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Directive 2006/125/EC) (c) te chnical support agent in concentrations up to 0.1% in the final product. Furthermore, for certain plasticizers listed in Regulation (EU) 10/2011, including a number of phthalates, applies a group restriction (Group restriction number 32), that is, the sum of these substances must not exceed an SML of 60 mg/kg foodstuff. DEHP, BBP, DBP and DIBP must not be contained in homogenous materials above the concentration of 0.1% w/w from July 2019 on according to the Restriction of Hazardous Substances Directive in electrical and electronic equipment RoHS2 (2011/65/EC). For medical devices and in vitro diagnostic products this restriction takes effect in July 2021. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 57 Table 1 CMR Classification*) and ED designation**) of phthalates (status Jan 2019) Phthalate Abbreviation CAS number CMR Classification* ED identification** bis(2- methoxyethyl)phthalate DMEP 117-82- 8 Repr 1B - bis (2-ethylhexyl)phthalate DEHP 117-81- 7 Repr 1B ED dibutyl phthalate DBP 84-74-2 Repr 1B ED 1,2- benzenedicarboxylic acid, dipentylester, branched and linear 84777 - 06-0 Repr 1B - n-pentyl - isopentylphthalate PIPP No CAS 776297 - 69-9? Repr 1B - di-n-pentyl phthalate DnPP 131-18- 0 Repr 1B - diisopentylphthalate DiPeP 605-50- 5 Repr 1B - benzyl butyl phthalate BBP 85-68-7 Repr 1B - ED diisobutylphthalate DIBP 85-69-5 Repr 1B ED dihexylphthalate DHP 84-75-3 Repr 1B dicyclohexylphthalate DCHP 84-61-7 Repr 1B ED *) as indicated in Annex VI to CLP_ATP10 (in force from 1 December 2018). **) according to the ECHA Candidate List of substances of very high concern for Authorisation published in accordance with Article 59(10) of the REACH Regulation https://echa.europa.eu/candidate -list-table As substances of concern, knowledge on the exposure to phthalates is important and biomonitoring of populations provides important information. For some of the phthalates already human biomonitoring assessment values, namely Biomonitoring equi valents (BE) or human biomonitoring (HBM) values, have been derived – these are concentrations of biomarkers (metabolites) in urine, which reflect an acceptable chronic exposure, since the basic assumption is an equilibrium between external exposure and in ternal burden (Angerer et al. 2011, Apel et al. 2017). In the course of the work done within the HBM4EU project, Human Biomonitoring Guidance Values (HBM -GVs) could be derived for DEHP and DINCH (see HBM4EU Deliverable D5.2, https://www.hbm4eu.eu ). In addition, HBM-GVs for the following SVHC phthal ates are finalised in September 2019 (Deliverable D5.6) and will also be published on the website: BBzP, DiBP, and DnBP. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 58 Annex 6: Use of phthal ates in medical devices Phthalates are abundantly used in polyvinyl chloride (PVC) medical devices such as blood bags, intravenous bags, nutrition pockets, tubing, catheters, respiratory masks or disposable gloves. More than 40% of all plastic -based disposable medical devices are made from PVC. Di -2-ethylhexyl phthalate (DEHP) has been for many years the most commonly used phthalate ester plasticiser in medical devices. A survey among the Danish Medical Device Industry found that 95% of the products contained DEHP [Huntley P, edit or The classified phthalates should be phased out of medical devices. Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark]. Safety concerns have been expressed for several high -risk patients groups, s uch as neonates, infants, pregnant and breast -feeding women exposed to DEHP. The SCENIHR in its Opinion of 201 5 indicated that “a lack of evidence of causation between DEHP -PVC and any disease or adverse effect does not mean that there are no risks”. This lack of evidence applies to all phthalates classified as CMR and/or identified as ED. Therefore the requirement of patient subgroup analysis for the target patient groups as defined in the “Intended Use” of a medical device is now included in the Regulatio n (EU) 2017/745. For the use of DEHP, high risk groups were identified including patients undergoing haemodialysis, extracorporeal membrane oxygenation (ECMO), and prematurely born infants in Neonatal Intensive Care Units (NICU), (SCENIHR 201 5). The actua l exposure of such patient groups relative to the toxicity including CMR/ED property needs to be determined. However, even if the remaining risk is high, the benefit of the treatment should be considered as well. It might be useful to evaluate the patient subgroups separately:  Paediatric Population (see subgroups)  Peripubertal males  Pregnant women  Breast -feeding women  any other patient group considered particularly vulnerable or exposed to high levels of phthalates. For purposes of this Guideline, the following ranges of paediatric subpopulations are proposed to be used as a guide for manufacturers in medical devices (ref. SCCS Notes of Guidance – SCCS/1602/18, section 3 -6.9.1, page 7818) 18 https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs _o_224.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 59 Definition of Paediatric Population Subgroups Paediatri c Subgroup Approximate Age Range Full-term neonate <1 week Newborn 1 week–2 months Early infant 2–6 months Crawlers/toddler 6 months –2 years Preadolescent 2–12 years Adolescent 12–18 years In view of ED activity, a dditional (paediatric ) subpopulations may need to be considered includ ing:  very low birth weight describes newborns less than 1.5 Kg  low birth weight describes newborns less than 2.5 Kg  preadolescent age group typically ranges from 11 to 13 years.  peripubertal males or females It should be realised that the benefit of medical devices including the use of phthalates must also be considered: The survival of prematurely born infants often depends on the availability of the same medical devices that result in a relative ly high phthalate content exposure due to treatment. Whenever possible, material with low release potential should be used (see SCENIHR opinion 201 5). Besides the direct patient benefits of the treatment with a medical device containing phthalates, other functionalities may also need to be considered. For example, DEHP has a stabilising effect on red blood cells (RBCs). RBCs have increased survival rates when stored in DEHP containing blood bags. DEHP is incorporated into the cell walls of RBCs and stabil ises the membrane integrity of the RBCs. This results in a prolonged shelf life and thus patient availability of blood stored in DEHP containing blood bags (SCENIHR 2015). A maximum limit of extractable DEHP of 15 mg/100 mL for flexible PVC containing DEHP is indicated in EN ISO 3826 -1 on containers for the collection of human blood and blood components. The plasticiser industry has been investing and developing alternatives to DEHP in medical devices. Today, other plasticisers such as Di -isononyl cyclohe xanoate (DINCH, CAS 166412 -78-8), Tri -2-ethylhexyl trimellitate (TEHTM, CAS 3319 -31-1), butyryl tri -n- hexyl citrate (BTHC, CAS 102818 -95-1) and Dioctyl Terephthalate (DOTP, CAS ‎6422-86- 2) are being proposed in medical applications such as medical tubing and blood bags. https://www.plasticisers.org/applications/medical -applications/ Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 60 In conclusion, for any BRA on the use of phthalates and the development of alternatives in me dical devices, careful consideration should be used to appropriate patient subgroup analysis regarding medical device use and the resulting potential exposure. Reference Huntley P, Editor . The classified phthalates should be phased out of medical devices. Program Meeting on Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark. https://pvc.dk/wp -content/uploads/2016/02/pvc -alternativer -til-klassificerede -ftalater - program.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 61 Annex 7: Approaches for Benefit -Risk Assessment Several approaches for BRA have been proposed especially in the context of medicinal products. The Innovative Medicines Initiative PROTECT Project (www.imiprotect.eu), presented a detailed review of approaches used for BRA (Mt -Isa et al. 2014). In this review, a large number of approaches were identified and classified as descriptive (qualitative or semi -qualitative) or quantitative frameworks (relying on quantitative methods of trading risks and benefits following mathematical principles), metrics (measure s for benefits and risks that are usually endpoint specific), estimation techniques (i.e., simulation techniques and meta -analysis) , and utility survey techniques (to elicit stakeholders’ preferences). Concerning quantitative frameworks, according to the European Medicines Agency (EMA) Project Report (EMA/227124/2011), there is no agreement on any one approach to be used in regulatory submission on the benefits and risks of medicines. However, EMA has encouraged the use of quantitative frameworks in regulatory submissions of applications for marketing authorisation of medicinal products. Although there is little experience with quantitative frameworks in the area of medical devices, some of the BRA appro aches used for pharmaceuticals may also be relevant for medical devices and particularly regarding the use of CMR/ED phthalates. In particular, approaches based on multicriteria decision analysis ( MCDA) have attracted much attention during the past years in the field of medical decisions. For an introduction to MCDA see Dodgson et al. (2009). In brief, MCDA is based on decision theory and belongs to the general class of multi - criteria analysis mode ls that accommodate decision making with multiple objectives. The main purpose of MCDA is to bring together evaluations of options on different criteria into one overall evaluation. The starting point for MCDA approaches include s identification of the alte rnatives and the criteria against which the alternatives are appraised. MCDA includes weighting, which ensures that the units of value on all the criteria are comparable so that benefits and risks can be compared by using a common unit of value. In this wa y, the added value of benefits can be compared to the loss of value from the risks. A number of different weighting methods can be used, ranging from precise elicitation of weights, to weights based on qualitative judgements or including uncertainty. A generic framework for conducting an MCDA can be based on the steps of the PROACT - URL framework (Hammond et al. , 1999), as presented below. A detailed description of the different implementations of MCDA techniques is beyond the scope of this guideline. The c hosen techniques and analyses should be presented and justified among others on the basis of internal consistency, logical soundness and transparency. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 62 STEP Description and relation to framework for Benefit -Risk Assessment described in section A of the Guidelines Problem Describe the medical device, its intended use, and the therapeutic context; frame the decision problem in terms of potential alternatives to CMR/ED phthalate. See Step 1: Description and characterisation of the composition of the medic al device; and Step 2: Use and function of the phthalates in the medical device. Objectives Identify the full set of criteria to evaluate different alternatives. See Step 2: Use and function of the phthalates in the medical device; and Step 3: Assessment of the risks of the CMR/ED phthalate. See 7 Benefit assessment . Alternatives Identify alternatives that are being evaluated against each other. See Step 4: Inventory of possible alternatives; and Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates . Consequences Describe how the alternatives perform for each of the criteria, i.e., the magnitudes of all effects in terms of the different benefits and risks. See Step 2: Use and function of the phthalates in the medical device; Step 3: Assessment of the risks of the C MR/ED phthalate; Step 6: Description of identified relevant potential alternative(s); Step 7: Assessment of the risk of identified potential relevant alternatives. For a summary table see Table 1. Example for a comparison of CMR/ED phthalate with potential alternative(s). Trade -offs Assess the balance between benefits and risks using judgements of weights associated with the criteria and the value associated with the benefits and risks of every alternative. MCDA techniques commonly achieve this through num erical analysis. A number of different weighting methods can be used. Conduct sensitivity analyses to explore uncertainties using different scenarios, and assess how different weights affect the overall ordering of the alternatives. See also Step 8: Compar ison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternatives; Step 9: Comparison of risk(s) of original CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives; and Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Uncertainty Report the uncertainty associated with the benefits and Risks. Consider how the balance between benefits and risks is affected by uncertainty. A quantitative model will Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 63 explore in sensitivity analyses and scenario analyses (or by explicitly incorporating probability distributions in the model) the effects on the overall benefit -risk balance of all sources of uncertainty. See 1.9 Uncertainty analysis. Risk tolerance Describe any considerations that could or should affect the decision maker’s attitude toward risks (e.g., special population, unmet medical need). Linked -decisions Discuss how the value judgements and data are consistent with similar decisions on medical devices. References  Dodgson J, Spackman M, Pearman A, Phillips LD. Multi -criteria analysis: A manual. London: Department for Communities and Local Government, First published in 2000 by the Department for Environment, Transport and the Regions; 2009.  ECHA 2011 Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  Hammond JS, Keeney RL, Raiffa H, Smart Choices: A Practical Guide to making Better Decisions, Boston, MA: Harvard Business School Press; 1999.  Mt-Isa S, Hallgreen C.E., Wang N., Callréus T., Genov G., Hirsch I., Hobbiger S., Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki I., Micaleff A., Ashby D. - Balancing benefit and risk of medicines a systematic review and classification of available methodologies, Pharmacoepidemiology and Drug Safety, May 2014 .

md_transitional-provisions-art-3-and-4_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 rev. 1 Class I Transitional provisions under Article 120 (3 and 4) – (MDR) March 2020 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 revision 1 changes MDR postponement dates : from 2020 to 2021 How can a ffected manufacturers of some class I devices1 make efficient use of the transitional provisions in A rticle 120 (3 ) and (4) of Regulation (EU) 2017/745 – Medical Devices Regulation ( MDR )? Background: The corrected MDR2 Article 120 (3) allows under certain condition s, some class I devices pursuant to Directive 93/42/EEC – Medical Devices Directive (MDD) , for which the Declaration of C onformity was drawn up prior to 26 May 2021 and for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body, to be placed on the market3 until 2 6 May 20244. In order to make use of this article , the following conditions must be met: 1. The device continues to comply with Directive 93/42/EEC, 2. A notified body will need to be involved under the MDR (e.g. re -usable surgical instruments or up -classified devices) 3. A valid Declaration of C onformity , according to Annex VII of the MDD , must be drawn up befor e 26 May 2021, 4. No significant changes to the design or intended purpose of the device after 26 May 202 15, 5. The requirements of the MDR relating to post -market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in Directive 93/42/EEC .6 This shall be in place on the 26 May 2021. Scope The scope of this document is to provide guidance related to the information to be provided in the form of a Declaration of Conformity by manufacturers of Class I devices (devices which are non - 1 Class I devices for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body. 2 Corrigendum to Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/E EC and 93/42/EEC (OJ L 117, 5.5.2017), of 27.12.2019. 3 Devices which are not placed on the market but put into service may also make use of the transitional provisions . 4 Article 120(4) ‘and may continue to be made available on the market …until 26 May 2025’ . 5 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD . 6 Upcoming guidance on harmonised practices and technical solutions to facilitate exchange of information in absence of EUDAMED . Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 sterile or do not have a measuring function) that are required to have certificates after 26 May 2024 according to the MDR. Content of a val id Declaration of Conformity The manufacturer or his authorised representative established in the European Union is obliged to issue a Declaration of Conformity that the product has undergone a conformity assessment procedure required by the MDD before being placed on the market. With the Declaration of Conformity, the manufacturer declares that the products concerned meet the relevant provisions of the MDD. MDD Annex II, Annex V, Annex VI set out that a Declaration of Conformity must cover one or more medical devices manufactured 7 clearly identified by means of product name, product code or other unambiguous reference for class IIa, IIb and III devices, and also class Im and class Is devices. This is however not necessary for other Class I devices, as it is not required by the MD D (Annex VII) and as there is no certificate from a notified body to which the issued Declaration of Conformity is related. Guidance on the content of the Declaration of C onformity can be found, inter alia, in the “The ‘Blue Guide’ on the implementa tion of EU products rules 2016 (2016/C272/01) ”8 and the standard EN ISO/IEC 17050 -1.9 According to this standard , the declaration may take the form of a document or any other suitable medium , and should contain sufficient information to enable all products covered to be traced back to it. The model declaration in Annex III of Decision No 768/2008/EC and the ‘Blue Guide’ on the implementation of EU products rules 2016 (2016/C272/0 1) describe the content of the Declaration of C onformity to be as follows: 1. A number identifying the product. This number does not need to be unique to each product. It could refer to a product, batch, type or a serial number .10 This is left to the discretion of the manufacturer .11 2. The name and address of the manufacturer or the authorised representative issuing the declaration. 3. A statement that the declaration is issued under the sole responsibility of the manufacturer. 7 MDD Annex II, paragraph 2 ‘This declaration must cover one or more medical devices manufactured, clearly identified by means of product name, product code or other unambiguous reference and must be kept by the manufacturer.’ 8 https://eur -lex.europa.eu/legal -content/GA/TXT/?uri=CELEX:52016XC0726(02) . 9 EN ISO/IEC 17050 -1 : 2004 Conf ormity assessment – Supplier’s D eclaration of Conformity – Part 1: General requirements /EN ISO/IEC 17050 -2 : 200 4 Conformity assessment – Supplier’s Declaration of C onformity – Part 2: Supporting documentation . 10 The ‘number’ may be an alpha -numerical code or could also refer to a software version . 11 In addition, whether this is expressly envisaged or not by the Union harmonisation legislation, manufacturers are free to add a number identifying the Declaration of Conformity itself in line with EN ISO/IEC 17050 -2. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 4. The identification of the product allowing traceability. This is any relevant information suppleme ntary to point 1 describing the product and allowing for its traceability . Where relevant for the identification of the product , it may contain an image, but unless specified as a requirement in the Union harmonisation legislation this is left to the discr etion of the manufacturer. 5. All relevant Union harmonisation legislation complied with; the referenced standards or other technical specifications (such as national technical standards and specifications) in a precise, complete and clearly defined way; this implies that the version and/or date of the relevant standard is specified.12 6. If applicable, t he name and identification number of the notified body ,13 when it has been involved in the conformity assessment procedure ,14 15 and the reference to the relevant certificate. 7. If applicable, a ll supplementary information that may be required (for example category) . 8. The date of issue of the declaration; signature and title or an equivalent marking of the authorised person16 17  This could be any date after the complet ion of the conformity assessment , but must be before 26 May 202 1 if the manufacturer wants to make use of the transitional period in Article 120(3) and (4) of the MDR . Every Declaration of C onformity must be based on proper technical documentation according to Annex VII para graph 3 of the MDD. The technical documentation and the D eclaration of Conformity should be subject to appropriate measures of document and record control. The Declaration of Conformity is to be kept by the manufacturer and shall be at the disposal of the competent authorities for a period ending at least five years after the last product has been manufactured. Necessary amendm ents/updates to the t echnical documentation should be done in a transparent manner. Both t he changes and the dates of when the changes were made should be recorded. On the basis of the Declaration of Conformity and the corresponding technical documentation, the manufacturer should be able to demonstrate that the Declaration of Conformity was lawfully18 issued before 26 May 202 1 and that, subsequently, there are no significant changes in the design or intended 12 According to the MDD , referencing st andards or technical specifications complied with is voluntary . 13 For class I devices in scope of this guidance document, the involvement of a notified body is not required. 14 Not all Union harmonisation legislation requires the intervention of a notified body (e.g. the Low Voltage Directive and the Toys D irective . 15 The name and address of the person who keeps the technical documentation may also be required by some pieces of Union harmonisation legislation since according to those, not only the manufactu rer shall keep the technical documentation. 16 This could be the m anaging director of the company or another representative of the company to whom this responsibility has been delegated. 17 It is not necessary for the signatory to be domiciled in the Europea n Union. A manufacturer established outside the Union is entitled to carry out all the conformity assessment procedures at his premises and, to sign the Declaration of Conformity . 18 Lawfully according to the Directive and to any relevant national provisions which apply. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 purpose19 in the meaning of Article 120(3) MDR. Taking into account Article 123(3) and 123 (3)(d), and a s EUDAMED will not be fully functional in May 202 1, it is required that the manufacturer keep the Declaration of Conformity together with the technical documentation available to the Competent Authorities . This would also include details o f all device registrations and economic operator registrations completed pursuant to national provisions implementing the requirements of Articles 14 (1) and (2) of Directive 93/42/EEC. 19 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD .

09 MDCG 2020-9 Regulatory Requirements for Ventilators and Reated Accessories.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-9 MDCG 2020-9 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES Options for supporting production and/or placing on the market of ventilators in the context of COVID-19 pandemic 1. INTRODUCTION AND SCOPE The World Health Organization (WHO) declared the COVID-19 outbreak a pandemic on March the 12th 2020. Patients infected by SARS-CoV-2 virus and developing the COVID-19 disease with acute and severe respiratory symptoms have to be treated with mechanical ventilators to assure possibilities of survival. This guidance document focuses on ventilators and related accessories that are currently regulated under the Council Directive 93/42/EEC (MDD)1. According to the MDD, devices may be placed on the market and/or put into service only if they comply with the requirements laid down in this Directive when duly supplied and properly installed, maintained and used in accordance with their intended purpose2. The devices must meet the essential requirements set out in Annex I of the MDD, which apply to them, taking account of the intended purpose of the devices concerned. In addition, devices may be placed and circulate on the European single market if they have been subject to a conformity assessment in accordance with the provisions of Article 11 of the MDD. Under the current COVID-19 context, the demand for ventilators and related accessories has rapidly increased. Therefore, this document intends to outline the different regulatory options for placing these devices on the EU market indicating their feasibility to allow short-term supply. 2. TYPES OF MEDICAL DEVICES AND THEIR PARTS /COMPONENTS 2.1. Ventilators Ventilators are breathing support devices and can fall into different types according to their intended use and characteristics3: 1 However, placing on the market of devices which comply with MDD is limited to 27 May 2024. After this date every device placed on the market has to comply with the requirements of Regulation (EU) 2017/745 (MDR). According to the Article 120 section 5 and 6 of the MDR devices which comply with MDR may be placed on the market before its application and notified bodies which are designated and notified in accordance with MDR may carry out the conformity assessment procedures laid down in MDR and issue certificates in accordance with MDR. 2 According to Article 1(g) of the MDD, intended purpose is the use for which the device is intended according to the data supplied by the manufacturer on the labelling, in the instructions and/or in promotional materials. 3 This list of ventilators includes some standards applicable to the specific ventilator. However, it should be noted that this is not an exhaustive list and other standards also apply to these devices and should be taken into account (e.g. EN 60601-1-2, EN 60601-1-6, EN 60601-1-8, EN 60601-1-11, EN 62304, EN 62366). In addition, the current state of the art should be considered. This applies also to accessories. 3 - Ventilator for critical care: automatic equipment that is intended to augment or provide ventilation of the lungs of the patient when connected to the airway of the patient: o intended for use in an environment that provides specialized care for patients whose conditions can be life threatening and who can require comprehensive care and constant monitoring in a professional healthcare facility; o intended to be operated by a healthcare professional operator; and o intended for those patients who need differing levels of support from artificial ventilation including for ventilator-dependent patients. (See e.g. EN ISO/IEC 80601-2-12:2011 + Cor.:2011). - Home healthcare environment ventilators for ventilator-dependent patients: intended for use in the home healthcare environment; intended for use by a lay operator; intended for use with patients who are dependent on mechanical ventilation for their life support. Depending on the intended purpose can be also used in the clinical setting (See e.g. EN ISO 80601-2-72:2015). - Ventilators for emergency and transport : these ventilators are used in Emergency Medical Service environment, e.g. in ambulances, transport of patients to the hospital, patient transport from hospital to hospital or transport within the hospital. The alarm and safety concept of emergency and transport ventilators in general is designed for a permanent presence of the user. This facilitates fast recognition and response in the event of an alarm or in the event of any malfunction (See e.g. EN 794-3:1998+A2:2009). - Anaesthetic ventilator: are designed for use during anaesthesia with an anaesthetic breathing system (See e.g. EN ISO 80601-2-13:2012). Ventilators for critical care are usually invasive, which enables the ventilator machine to provide lung support for inspiration and expiration through tracheal intubation. However, most critical care ventilators allow non-invasive ventilation modes for critical care patients as well. Ventilators for non-critical care are usually non-invasive and therefore provide air pressure support to natural breathing through e.g. a facemask. Ventilators may offer different types of additional complementary functions that include:  High flow oxygen supply (nasal high flow therapy);  Monitoring systems;  Nebulisation systems. 2.2. Accessories Ventilators need to be “connected” to the patients through dedicated accessories4 to the ventilator that allow the machine to support the patient’s breathing; therefore, it is important to proof compatibility with the ventilator(s). These accessories can be placed on the market individually and usually fall into one of the following categories: 4 See MEDDEV 2.1/1 Definitions of 'medical devices', 'accessory' and 'manufacturer' (https://ec.europa.eu/docsroom/documents/10278/attachments/1/translations ). 4  Breathing systems and circuits, such as: o Circuits; o Connections/Adapters; o Tubes; o Nasal cannulas for O 2; o Masks or helmets for non-invasive ventilation; o Air compressors;  Nebulizers;  Humidifiers and filters;  Monitoring accessories, including alarms, in-built safety features. Accessories are provided either disposable or reusable and are treated as medical devices in their own right5. 2.3. Parts or components Parts or components of medical devices that do not qualify as accessories are generally not considered medical devices and thus not requiring themselves to be CE marked according to the MDD (e.g. expiratory valves or flow sensors). 3. CLASSIFICATION 3.1. Ventilators There are different types of ventilators depending on the degree of invasiveness and the setting in which they are used in (e.g. Intensive Care Unit - ICU). Ventilators fall under two different classes in accordance with rule 11 (or rule 9) of Annex IX6,7 to the MDD: - Class IIa: only applicable to non-invasive devices, e.g. continuous positive airway pressure – CPAP non-intended for critical care, or devices that only support spontaneous breathing. - Class IIb: applicable to most ventilators. The classification depends on the intended purpose of the ventilator and has important implications in the selection of appropriate conformity assessment procedure(s) for the device including timing and complexity (see section 4 for details). 3.2. Accessories Accessories are classified in their own right usually in accordance with rule 2 or 5 of Annex IX to the MDD, under Class I, IIa or IIb. 5 Art. 1(1) of the MDD 6 See MEDDEV 2.4/1 rev.9 Classification of Medical Devices - (https://ec.europa.eu/docsroom/documents/10337/attachments/1/translations). 7 Please note that if a conformity assessment under the MDR is followed, the rules of classification specified in Annex VIII to the MDR apply. Breathing support devices may be classified to class IIa or IIb (rule 12) or class III (rule 22) if they integrate or incorporate diagnostic functions which significantly determine the patient management by the device, such as closed loop systems. 5 3.3. Impact of classification on conformity assessment Given that ventilators are classified as Class IIa or Class IIb, and accessories (except for Class I non-sterile and without measuring function), will in principle need the involvement of a notified body prior to their placing on the market. Other options for the placing on the market are provided in section 4 for both ventilators and accessories. 4. REGULATORY OPTIONS FOR PLACING VENTILATORS ON THE MARKET In the context of the COVID-19 outbreak, several industries have expressed their willingness to support and scale up the production of ventilators8. There are different regulatory options9 available for supporting production or placing on the market of ventilators. These options are presented below, ordered by feasibility, to allow a swift supply in the current context. 4.1. Supplying parts, components or the finished devices to medical devices manufacturers currently placing on the market ventilators When the legal manufacturer10 has already undergone a conformity assessment for the ventilator, has obtained a certificate and is lawfully placing ventilators on the market under its own name, other producers (e.g. not currently working in the medical devices field) can support its production. Such producers can provide parts or components, or the finished device, therefore becoming suppliers or subcontractors of this manufacturer. Given that the medical devices sector is highly regulated and complex, leveraging the knowledge and responsibilities of an already established manufacturer of ventilators could be the least burdensome and fastest option to scale up the production of ventilators. 4.1.1. Producers supplying parts or components to medical devices manufacturers currently placing on the market ventilators Manufacturers of medical devices can have many suppliers, which in case of quality system certification are qualified, approved and controlled by the manufacturer. These suppliers may need to be assessed by a notified body as part of the conformity assessment procedure on the basis of their criticality and the manufacturer’s process in place to control suppliers and the verification of purchased products11. When the manufacturer wishes to use an additional supplier, this might need to be communicated in advance to the notified body. 8 Scaling up of production might also be needed for accessories. These medical devices can follow the same options explained in section 4 but small differences can be applicable in case they have a different classification (e.g. class Is). 9 This document mainly focuses on regulatory options provided by the MDD. If a conformity assessment under the MDR is followed, similar procedures will apply under Annex IX, X or XI of the MDR depending on the classification of the product. 10 Legal manufacturer refers to the definition of manufacturer established in Art. 1(f) of the MDD. 11 See Guidance for Notified Bodies auditing suppliers to medical device manufacturers – (http://www.doks.nbog.eu/Doks/NBOG_BPG_2010_1.pdf) 6 4.1.2. Producers manufacturing the ventilator itself for the medical device manufacturer currently placing on the market ventilators Manufacturers of medical devices producing ventilators may provide the specifications of a ventilator (e.g. current or older/simpler design) including parts of the technical documentation to a producer that becomes its subcontractor. The producer will manufacture the ventilator but the medical device manufacturer will keep its role of legal manufacturer according to the MDD. The legal manufacturer of the ventilator, which holds a quality system certification, qualifies, approves and controls the subcontractor that will need to be assessed by a notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on-site12) audit. Alternatively, the manufacturer of medical devices could also follow other conformity assessment routes such as the EC type-examination, as established in Annex III to the MDD, and/or EC verification, as established in Annex IV to the MDD (these routes are elaborated in 4.3.2). 4.2. Derogation procedure – placing on the market authorised by the relevant authorities of one Member State in the interest of public health The relevant authority of one Member State may decide to authorise the placing on the market of devices in the interest of protection of health, even if the applicable conformity assessment procedures have not been finalised or initiated ('national derogation'). In view of the epidemiological context as well as the exponential growth in demand for medical devices, the Commission has published a Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the Covid-19 context. Question 5 of this guidance provides information on the derogation procedures for medical devices which is established in Article 11(13) of the MDD. In particular, the guidance specifies that the Covid-19 context warrants the application of such derogations. By amendment of 23 April 202013, Article 59(1) of Medical Devices Regulation (EU) 2017/745 (MDR) empowers Member States to adopt national derogations under both the MDD and the MDR from the date of entry into force of that amendment. The relevant competent authority of the Member State in this case authorises the placing on the market within its territory and can also organise the purchase. 12 See MDCG 2020-4 Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID-19 quarantine orders and travel restrictions (https://ec.europa.eu/docsroom/documents/40705). 13 Regulation 2020/561 amending Regulation (EU) 2017/745 on medical devices as regards the dates of application of certain of its provisions. 7 In practice, this implies that each competent authority would need to assess whether the products produced by the manufacture provides an adequate level of safety in respect to the applicable legal requirements. The assessment procedures can vary among Member States and in some cases will involve the support of third parties (e.g. testing laboratories). In the exceptional COVID-19 context, the assessment procedures will ensure a short- term supply while guaranteeing patient safety14. The Member State will evaluate the available technical documentation to find evidence that essential performance and safety requirements are guaranteed in the context of use. In particular, the role of healthcare teams and health facilities is essential to allow a rational use and a continuous assessment of these crisis solutions. Once this assessment is performed, the authority has to take a decision, whether or not the respective device produced by the manufacturer may enter the national territory of the Member State. Competent authorities should inform the Commission and their counterparts in other Member States of any temporary agreement they have granted to specific devices. In addition, Article 59(3) of the MDR empowers the Commission to extend, in exceptional cases relating to public health or patient safety or health, by means of implementing acts, for a limited period of time the validity of a national derogation, granted by a Member State under the MDD or the MDR, to the territory of the Union and set the conditions under which a device may be placed on the market or put into service. This allows the Commission and the Member States to address potential shortages Union wide of vitally important medical devices in an effective manner. Timing to obtain a national derogation by a competent authority will greatly depend on the quality and adequacy of the evidence provided by the manufacturer. When technical documentation and evidence of safety of performance is adequate, this can be a feasible option to ensure short-term supply. 4.3. Manufacturing of the finished device by a producer that was not previously placing on the market ventilators If the ventilator is entirely manufactured by a producer that decides to place it on the market under its name, such producer will become the legal manufacturer in its own right. This means that the manufacturer will need to fulfil all requirements of the MDD (e.g. including the need to draw up the technical documentation and clinical evaluation related to the ventilator, and to establish and keep up to date a systematic procedure to review experience gained from devices in the post-production phase). The manufacturer who places the finished CE marked ventilator on the market under its own name needs to ensure that the device complies with the essential requirements (established in Annex I of the MDD) and provide relevant evidence. A notified body will be involved in the conformity assessment in all cases. 14 Some Member States have published guidance on their respective websites to support this assessment e.g. in case of implementation of innovative manufacturing processes such as 3D printing. 8 Given that the medical devices sector is highly regulated and complex, the scenarios presented below will be the most burdensome and therefore only applicable to increase supply in the medium-long term. 4.3.1. Medical devices manufacturers’ not currently producing ventilators request an extension of their product range. This option is available for medical devices manufacturers currently certified. It includes, for instance, medical devices manufacturers already holding a full quality management system certificate under Annex II to the MDD for other devices and wishing to add ventilators to their certification. They could seek the support from (non-medical devices) producers to act as subcontractors and extend the scope of their certificate. From a procedural point of view, the medical devices manufacturer may produce the ventilator itself or may utilise a subcontractor (i.e. producer linked or not to the medical devices field). In the latter case, the manufacturer will qualify, approve and control the subcontractor that will be assessed by the notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on- site12) audit. Most importantly, the manufacturer will need to request an extension of the product range from its notified body. The notified body will assess the available information in relation to the new product (that include an assessment of the technical documentation and clinical evaluation) and update the certificate. The manufacturer of medical devices could also use other conformity assessment routes such as the EC Type-Examination and EC Verification and testing of every product under Annex III and IV respectively (these routes are elaborated in section 4.3.2). 4.3.2. Ventilator manufactured entirely by a producer that is not currently a legal manufacturer under the MDD Producers that do not currently qualify as legal manufacturers under the MDD and decide to place ventilators on the market under their own name need to be aware of all the legal requirements for manufactures under the MDD. It is important to mention that in the field of medical devices some Member States could have additional requirements, for instance, the need to authorise the facility of the medical device manufacturer prior to starting production. In addition to this, the involvement of a notified body will depend on the classification. In particular: 1. Class IIa ventilators can follow the following routes established in the relevant Annexes of the MDD: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and 9 regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the product to be certified prior to certification on a sampling basis15. b. Declaration of conformity (Annex VII) combined with either an assessment of the quality assurance of the production or of the product (Annex V or VI) or a EC verification (set out in Annex IV):  The assessment of the quality system performed by the notified body will be similar to the one outlined in section 1.a above.  The verification by testing of products by the notified body will be performed by examination and testing of every product. 2. Class IIb ventilators can follow the following routes: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the products to be certified prior to certification on a sampling basis15. b. EC type-examination (Annex III) combined with either an assessment of the quality assurance either of the production or of the product (Annex V or VI) or EC verification by testing of products (set out in Annex IV). EC Type-examination consists in the assessment of the technical documentation and testing of a number of features of the device type to ensure it conforms to the requirements. The additional procedures (Annex IV, V or VI) are the same as the ones described in 1.b above. The assessment of the quality management system of the manufacturer (Annex II, V and VI) can be partly fulfilled by compliance with a harmonised standard (EN ISO 13485) but this route will unlikely be fast enough to ensure short-term supply. This is due to the timelines and experience required to get a certificate under these annexes of the MDD and taking into account the current circumstances where auditing capacity is restricted by the Covid19 situation. A faster route but also time-consuming route will probably be the performance of tests on the products that might be combined with the assessment of the technical documentation, namely: - declaration of conformity (Annex VII) + verification of products (Annex IV) for Class IIa; or - EC type-examination (Annex III) + verification of products (Annex IV) for Class IIb. Through this route, the device type or device samples are tested and there is no obligation to have a certified quality management system in place and subject to regular surveillance audits. However, quality management processes are important and critical to the production of safe and functional medical devices. The conformity assessment will be 15 See Annex II, section 3.3 to the MDD 10 based on the manufacturers testing strategy that must ensure compliance with the safety and performance requirements. It should be noted that this option is burdensome and will take several months, especially to draw up an adequate technical documentation. In addition, there is only a limited number of notified bodies designated to perform EC type-examination and/or EC verification in ventilators (according to NANDO16 18 notified bodies out of 56 are authorised to perform these tests at the moment). 16 This information can be found in NANDO, by searching notified bodies under the MDD that are designated under Annex III and IV for code MD 1102 - Respiratory devices, devices including hyperbaric chambers for oxygen therapy, inhalation anaesthesia - https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13

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L_2017117EN.01000101.xml 5.5.2017    EN Official Journal of the European Union L 117/1 REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Text with EEA relevance) THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, Having regard to the Treaty on the Functioning of the European Union, and in particular Article 114 and Article 168(4)(c) thereof, Having regard to the proposal from the European Commission, After transmission of the draft legislative act to the national parliaments, Having regard to the opinion of the European Economic and Social Committee (1), After consulting the Committee of the Regions, Acting in accordance with the ordinary legislative procedure (2), Whereas: (1) Council Directive 90/385/EEC (3) and Council Directive 93/42/EEC (4) constitute the Union regulatory framework for medical devices, other than in vitro diagnostic medical devices. However, a fundamental revision of those Directives is needed to establish a robust, transparent, predictable and sustainable regulatory framework for medical devices which ensures a high level of safety and health whilst supporting innovation. (2) This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users, and taking into account the small- and medium-sized enterprises that are active in this sector. At the same time, this Regulation sets high standards of quality and safety for medical devices in order to meet common safety concerns as regards such products. Both objectives are being pursued simultaneously and are inseparably linked whilst one not being secondary to the other. As regards Article 114 of the Treaty on the Functioning of the European Union (TFEU), this Regulation harmonises the rules for the placing on the market and putting into service of medical devices and their accessories on the Union market thus allowing them to benefit from the principle of free movement of goods. As regards Article 168(4)(c) TFEU, this Regulation sets high standards of quality and safety for medical devices by ensuring, among other things, that data generated in clinical investigations are reliable and robust and that the safety of the subjects participating in a clinical investigation is protected. (3) This Regulation does not seek to harmonise rules relating to the further making available on the market of medical devices after they have already been put into service such as in the context of second-hand sales. (4) Key elements of the existing regulatory approach, such as the supervision of notified bodies, conformity assessment procedures, clinical investigations and clinical evaluation, vigilance and market surveillance should be significantly reinforced, whilst provisions ensuring transparency and traceability regarding medical devices should be introduced, to improve health and safety. (5) To the extent possible, guidance developed for medical devices at international level, in particular in the context of the Global Harmonization Task Force (GHTF) and its follow-up initiative, the International Medical Devices Regulators Forum (IMDRF), should be taken into account to promote the global convergence of regulations which contributes to a high level of safety protection worldwide, and to facilitate trade, in particular in the provisions on Unique Device Identification, general safety and performance requirements, technical documentation, classification rules, conformity assessment procedures and clinical investigations. (6) For historical reasons, active implantable medical devices, covered by Directive 90/385/EEC, and other medical devices, covered by Directive 93/42/EEC, were regulated in two separate legal instruments. In the interest of simplification, both directives, which have been amended several times, should be replaced by a single legislative act applicable to all medical devices other than in vitro diagnostic medical devices. (7) The scope of application of this Regulation should be clearly delimited from other Union harmonisation legislation concerning products, such as in vitro diagnostic medical devices, medicinal products, cosmetics and food. Therefore, Regulation (EC) No 178/2002 of the European Parliament and of the Council (5) should be amended to exclude medical devices from its scope. (8) It should be the responsibility of the Member States to decide on a case-by-case basis whether or not a product falls within the scope of this Regulation. In order to ensure consistent qualification decisions in that regard across all Member States, particularly with regard to borderline cases, the Commission should be allowed to, on its own initiative or at the duly substantiated request of a Member State, having consulted the Medical Device Coordination Group (‘MDCG’), decide on a case-by-case basis whether or not a specific product, category or group of products falls within the scope of this Regulation. When deliberating on the regulatory status of products in borderline cases involving medicinal products, human tissues and cells, biocidal products or food products, the Commission should ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency and the European Food Safety Authority, as relevant. (9) Since in some cases it is difficult to distinguish between medical devices and cosmetic products, the possibility of taking a Union-wide decision regarding the regulatory status of a product should also be introduced in Regulation (EC) No 1223/2009 of the European Parliament and of the Council (6). (10) Products which combine a medicinal product or substance and a medical device are regulated either under this Regulation or under Directive 2001/83/EC of the European Parliament and of the Council. (7) The two legislative acts should ensure appropriate interaction in terms of consultations during pre-market assessment, and of exchange of information in the context of vigilance activities involving such combination products. For medicinal products that integrate a medical device part, compliance with the general safety and performance requirements laid down in this Regulation for the device part should be adequately assessed in the context of the marketing authorisation for such medicinal products. Directive 2001/83/EC should therefore be amended. (11) Union legislation, in particular Regulation (EC) No 1394/2007 of the European Parliament and of the Council (8) and Directive 2004/23/EC of the European Parliament and of the Council (9), is incomplete in respect of certain products manufactured utilising derivatives of tissues or cells of human origin that are non-viable or are rendered non-viable. Such products should come under the scope of this Regulation, provided they comply with the definition of a medical device or are covered by this Regulation. (12) Certain groups of products for which a manufacturer claims only an aesthetic or another non-medical purpose but which are similar to medical devices in terms of functioning and risks profile should be covered by this Regulation. In order for manufacturers to be able to demonstrate the conformity of such products, the Commission should adopt common specifications at least with regard to application of risk management and, where necessary, clinical evaluation regarding safety. Such common specifications should be developed specifically for a group of products without an intended medical purpose and should not be used for conformity assessment of the analogous devices with a medical purpose. Devices with both a medical and a non-medical intended purpose should fulfil both the requirements applicable to devices with, and to devices without, an intended medical purpose. (13) As is the case for products that contain viable tissues or cells of human or animal origin, that are explicitly excluded from Directives 90/385/EEC and 93/42/EEC and hence from this Regulation, it should be clarified that products that contain or consist of viable biological materials or viable organisms of another origin in order to achieve or support the intended purpose of those products are not covered by this Regulation either. (14) The requirements laid down in Directive 2002/98/EC of the European Parliament and of the Council (10) should continue to apply. (15) There is scientific uncertainty about the risks and benefits of nanomaterials used for devices. In order to ensure a high level of health protection, free movement of goods and legal certainty for manufacturers, it is necessary to introduce a uniform definition for nanomaterials based on Commission Recommendation 2011/696/EU (11), with the necessary flexibility to adapt that definition to scientific and technical progress and subsequent regulatory development at Union and international level. In the design and manufacture of devices, manufacturers should take special care when using nanoparticles for which there is a high or medium potential for internal exposure. Such devices should be subject to the most stringent conformity assessment procedures. In preparation of implementing acts regulating the practical and uniform application of the corresponding requirements laid down in this Regulation, the relevant scientific opinions of the relevant scientific committees should be taken into account. (16) Safety aspects addressed by Directive 2014/30/EU of the European Parliament and of the Council (12) are an integral part of the general safety and performance requirements laid down in this Regulation for devices. Consequently, this Regulation should be considered a lex specialis in relation to that Directive. (17) This Regulation should include requirements regarding the design and manufacture of devices emitting ionizing radiation without affecting the application of Council Directive 2013/59/Euratom (13) which pursues other objectives. (18) This Regulation should include requirements for devices' design, safety and performance characteristics which are developed in such a way as to prevent occupational injuries, including protection from radiation. (19) It is necessary to clarify that software in its own right, when specifically intended by the manufacturer to be used for one or more of the medical purposes set out in the definition of a medical device, qualifies as a medical device, while software for general purposes, even when used in a healthcare setting, or software intended for life-style and well-being purposes is not a medical device. The qualification of software, either as a device or an accessory, is independent of the software's location or the type of interconnection between the software and a device. (20) The definitions in this Regulation, regarding devices themselves, the making available of devices, economic operators, users and specific processes, the conformity assessment, clinical investigations and clinical evaluations, post-market surveillance, vigilance and market surveillance, standards and other technical specifications, should be aligned with well-established practice in the field at Union and international level in order to enhance legal certainty. (21) It should be made clear that it is essential that devices offered to persons in the Union by means of information society services within the meaning of Directive (EU) 2015/1535 of the European Parliament and of the Council (14) and devices used in the context of a commercial activity to provide a diagnostic or therapeutic service to persons within the Union comply with the requirements of this Regulation, where the product in question is placed on the market or the service is provided in the Union. (22) To recognise the important role of standardisation in the field of medical devices, compliance with harmonised standards as defined in Regulation (EU) No 1025/2012 of the European Parliament and of the Council (15) should be a means for manufacturers to demonstrate conformity with the general safety and performance requirements and other legal requirements, such as those relating to quality and risk management, laid down in this Regulation. (23) Directive 98/79/EC of the European Parliament and of the Council (16) allows the Commission to adopt common technical specifications for specific categories of in vitro diagnostic medical devices. In areas where no harmonised standards exist or where they are insufficient, the Commission should be empowered to lay down common specifications which provide a means of complying with the general safety and performance requirements, and the requirements for clinical investigations and clinical evaluation and/or post-market clinical follow-up, laid down in this Regulation. (24) Common specifications (‘CS’) should be developed after consulting the relevant stakeholders and taking account of European and international standards. (25) The rules applicable to devices should be aligned, where appropriate, with the New Legislative Framework for the Marketing of Products, which consists of Regulation (EC) No 765/2008 of the European Parliament and of the Council (17) and Decision No 768/2008/EC of the European Parliament and of the Council (18). (26) The rules on Union market surveillance and control of products entering the Union market laid down in Regulation (EC) No 765/2008 apply to devices covered by this Regulation which does not prevent Member States from choosing the competent authorities to carry out those tasks. (27) It is appropriate to set out clearly the general obligations of the different economic operators, including importers and distributors, building on the New Legislative Framework for the Marketing of Products, without prejudice to the specific obligations laid down in the various parts of this Regulation, to enhance understanding of the requirements laid down in this Regulation and thus to improve regulatory compliance by the relevant operators. (28) For the purpose of this Regulation, the activities of distributors should be deemed to include acquisition, holding and supplying of devices. (29) Several of the obligations on manufacturers, such as clinical evaluation or vigilance reporting, that were set out only in the Annexes to Directives 90/385/EEC and 93/42/EEC, should be incorporated into the enacting provisions of this Regulation to facilitate its application. (30) Health institutions should have the possibility of manufacturing, modifying and using devices in-house and thereby address, on a non-industrial scale, the specific needs of target patient groups which cannot be met at the appropriate level of performance by an equivalent device available on the market. In that context, it is appropriate to provide that certain rules of this Regulation, as regards medical devices manufactured and used only within health institutions, including hospitals as well as institutions, such as laboratories and public health institutes that support the healthcare system and/or address patient needs, but which do not treat or care for patients directly, should not apply, since the aims of this Regulation would still be met in a proportionate manner. It should be noted that the concept of ‘health institution’ does not cover establishments primarily claiming to pursue health interests or healthy lifestyles, such as gyms, spas, wellness and fitness centres. As a result, the exemption applicable to health institutions does not apply to such establishments. (31) In view of the fact that natural or legal persons can claim compensation for damage caused by a defective device in accordance with applicable Union and national law, it is appropriate to require manufacturers to have measures in place to provide sufficient financial coverage in respect of their potential liability under Council Directive 85/374/EEC (19). Such measures should be proportionate to the risk class, type of device and the size of the enterprise. In this context, it is also appropriate to lay down rules concerning the facilitation, by a competent authority, of the provision of information to persons who may have been injured by a defective device. (32) To ensure that devices manufactured in series production continue to be in conformity with the requirements of this Regulation and that experience from the use of the devices they manufacture is taken into account for the production process, all manufacturers should have a quality management system and a post-market surveillance system in place which should be proportionate to the risk class and the type of the device in question. In addition, in order to minimize risks or prevent incidents related to devices, manufacturers should establish a system for risk management and a system for reporting of incidents and field safety corrective actions. (33) The risk management system should be carefully aligned with and reflected in the clinical evaluation for the device, including the clinical risks to be addressed as part of clinical investigations, clinical evaluation and post-market clinical follow up. The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated. (34) It should be ensured that supervision and control of the manufacture of devices, and the post-market surveillance and vigilance activities concerning them, are carried out within the manufacturer's organisation by a person responsible for regulatory compliance who fulfils minimum conditions of qualification. (35) For manufacturers who are not established in the Union, the authorised representative plays a pivotal role in ensuring the compliance of the devices produced by those manufacturers and in serving as their contact person established in the Union. Given that pivotal role, for the purposes of enforcement it is appropriate to make the authorised representative legally liable for defective devices in the event that a manufacturer established outside the Union has not complied with its general obligations. The liability of the authorised representative provided for in this Regulation is without prejudice to the provisions of Directive 85/374/EEC, and accordingly the authorised representative should be jointly and severally liable with the importer and the manufacturer. The tasks of an authorised representative should be defined in a written mandate. Considering the role of authorised representatives, the minimum requirements they should meet should be clearly defined, including the requirement of having available a person who fulfils minimum conditions of qualification which should be similar to those for a manufacturer's person responsible for regulatory compliance. (36) To ensure legal certainty in respect of the obligations incumbent on economic operators, it is necessary to clarify when a distributor, importer or other person is to be considered the manufacturer of a device. (37) Parallel trade in products already placed on the market is a lawful form of trade within the internal market on the basis of Article 34 TFEU subject to the limitations arising from the need for protection of health and safety and from the need for protection of intellectual property rights provided for under Article 36 TFEU. Application of the principle of parallel trade is, however, subject to different interpretations in the Member States. The conditions, in particular the requirements for relabelling and repackaging, should therefore be specified in this Regulation, taking into account the case-law of the Court of Justice (20) in other relevant sectors and existing good practice in the field of medical devices. (38) The reprocessing and further use of single-use devices should only take place where permitted by national law and while complying with the requirements laid down in this Regulation. The reprocessor of a single-use device should be considered to be the manufacturer of the reprocessed device and should assume the obligations incumbent on manufacturers under this Regulation. Nevertheless, Member States should have the possibility of deciding that the obligations relating to reprocessing and re-use of single-use devices within a health institution or by an external reprocessor acting on its behalf may differ from the obligations on a manufacturer described in this Regulation. In principle, such divergence should only be permitted where reprocessing and reuse of single-use devices within a health institution or by an external reprocessor are compliant with CS that have been adopted, or, in the absence of such CS, with relevant harmonised standards and national provisions. The reprocessing of such devices should ensure an equivalent level of safety and performance to that of the corresponding initial single-use device. (39) Patients who are implanted with a device should be given clear and easily accessible essential information allowing the implanted device to be identified and other relevant information about the device, including any necessary health risk warnings or precautions to be taken, for example indications as to whether or not it is compatible with certain diagnostic devices or with scanners used for security controls. (40) Devices should, as a general rule, bear the CE marking to indicate their conformity with this Regulation so that they can move freely within the Union and be put into service in accordance with their intended purpose. Member States should not create obstacles to the placing on the market or putting into service of devices that comply with the requirements laid down in this Regulation. However, Member States should be allowed to decide whether to restrict the use of any specific type of device in relation to aspects that are not covered by this Regulation. (41) The traceability of devices by means of a Unique Device Identification system (UDI system) based on international guidance should significantly enhance the effectiveness of the post-market safety-related activities for devices, which is owing to improved incident reporting, targeted field safety corrective actions and better monitoring by competent authorities. It should also help to reduce medical errors and to fight against falsified devices. Use of the UDI system should also improve purchasing and waste disposal policies and stock-management by health institutions and other economic operators and, where possible, be compatible with other authentication systems already in place in those settings. (42) The UDI system should apply to all devices placed on the market except custom-made devices, and be based on internationally recognised principles including definitions that are compatible with those used by major trade partners. In order for the UDI system to become functional in time for the application of this Regulation, detailed rules should be laid down in this Regulation. (43) Transparency and adequate access to information, appropriately presented for the intended user, are essential in the public interest, to protect public health, to empower patients and healthcare professionals and to enable them to make informed decisions, to provide a sound basis for regulatory decision-making and to build confidence in the regulatory system. (44) One key aspect in fulfilling the objectives of this Regulation is the creation of a European database on medical devices (Eudamed) that should integrate different electronic systems to collate and process information regarding devices on the market and the relevant economic operators, certain aspects of conformity assessment, notified bodies, certificates, clinical investigations, vigilance and market surveillance. The objectives of the database are to enhance overall transparency, including through better access to information for the public and healthcare professionals, to avoid multiple reporting requirements, to enhance coordination between Member States and to streamline and facilitate the flow of information between economic operators, notified bodies or sponsors and Member States as well as between Member States among themselves and with the Commission. Within the internal market, this can be ensured effectively only at Union level and the Commission should therefore further develop and manage the European databank on medical devices set up by Commission Decision 2010/227/EU (21). (45) To facilitate the functioning of Eudamed, an internationally recognised medical device nomenclature should be available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. Furthermore, that nomenclature should be available, where reasonably practicable, free of charge also to other stakeholders. (46) Eudamed's electronic systems regarding devices on the market, the relevant economic operators and certificates should enable the public to be adequately informed about devices on the Union market. The electronic system on clinical investigations should serve as a tool for the cooperation between Member States and for enabling sponsors to submit, on a voluntary basis, a single application for several Member States and to report serious adverse events, device deficiencies and related updates. The electronic system on vigilance should enable manufacturers to report serious incidents and other reportable events and to support the coordination of the evaluation of such incidents and events by competent authorities. The electronic system regarding market surveillance should be a tool for the exchange of information between competent authorities. (47) In respect of data collated and processed through the electronic systems of Eudamed, Directive 95/46/EC of the European Parliament and of the Council (22) applies to the processing of personal data carried out in the Member States, under the supervision of the Member States' competent authorities, in particular the public independent authorities designated by the Member States. Regulation (EC) No 45/2001 of the European Parliament and of the Council (23) applies to the processing of personal data carried out by the Commission within the framework of this Regulation, under the supervision of the European Data Protection Supervisor. In accordance with Regulation (EC) No 45/2001, the Commission should be designated as the controller of Eudamed and its electronic systems. (48) For implantable devices and for class III devices, manufacturers should summarise the main safety and performance aspects of the device and the outcome of the clinical evaluation in a document that should be publicly available. (49) The summary of safety and clinical performance for a device should include in particular the place of the device in the context of diagnostic or therapeutic options taking into account the clinical evaluation of that device when compared to the diagnostic or therapeutic alternatives and the specific conditions under which that device and its alternatives can be considered. (50) The proper functioning of notified bodies is crucial for ensuring a high level of health and safety protection and citizens' confidence in the system. Designation and monitoring of notified bodies by the Member States, in accordance with detailed and strict criteria, should therefore be subject to controls at Union level. (51) Notified bodies' assessments of manufacturers' technical documentation, in particular documentation on clinical evaluation, should be critically evaluated by the authority responsible for notified bodies. That evaluation should be part of the risk-based approach to the oversight and monitoring activities of notified bodies and should be based on sampling of the relevant documentation. (52) The position of notified bodies vis-à-vis manufacturers should be strengthened, including with regard to their right and duty to carry out unannounced on-site audits and to conduct physical or laboratory tests on devices to ensure continuous compliance by manufacturers after receipt of the original certification. (53) To increase transparency with regard to the oversight of notified bodies by national authorities, the authorities responsible for notified bodies should publish information on the national measures governing the assessment, designation and monitoring of notified bodies. In accordance with good administrative practice, this information should be kept up to date by those authorities in particular to reflect relevant, significant or substantive changes to the procedures in question. (54) The Member State in which a notified body is established should be responsible for enforcing the requirements of this Regulation with regard to that notified body. (55) In view, in particular, of the responsibility of Member States for the organisation and delivery of health services and medical care, they should be allowed to lay down additional requirements on notified bodies designated for the conformity assessment of devices and established on their territory as far as issues that are not regulated in this Regulation are concerned. Any such additional requirements laid down should not affect more specific horizontal Union legislation on notified bodies and equal treatment of notified bodies. (56) For class III implantable devices and class IIb active devices intended to administer and/or remove a medicinal product, notified bodies should, except in certain cases, be obliged to request expert panels to scrutinise their clinical evaluation assessment report. Competent authorities should be informed about devices that have been granted a certificate following a conformity assessment procedure involving an expert panel. The consultation of expert panels in relation to the clinical evaluation should lead to a harmonised evaluation of high-risk medical devices by sharing expertise on clinical aspects and developing CS on categories of devices that have undergone that consultation process. (57) For class III devices and for certain class IIb devices, a manufacturer should be able to consult voluntarily an expert panel, prior to that manufacturer's clinical evaluation and/or investigation, on its clinical development strategy and on proposals for clinical investigations. (58) It is necessary, in particular for the purpose of the conformity assessment procedures, to maintain the division of devices into four product classes in line with international practice. The classification rules, which are based on the vulnerability of the human body, should take into account the potential risks associated with the technical design and manufacture of the devices. To maintain the same level of safety as provided by Directive 90/385/EEC, active implantable devices should be in the highest risk class. (59) Rules under the old regime applied to invasive devices do not sufficiently take account of the level of invasiveness and potential toxicity of certain devices which are introduced into the human body. In order to obtain a suitable risk-based classification of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body, it is necessary to introduce specific classification rules for such devices. The classification rules should take into account the place where the device performs its action in or on the human body, where it is introduced or applied, and whether a systemic absorption of the substances of which the device is composed, or of the products of metabolism in the human body of those substances occurs. (60) The conformity assessment procedure for class I devices should be carried out, as a general rule, under the sole responsibility of manufacturers in view of the low level of vulnerability associated with such devices. For class IIa, class IIb and class III devices, an appropriate level of involvement of a notified body should be compulsory. (61) The conformity assessment procedures for devices should be further strengthened and streamlined whilst the requirements for notified bodies as regards the performance of their assessments should be clearly specified to ensure a level playing field. (62) It is appropriate that certificates of free sale contain information that makes it possible to use Eudamed in order to obtain information on the device, in particular with regard to whether it is on the market, withdrawn from the market or recalled, and on any certificate on its conformity. (63) To ensure a high level of safety and performance, demonstration of compliance with the general safety and performance requirements laid down in this Regulation should be based on clinical data that, for class III devices and implantable devices should, as a general rule, be sourced from clinical investigations that have been carried out under the responsibility of a sponsor. It should be possible both for the manufacturer and for another natural or legal person to be the sponsor taking responsibility for the clinical investigation. (64) The rules on clinical investigations should be in line with well-established international guidance in this field, such as the international standard ISO 14155:2011 on good clinical practice for clinical investigations of medical devices for human subjects, so as to make it easier for the results of clinical investigations conducted in the Union to be accepted as documentation outside the Union and to make it easier for the results of clinical investigations conducted outside the Union in accordance with international guidelines to be accepted within the Union. In addition, the rules should be in line with the most recent version of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. (65) It should be left to the Member State where a clinical investigation is to be conducted to determine the appropriate authority to be involved in the assessment of the application to conduct a clinical investigation and to organise the involvement of ethics committees within the timelines for the authorisation of that clinical investigation as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. In that context, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. (66) Where, in the course of a clinical investigation, harm caused to a subject leads to the civil or criminal liability of the investigator or the sponsor being invoked, the conditions for liability in such cases, including issues of causality and the level of damages and sanctions, should remain governed by national law. (67) An electronic system should be set up at Union level to ensure that every clinical investigation is recorded and reported in a publicly accessible database. To protect the right to the protection of personal data, recognised by Article 8 of the Charter of Fundamental Rights of the European Union (‘the Charter’), no personal data of subjects participating in a clinical investigation should be recorded in the electronic system. To ensure synergies with the area of clinical trials on medicinal products, the electronic system on clinical investigations should be interoperable with the EU database to be set up for clinical trials on medicinal products for human use. (68) Where a clinical investigation is to be conducted in more than one Member State, the sponsor should have the possibility of submitting a single application in order to reduce administrative burden. In order to allow for resource-sharing and to ensure consistency regarding the assessment of the health and safety-related aspects of the investigational device and of the scientific design of that clinical investigation, the procedure for the assessment of such single application should be coordinated between the Member States under the direction of a coordinating Member State. Such coordinated assessment should not include the assessment of intrinsically national, local and ethical aspects of a clinical investigation, including informed consent. For an initial period of seven years from the date of application of this Regulation, Member States should be able to participate on a voluntary basis in the coordinated assessment. After that period, all Member States should be obliged to participate in the coordinated assessment. The Commission, based on the experience gained from the voluntary coordination between Member States, should draw up a report on the application of the relevant provisions regarding the coordinated assessment procedure. In the event that the findings of the report are negative, the Commission should submit a proposal to extend the period of participation on a voluntary basis in the coordinated assessment procedure. (69) Sponsors should report certain adverse events and device deficiencies that occur during clinical investigations to the Member States in which those clinical investigations are being conducted. Member States should have the possibility of terminating or suspending the investigations or revoking the authorisation for those investigations, if considered necessary to ensure a high level of protection of the subjects participating in a clinical investigation. Such information should be communicated to the other Member States. (70) The sponsor of a clinical investigation should submit a summary of results of the clinical investigation that is easily understandable for the intended user together with the clinical investigation report, where applicable, within the timelines laid down in this Regulation. Where it is not possible to submit the summary of the results within the defined timelines for scientific reasons, the sponsor should justify this and specify when the results will be submitted. (71) This Regulation should cover clinical investigations intended to gather clinical evidence for the purpose of demonstrating conformity of devices and should also lay down basic requirements regarding ethical and scientific assessments for other types of clinical investigations of medical devices. (72) Incapacitated subjects, minors, pregnant women and breastfeeding women require specific protection measures. However, it should be left to Member States to determine the legally designated representatives of incapacitated subjects and minors. (73) The principles of replacement, reduction and refinement in the area of animal experimentation laid down in the Directive 2010/63/EU of the European Parliament and of the Council (24) should be observed. In particular, the unnecessary duplication of tests and studies should be avoided. (74) Manufacturers should play an active role during the post-market phase by systematically and actively gathering information from post-market experience with their devices in order to update their technical documentation and cooperate with the national competent authorities in charge of vigilance and market surveillance activities. To this end, manufacturers should establish a comprehensive post-market surveillance system, set up under their quality management system and based on a post-market surveillance plan. Relevant data and information gathered through post-market surveillance, as well as lessons learned from any implemented preventive and/or corrective actions, should be used to update any relevant part of technical documentation, such as those relating to risk assessment and clinical evaluation, and should also serve the purpose of transparency. (75) In order to better protect health and safety regarding devices on the market, the electronic system on vigilance for devices should be made more effective by creating a central portal at Union level for reporting serious incidents and field safety corrective actions. (76) Member States should take appropriate measures to raise awareness among healthcare professionals, users and patients about the importance of reporting incidents. Healthcare professionals, users and patients should be encouraged and enabled to report suspected serious incidents at national level using harmonised formats. The national competent authorities should inform manufacturers of any suspected serious incidents and, where a manufacturer confirms that such an incident has occurred, the authorities concerned should ensure that appropriate follow-up action is taken in order to minimise recurrence of such incidents. (77) The evaluation of reported serious incidents and field safety corrective actions should be conducted at national level but coordination should be ensured where similar incidents have occurred or field safety corrective actions have to be carried out in more than one Member State, with the objective of sharing resources and ensuring consistency regarding the corrective action. (78) In the context of the investigation of incidents, the competent authorities should take into account, where appropriate, the information provided by and views of relevant stakeholders, including patient and healthcare professionals' organisations and manufacturers' associations. (79) The reporting of serious adverse events or device deficiencies during clinical investigations and the reporting of serious incidents occurring after a device has been placed on the market should be clearly distinguished to avoid double reporting. (80) Rules on market surveillance should be included in this Regulation to reinforce the rights and obligations of the national competent authorities, to ensure effective coordination of their market surveillance activities and to clarify the applicable procedures. (81) Any statistically significant increase in the number or severity of incidents that are not serious or in expected side-effects that could have a significant impact on the benefit-risk analysis and which could lead to unacceptable risks should be reported to the competent authorities in order to permit their assessment and the adoption of appropriate measures. (82) An expert committee, the Medical Device Coordination Group (MDCG), composed of persons designated by the Member States based on their role and expertise in the field of medical devices including in vitro diagnostic medical devices, should be established to fulfil the tasks conferred on it by this Regulation and by Regulation (EU) 2017/746 of the European Parliament and of the Council (25), to provide advice to the Commission and to assist the Commission and the Member States in ensuring a harmonised implementation of this Regulation. The MDCG should be able to establish subgroups in order to have access to necessary in-depth technical expertise in the field of medical devices including in vitro diagnostic medical devices. When establishing subgroups, appropriate consideration should be given to the possibility of involving existing groups at Union level in the field of medical devices. (83) Expert panels and expert laboratories should be designated by the Commission on the basis of their up-to-date clinical, scientific or technical expertise, with the aim of providing scientific, technical and clinical assistance to the Commission, the MDCG, manufacturers and notified bodies in relation to the implementation of this Regulation. Moreover, expert panels should fulfil the tasks of providing an opinion on clinical evaluation assessment reports of notified bodies in the case of certain high-risk devices. (84) Closer coordination between national competent authorities through information exchange and coordinated assessments under the direction of a coordinating authority is essential for ensuring a consistently high level of health and safety protection within the internal market, in particular in the areas of clinical investigations and vigilance. The principle of coordinated exchange and assessment should also apply across other authority activities described in this Regulation, such as the designation of notified bodies and should be encouraged in the area of market surveillance of devices. Joint working, coordination and communication of activities should also lead to more efficient use of resources and expertise at national level. (85) The Commission should provide scientific, technical and corresponding logistical support to coordinating national authorities and ensure that the regulatory system for devices is effectively and uniformly implemented at Union level based on sound scientific evidence. (86) The Union and, where appropriate, the Member States should actively participate in international regulatory cooperation in the field of medical devices to facilitate the exchange of safety-related information regarding medical devices and to foster the further development of international regulatory guidelines that promote the adoption in other jurisdictions of regulations that lead to a level of health and safety protection equivalent to that set by this Regulation. (87) Member States should take all necessary measures to ensure that the provisions of this Regulation are implemented, including by laying down effective, proportionate and dissuasive penalties for their infringement. (88) Whilst this Regulation should not affect the right of Member States to levy fees for activities at national level, Member States should, in order to ensure transparency, inform the Commission and the other Member States before they decide on the level and structure of such fees. In order to further ensure transparency, the structure and level of the fees should be publicly available on request. (89) This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter and in particular human dignity, the integrity of the person, the protection of personal data, the freedom of art and science, the freedom to conduct business and the right to property. This Regulation should be applied by the Member States in accordance with those rights and principles. (90) The power to adopt delegated acts in accordance with Article 290 TFEU should be delegated to the Commission in order to amend certain non-essential provisions of this Regulation. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making (26). In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States' experts, and their experts systematically have access to meetings of Commission expert groups dealing with preparation of delegated acts. (91) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council (27). (92) The advisory procedure should be used for implementing acts that set out the form and presentation of the data elements of manufacturers' summaries of safety and clinical performance, and that establish the model for certificates of free sale, given that such implementing acts are of a procedural nature and do not directly have an impact on health and safety at Union level. (93) The Commission should adopt immediately applicable implementing acts where, in duly justified cases relating to the extension to the territory of the Union of a national derogation from the applicable conformity assessment procedures, imperative grounds of urgency so require. (94) In order to enable it to designate issuing entities, expert panels and expert laboratories, implementing powers should be conferred on the Commission. (95) To allow economic operators, especially SMEs, notified bodies, Member States and the Commission to adapt to the changes introduced by this Regulation and to ensure its proper application, it is appropriate to provide for a sufficient transitional period for that adaptation and for the organisational arrangements that are to be made. However, certain parts of the Regulation that directly affect Member States and the Commission should be implemented as soon as possible. It is also particularly important that, by the date of application of this Regulation, a sufficient number of notified bodies be designated in accordance with the new requirements so as to avoid any shortage of medical devices on the market. Nonetheless, it is necessary that any designation of a notified body in accordance with the requirements of this Regulation prior to the date of its application be without prejudice to the validity of the designation of those notified bodies under Directives 90/385/EEC and 93/42/EEC and to their capacity to continue issuing valid certificates under those two Directives until the date of application of this Regulation. (96) In order to ensure a smooth transition to the new rules for registration of devices and of certificates, the obligation to submit the relevant information to the electronic systems set up at Union level pursuant to this Regulation should, in the event that the corresponding IT systems are developed according to plan, only become fully effective from 18 months after the date of application of this Regulation. During this transitional period, certain provisions of Directives 90/385/EEC and 93/42/EEC should remain in force. However, in order to avoid multiple registrations, economic operators and notified bodies who register in the relevant electronic systems set up at Union level pursuant to this Regulation should be considered to be in compliance with the registration requirements adopted by the Member States pursuant to those provisions. (97) In order to provide for a smooth introduction of the UDI system, the moment of application of the obligation to place the UDI carrier on the label of the device should vary from one to five years after the date of application of this Regulation depending upon the class of the device concerned. (98) Directives 90/385/EEC and 93/42/EEC should be repealed to ensure that only one set of rules applies to the placing of medical devices on the market and the related aspects covered by this Regulation. Manufacturers' obligations as regards the making available of documentation regarding devices they placed on the market and manufacturers' and Member States' obligations as regards vigilance activities for devices placed on the market pursuant to those Directives should however continue to apply. While it should be left to Member States to decide how to organise vigilance activities, it is desirable for them to have the possibility of reporting incidents related to devices placed on the market pursuant to the Directives using the same tools as those for reporting on devices placed on the market pursuant to this Regulation. It is furthermore appropriate, in order to ensure a smooth transition from the old regime to the new regime, to provide that Commission Regulation (EU) No 207/2012 (28) and Commission Regulation (EU) No 722/2012 (29) should remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. Decision 2010/227/EU adopted in implementation of those Directives and Directive 98/79/EC should also remain in force and continue to apply until the date when Eudamed becomes fully functional. Conversely, no such maintenance in force is required for Commission Directives 2003/12/EC (30) and 2005/50/EC (31) and Commission Implementing Regulation (EU) No 920/2013 (32). (99) The requirements of this Regulation should be applicable to all devices placed on the market or put into service from the date of application of this Regulation. However, in order to provide for a smooth transition it should be possible, for a limited period of time from that date, for devices to be placed on the market or put into service by virtue of a valid certificate issued pursuant to Directive 90/385/EEC or pursuant to Directive 93/42/EEC. (100) The European Data Protection Supervisor has given an opinion (33) pursuant to Article 28(2) of Regulation (EC) No 45/2001. (101) Since the objectives of this Regulation, namely to ensure the smooth functioning of the internal market as regards medical devices and to ensure high standards of quality and safety for medical devices, thus ensuring a high level of protection of health and safety of patients, users and other persons, cannot be sufficiently achieved by the Member States but can rather, by reason of its scale and effects, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve those objectives, HAVE ADOPTED THIS REGULATION: CHAPTER I SCOPE AND DEFINITIONS Article 1 Subject matter and scope 1.   This Regulation lays down rules concerning the placing on the market, making available on the market or putting into service of medical devices for human use and accessories for such devices in the Union. This Regulation also applies to clinical investigations concerning such medical devices and accessories conducted in the Union. 2.   This Regulation shall also apply, as from the date of application of common specifications adopted pursuant to Article 9, to the groups of products without an intended medical purpose that are listed in Annex XVI, taking into account the state of the art, and in particular existing harmonised standards for analogous devices with a medical purpose, based on similar technology. The common specifications for each of the groups of products listed in Annex XVI shall address, at least, application of risk management as set out in Annex I for the group of products in question and, where necessary, clinical evaluation regarding safety. The necessary common specifications shall be adopted by 26 May 2020. They shall apply as from six months after the date of their entry into force or from 26 May 2020, whichever is the latest. Notwithstanding Article 122, Member States' measures regarding the qualification of the products covered by Annex XVI as medical devices pursuant to Directive 93/42/EEC shall remain valid until the date of application, as referred to in the first subparagraph, of the relevant common specifications for that group of products. This Regulation also applies to clinical investigations conducted in the Union concerning the products referred to in the first subparagraph. 3.   Devices with both a medical and a non-medical intended purpose shall fulfil cumulatively the requirements applicable to devices with an intended medical purpose and those applicable to devices without an intended medical purpose. 4.   For the purposes of this Regulation, medical devices, accessories for medical devices, and products listed in Annex XVI to which this Regulation applies pursuant to paragraph 2 shall hereinafter be referred to as ‘devices’. 5.   Where justified on account of the similarity between a device with an intended medical purpose placed on the market and a product without an intended medical purpose in respect of their characteristics and risks, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list in Annex XVI, by adding new groups of products, in order to protect the health and safety of users or other persons or other aspects of public health. 6.   This Regulation does not apply to: (a) in vitro diagnostic medical devices covered by Regulation (EU) 2017/746; (b) medicinal products as defined in point 2 of Article 1 of Directive 2001/83/EC. In deciding whether a product falls under Directive 2001/83/EC or under this Regulation, particular account shall be taken of the principal mode of action of the product; (c) advanced therapy medicinal products covered by Regulation (EC) No 1394/2007; (d) human blood, blood products, plasma or blood cells of human origin or devices which incorporate, when placed on the market or put into service, such blood products, plasma or cells, except for devices referred to in paragraph 8 of this Article; (e) cosmetic products covered by Regulation (EC) No 1223/2009; (f) transplants, tissues or cells of animal origin, or their derivatives, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or are rendered non-viable; (g) transplants, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable; (h) products, other than those referred to in points (d), (f) and (g), that contain or consist of viable biological material or viable organisms, including living micro-organisms, bacteria, fungi or viruses in order to achieve or support the intended purpose of the product; (i) food covered by Regulation (EC) No 178/2002. 7.   Any device which, when placed on the market or put into service, incorporates as an integral part an in vitro diagnostic medical device as defined in point 2 of Article 2 of Regulation (EU) 2017/746, shall be governed by this Regulation. The requirements of Regulation (EU) 2017/746 shall apply to the in vitro diagnostic medical device part of the device. 8.   Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation. However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council (34), as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 9.   Any device which is intended to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal product. However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned. 10.   Any device which, when placed on the market or put into service, incorporates, as an integral part, non-viable tissues or cells of human origin or their derivatives that have an action ancillary to that of the device shall be assessed and authorised in accordance with this Regulation. In that case, the provisions for donation, procurement and testing laid down in Directive 2004/23/EC shall apply. However, if the action of those tissues or cells or their derivatives is principal and not ancillary to that of the device and the product is not governed by Regulation (EC) No 1394/2007, the product shall be governed by Directive 2004/23/EC. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 11.   This Regulation is specific Union legislation within the meaning of Article 2(3) of Directive 2014/30/EU. 12.   Devices that are also machinery within the meaning of point (a) of the second paragraph of Article 2 of Directive 2006/42/EC of the European Parliament and of the Council (35) shall, where a hazard relevant under that Directive exists, also meet the essential health and safety requirements set out in Annex I to that Directive to the extent to which those requirements are more specific than the general safety and performance requirements set out in Chapter II of Annex I to this Regulation. 13.   This Regulation shall not affect the application of Directive 2013/59/Euratom. 14.   This Regulation shall not affect the right of a Member State to restrict the use of any specific type of device in relation to aspects not covered by this Regulation. 15.   This Regulation shall not affect national law concerning the organisation, delivery or financing of health services and medical care, such as the requirement that certain devices may only be supplied on a medical prescription, the requirement that only certain health professionals or healthcare institutions may dispense or use certain devices or that their use be accompanied by specific professional counselling. 16.   Nothing in this Regulation shall restrict the freedom of the press or the freedom of expression in the media in so far as those freedoms are guaranteed in the Union and in the Member States, in particular under Article 11 of the Charter of Fundamental Rights of the European Union. Article 2 Definitions For the purposes of this Regulation, the following definitions apply: (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conception; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (2) ‘accessory for a medical device’ means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); (3) ‘custom-made device’ means any device specifically made in accordance with a written prescription of any person authorised by national law by virtue of that person's professional qualifications which gives, under that person's responsibility, specific design characteristics, and is intended for the sole use of a particular patient exclusively to meet their individual conditions and needs. However, mass-produced devices which need to be adapted to meet the specific requirements of any professional user and devices which are mass-produced by means of industrial manufacturing processes in accordance with the written prescriptions of any authorised person shall not be considered to be custom-made devices; (4) ‘active device’ means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; (5) ‘implantable device’ means any device, including those that are partially or wholly absorbed, which is intended: — to be totally introduced into the human body, or — to replace an epithelial surface or the surface of the eye, by clinical intervention and which is intended to remain in place after the procedure. Any device intended to be partially introduced into the human body by clinical intervention and intended to remain in place after the procedure for at least 30 days shall also be deemed to be an implantable device; (6) ‘invasive device’ means any device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body; (7) ‘generic device group’ means a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics; (8) ‘single-use device’ means a device that is intended to be used on one individual during a single procedure; (9) ‘falsified device’ means any device with a false presentation of its identity and/or of its source and/or its CE marking certificates or documents relating to CE marking procedures. This definition does not include unintentional non-compliance and is without prejudice to infringements of intellectual property rights; (10) ‘procedure pack’ means a combination of products packaged together and placed on the market with the purpose of being used for a specific medical purpose; (11) ‘system’ means a combination of products, either packaged together or not, which are intended to be inter-connected or combined to achieve a specific medical purpose; (12) ‘intended purpose’ means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation; (13) ‘label’ means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices; (14) ‘instructions for use’ means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use and of any precautions to be taken; (15) ‘Unique Device Identifier’ (‘UDI’) means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market; (16) ‘non-viable’ means having no potential for metabolism or multiplication; (17) ‘derivative’ means a ‘non-cellular substance’ extracted from human or animal tissue or cells through a manufacturing process. The final substance used for manufacturing of the device in this case does not contain any cells or tissues; (18) ‘nanomaterial’ means a natural, incidental or manufactured material containing particles in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1-100 nm; Fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1 nm shall also be deemed to be nanomaterials; (19) ‘particle’, for the purposes of the definition of nanomaterial in point (18), means a minute piece of matter with defined physical boundaries; (20) ‘agglomerate’, for the purposes of the definition of nanomaterial in point (18), means a collection of weakly bound particles or aggregates where the resulting external surface area is similar to the sum of the surface areas of the individual components; (21) ‘aggregate’, for the purposes of the definition of nanomaterial in point (18), means a particle comprising of strongly bound or fused particles; (22) ‘performance’ means the ability of a device to achieve its intended purpose as stated by the manufacturer; (23) ‘risk’ means the combination of the probability of occurrence of harm and the severity of that harm; (24) ‘benefit-risk determination’ means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer; (25) ‘compatibility’ is the ability of a device, including software, when used together with one or more other devices in accordance with its intended purpose, to: (a) perform without losing or compromising the ability to perform as intended, and/or (b) integrate and/or operate without the need for modification or adaption of any part of the combined devices, and/or (c) be used together without conflict/interference or adverse reaction. (26) ‘interoperability’ is the ability of two or more devices, including software, from the same manufacturer or from different manufacturers, to: (a) exchange information and use the information that has been exchanged for the correct execution of a specified function without changing the content of the data, and/or (b) communicate with each other, and/or (c) work together as intended. (27) ‘making available on the market’ means any supply of a device, other than an investigational device, for distribution, consumption or use on the Union market in the course of a commercial activity, whether in return for payment or free of charge; (28) ‘placing on the market’ means the first making available of a device, other than an investigational device, on the Union market; (29) ‘putting into service’ means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; (30) ‘manufacturer’ means a natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark; (31) ‘fully refurbishing’, for the purposes of the definition of manufacturer, means the complete rebuilding of a device already placed on the market or put into service, or the making of a new device from used devices, to bring it into conformity with this Regulation, combined with the assignment of a new lifetime to the refurbished device; (32) ‘authorised representative’ means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under this Regulation; (33) ‘importer’ means any natural or legal person established within the Union that places a device from a third country on the Union market; (34) ‘distributor’ means any natural or legal person in the supply chain, other than the manufacturer or the importer, that makes a device available on the market, up until the point of putting into service; (35) ‘economic operator’ means a manufacturer, an authorised representative, an importer, a distributor or the person referred to in Article 22(1) and 22(3); (36) ‘health institution’ means an organisation the primary purpose of which is the care or treatment of patients or the promotion of public health; (37) ‘user’ means any healthcare professional or lay person who uses a device; (38) ‘lay person’ means an individual who does not have formal education in a relevant field of healthcare or medical discipline; (39) ‘reprocessing’ means a process carried out on a used device in order to allow its safe reuse including cleaning, disinfection, sterilisation and related procedures, as well as testing and restoring the technical and functional safety of the used device; (40) ‘conformity assessment’ means the process demonstrating whether the requirements of this Regulation relating to a device have been fulfilled; (41) ‘conformity assessment body’ means a body that performs third-party conformity assessment activities including calibration, testing, certification and inspection; (42) ‘notified body’ means a conformity assessment body designated in accordance with this Regulation; (43) ‘CE marking of conformity’ or ‘CE marking’ means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in this Regulation and other applicable Union harmonisation legislation providing for its affixing; (44) ‘clinical evaluation’ means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer; (45) ‘clinical investigation’ means any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device; (46) ‘investigational device’ means a device that is assessed in a clinical investigation; (47) ‘clinical investigation plan’ means a document that describes the rationale, objectives, design, methodology, monitoring, statistical considerations, organisation and conduct of a clinical investigation; (48) ‘clinical data’ means information concerning safety or performance that is generated from the use of a device and is sourced from the following: — clinical investigation(s) of the device concerned, — clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated, — reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated, — clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up; (49) ‘sponsor’ means any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation; (50) ‘subject’ means an individual who participates in a clinical investigation; (51) ‘clinical evidence’ means clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer; (52) ‘clinical performance’ means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; (53) ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health; (54) ‘investigator’ means an individual responsible for the conduct of a clinical investigation at a clinical investigation site; (55) ‘informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in a particular clinical investigation, after having been informed of all aspects of the clinical investigation that are relevant to the subject's decision to participate or, in the case of minors and of incapacitated subjects, an authorisation or agreement from their legally designated representative to include them in the clinical investigation; (56) ‘ethics committee’ means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations; (57) ‘adverse event’ means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device; (58) ‘serious adverse event’ means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitalisation or prolongation of patient hospitalisation, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect; (59) ‘device deficiency’ means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer; (60) ‘post-market surveillance’ means all activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions; (61) ‘market surveillance’ means the activities carried out and measures taken by competent authorities to check and ensure that devices comply with the requirements set out in the relevant Union harmonisation legislation and do not endanger health, safety or any other aspect of public interest protection; (62) ‘recall’ means any measure aimed at achieving the return of a device that has already been made available to the end user; (63) ‘withdrawal’ means any measure aimed at preventing a device in the supply chain from being further made available on the market; (64) ‘incident’ means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; (65) ‘serious incident’ means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; (66) ‘serious public health threat’ means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time; (67) ‘corrective action’ means action taken to eliminate the cause of a potential or actual non-conformity or other undesirable situation; (68) ‘field safety corrective action’ means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market; (69) ‘field safety notice’ means a communication sent by a manufacturer to users or customers in relation to a field safety corrective action; (70) ‘harmonised standard’ means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) No 1025/2012; (71) ‘common specifications’ (CS) means a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system. Article 3 Amendment of certain definitions The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend the definition of nanomaterial set out in point (18) and the related definitions in points (19), (20) and (21) of Article 2 in the light of technical and scientific progress and taking into account definitions agreed at Union and international level. Article 4 Regulatory status of products 1.   Without prejudice to Article 2(2) of Directive 2001/83/EC, upon a duly substantiated request of a Member State, the Commission shall, after consulting the Medical Device Coordination Group established under Article 103 of this Regulation (‘MDCG’), by means of implementing acts, determine whether or not a specific product, or category or group of products, falls within the definitions of ‘medical device’ or ‘accessory for a medical device’. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3) of this Regulation. 2.   The Commission may also, on its own initiative, after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 3.   The Commission shall ensure that Member States share expertise in the fields of medical devices, in vitro diagnostic medical devices, medicinal products, human tissues and cells, cosmetics, biocides, food and, if necessary, other products, in order to determine the appropriate regulatory status of a product, or category or group of products. 4.   When deliberating on the possible regulatory status as a device of products involving medicinal products, human tissues and cells, biocides or food products, the Commission shall ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA), as relevant. CHAPTER II MAKING AVAILABLE ON THE MARKET AND PUTTING INTO SERVICE OF DEVICES, OBLIGATIONS OF ECONOMIC OPERATORS, REPROCESSING, CE MARKING, FREE MOVEMENT Article 5 Placing on the market and putting into service 1.   A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose. 2.   A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose. 3.   Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61. 4.   Devices that are manufactured and used within health institutions shall be considered as having been put into service. 5.   With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices, manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met: (a) the devices are not transferred to another legal entity, (b) manufacture and use of the devices occur under appropriate quality management systems, (c) the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market, (d) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use; (e) the health institution draws up a declaration which it shall make publicly available, including: (i) the name and address of the manufacturing health institution; (ii) the details necessary to identify the devices; (iii) a declaration that the devices meet the general safety and performance requirements set out in Annex I to this Regulation and, where applicable, information on which requirements are not fully met with a reasoned justification therefor, (f) the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met; (g) the health institution takes all necessary measures to ensure that all devices are manufactured in accordance with the documentation referred to in point (f), and (h) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions. Member States may require that such health institutions submit to the competent authority any further relevant information about such devices which have been manufactured and used on their territory. Member States shall retain the right to restrict the manufacture and the use of any specific type of such devices and shall be permitted access to inspect the activities of the health institutions. This paragraph shall not apply to devices that are manufactured on an industrial scale. 6.   In order to ensure the uniform application of Annex I, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 6 Distance sales 1.   A device offered by means of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to a natural or legal person established in the Union shall comply with this Regulation. 2.   Without prejudice to national law regarding the exercise of the medical profession, a device that is not placed on the market but used in the context of a commercial activity, whether in return for payment or free of charge, for the provision of a diagnostic or therapeutic service offered by means of information society services as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535 or by other means of communication, directly or through intermediaries, to a natural or legal person established in the Union shall comply with this Regulation. 3.   Upon request by a competent authority, any natural or legal person offering a device in accordance with paragraph 1 or providing a service in accordance with paragraph 2 shall make available a copy of the EU declaration of conformity of the device concerned. 4.   A Member State may, on grounds of protection of public health, require a provider of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to cease its activity. Article 7 Claims In the labelling, instructions for use, making available, putting into service and advertising of devices, it shall be prohibited to use text, names, trademarks, pictures and figurative or other signs that may mislead the user or the patient with regard to the device's intended purpose, safety and performance by: (a) ascribing functions and properties to the device which the device does not have; (b) creating a false impression regarding treatment or diagnosis, functions or properties which the device does not have; (c) failing to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; (d) suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. Article 8 Use of harmonised standards 1.   Devices that are in conformity with the relevant harmonised standards, or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union, shall be presumed to be in conformity with the requirements of this Regulation covered by those standards or parts thereof. The first subparagraph shall also apply to system or process requirements to be fulfilled in accordance with this Regulation by economic operators or sponsors, including those relating to quality management systems, risk management, post-market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-up (‘PMCF’). References in this Regulation to harmonised standards shall be understood as meaning harmonised standards the references of which have been published in the Official Journal of the European Union. 2.   References in this Regulation to harmonised standards shall also include the monographs of the European Pharmacopoeia adopted in accordance with the Convention on the Elaboration of a European Pharmacopoeia, in particular on surgical sutures and on interaction between medicinal products and materials used in devices containing such medicinal products, provided that references to those monographs have been published in the Official Journal of the European Union. Article 9 Common specifications 1.   Without prejudice to Article 1(2) and 17(5) and the deadline laid down in those provisions, where no harmonised standards exist or where relevant harmonised standards are not sufficient, or where there is a need to address public health concerns, the Commission, after having consulted the MDCG, may, by means of implementing acts, adopt common specifications (CS) in respect of the general safety and performance requirements set out in Annex I, the technical documentation set out in Annexes II and III, the clinical evaluation and post-market clinical follow-up set out in Annex XIV or the requirements regarding clinical investigation set out in Annex XV. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Devices that are in conformity with the CS referred to in paragraph 1 shall be presumed to be in conformity with the requirements of this Regulation covered by those CS or the relevant parts of those CS. 3.   Manufacturers shall comply with the CS referred to in paragraph 1 unless they can duly justify that they have adopted solutions that ensure a level of safety and performance that is at least equivalent thereto. 4.   Notwithstanding paragraph 3, manufacturers of products listed in Annex XVI shall comply with the relevant CS for those products. Article 10 General obligations of manufacturers 1.   When placing their devices on the market or putting them into service, manufacturers shall ensure that they have been designed and manufactured in accordance with the requirements of this Regulation. 2.   Manufacturers shall establish, document, implement and maintain a system for risk management as described in Section 3 of Annex I. 3.   Manufacturers shall conduct a clinical evaluation in accordance with the requirements set out in Article 61 and Annex XIV, including a PMCF. 4.   Manufacturers of devices other than custom-made devices shall draw up and keep up to date technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III. The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress, the Annexes II and III. 5.   Manufacturers of custom-made devices shall draw up, keep up to date and keep available for competent authorities documentation in accordance with Section 2 of Annex XIII. 6.   Where compliance with the applicable requirements has been demonstrated following the applicable conformity assessment procedure, manufacturers of devices, other than custom-made or investigational devices, shall draw up an EU declaration of conformity in accordance with Article 19, and affix the CE marking of conformity in accordance with Article 20. 7.   Manufacturers shall comply with the obligations relating to the UDI system referred to in Article 27 and with the registration obligations referred to in Articles 29 and 31. 8.   Manufacturers shall keep the technical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market. In the case of implantable devices, the period shall be at least 15 years after the last device has been placed on the market. Upon request by a competent authority, the manufacturer shall, as indicated therein, provide that technical documentation in its entirety or a summary thereof. A manufacturer with a registered place of business outside the Union shall, in order to allow its authorised representative to fulfil the tasks mentioned in Article 11(3), ensure that the authorised representative has the necessary documentation permanently available. 9.   Manufacturers shall ensure that procedures are in place to keep series production in conformity with the requirements of this Regulation. Changes in device design or characteristics and changes in the harmonised standards or CS by reference to which the conformity of a device is declared shall be adequately taken into account in a timely manner. Manufacturers of devices, other than investigational devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device. The quality management system shall cover all parts and elements of a manufacturer's organisation dealing with the quality of processes, procedures and devices. It shall govern the structure, responsibilities, procedures, processes and management resources required to implement the principles and actions necessary to achieve compliance with the provisions of this Regulation. The quality management system shall address at least the following aspects: (a) a strategy for regulatory compliance, including compliance with conformity assessment procedures and procedures for management of modifications to the devices covered by the system; (b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; (c) responsibility of the management; (d) resource management, including selection and control of suppliers and sub-contractors; (e) risk management as set out in in Section 3 of Annex I; (f) clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF; (g) product realisation, including planning, design, development, production and service provision; (h) verification of the UDI assignments made in accordance with Article 27(3) to all relevant devices and ensuring consistency and validity of information provided in accordance with Article 29; (i) setting-up, implementation and maintenance of a post-market surveillance system, in accordance with Article 83; (j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; (k) processes for reporting of serious incidents and field safety corrective actions in the context of vigilance; (l) management of corrective and preventive actions and verification of their effectiveness; (m) processes for monitoring and measurement of output, data analysis and product improvement. 10.   Manufacturers of devices shall implement and keep up to date the post-market surveillance system in accordance with Article 83. 11.   Manufacturers shall ensure that the device is accompanied by the information set out in Section 23 of Annex I in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label shall be indelible, easily legible and clearly comprehensible to the intended user or patient. 12.   Manufacturers who consider or have reason to believe that a device which they have placed on the market or put into service is not in conformity with this Regulation shall immediately take the necessary corrective action to bring that device into conformity, to withdraw it or to recall it, as appropriate. They shall inform the distributors of the device in question and, where applicable, the authorised representative and importers accordingly. Where the device presents a serious risk, manufacturers shall immediately inform the competent authorities of the Member States in which they made the device available and, where applicable, the notified body that issued a certificate for the device in accordance with Article 56, in particular, of the non-compliance and of any corrective action taken. 13.   Manufacturers shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88. 14.   Manufacturers shall, upon request by a competent authority, provide it with all the information and documentation necessary to demonstrate the conformity of the device, in an official Union language determined by the Member State concerned. The competent authority of the Member State in which the manufacturer has its registered place of business may require that the manufacturer provide samples of the device free of charge or, where that is impracticable, grant access to the device. Manufacturers shall cooperate with a competent authority, at its request, on any corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market or put into service. If the manufacturer fails to cooperate or the information and documentation provided is incomplete or incorrect, the competent authority may, in order to ensure the protection of public health and patient safety, take all appropriate measures to prohibit or restrict the device's being made available on its national market, to withdraw the device from that market or to recall it until the manufacturer cooperates or provides complete and correct information. If a competent authority considers or has reason to believe that a device has caused damage, it shall, upon request, facilitate the provision of the information and documentation referred to in the first subparagraph to the potentially injured patient or user and, as appropriate, the patient's or user's successor in title, the patient's or user's health insurance company or other third parties affected by the damage caused to the patient or user, without prejudice to data protection rules and, unless there is an overriding public interest in disclosure, without prejudice to the protection of intellectual property rights. The competent authority need not comply with the obligation laid down in the third subparagraph where disclosure of the information and documentation referred to in the first subparagraph is ordinarily dealt with in the context of legal proceedings. 15.   Where manufacturers have their devices designed or manufactured by another legal or natural person the information on the identity of that person shall be part of the information to be submitted in accordance with Article 30(1). 16.   Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Manufacturers shall, in a manner that is proportionate to the risk class, type of device and the size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to more protective measures under national law. Article 11 Authorised representative 1.   Where the manufacturer of a device is not established in a Member State, the device may only be placed on the Union market if the manufacturer designates a sole authorised representative. 2.   The designation shall constitute the authorised representative's mandate, it shall be valid only when accepted in writing by the authorised representative and shall be effective at least for all devices of the same generic device group. 3.   The authorised representative shall perform the tasks specified in the mandate agreed between it and the manufacturer. The authorised representative shall provide a copy of the mandate to the competent authority, upon request. The mandate shall require, and the manufacturer shall enable, the authorised representative to perform at least the following tasks in relation to the devices that it covers: (a) verify that the EU declaration of conformity and technical documentation have been drawn up and, where applicable, that an appropriate conformity assessment procedure has been carried out by the manufacturer; (b) keep available a copy of the technical documentation, the EU declaration of conformity and, if applicable, a copy of the relevant certificate, including any amendments and supplements, issued in accordance with Article 56, at the disposal of competent authorities for the period referred to in Article 10(8); (c) comply with the registration obligations laid down in Article 31 and verify that the manufacturer has complied with the registration obligations laid down in Articles 27 and 29; (d) in response to a request from a competent authority, provide that competent authority with all the information and documentation necessary to demonstrate the conformity of a device, in an official Union language determined by the Member State concerned; (e) forward to the manufacturer any request by a competent authority of the Member State in which the authorised representative has its registered place of business for samples, or access to a device and verify that the competent authority receives the samples or is given access to the device; (f) cooperate with the competent authorities on any preventive or corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices; (g) immediately inform the manufacturer about complaints and reports from healthcare professionals, patients and users about suspected incidents related to a device for which they have been designated; (h) terminate the mandate if the manufacturer acts contrary to its obligations under this Regulation. 4.   The mandate referred to in paragraph 3 of this Article shall not delegate the manufacturer's obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). 5.   Without prejudice to paragraph 4 of this Article, where the manufacturer is not established in a Member State and has not complied with the obligations laid down in Article 10, the authorised representative shall be legally liable for defective devices on the same basis as, and jointly and severally with, the manufacturer. 6.   An authorised representative who terminates its mandate on the ground referred to in point (h) of paragraph 3 shall immediately inform the competent authority of the Member State in which it is established and, where applicable, the notified body that was involved in the conformity assessment for the device of the termination of the mandate and the reasons therefor. 7.   Any reference in this Regulation to the competent authority of the Member State in which the manufacturer has its registered place of business shall be understood as a reference to the competent authority of the Member State in which the authorised representative, designated by a manufacturer referred to in paragraph 1, has its registered place of business. Article 12 Change of authorised representative The detailed arrangements for a change of authorised representative shall be clearly defined in an agreement between the manufacturer, where practicable the outgoing authorised representative, and the incoming authorised representative. That agreement shall address at least the following aspects: (a) the date of termination of the mandate of the outgoing authorised representative and date of beginning of the mandate of the incoming authorised representative; (b) the date until which the outgoing authorised representative may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the obligation of the outgoing authorised representative after the end of the mandate to forward to the manufacturer or incoming authorised representative any complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device for which it had been designated as authorised representative. Article 13 General obligations of importers 1.   Importers shall place on the Union market only devices that are in conformity with this Regulation. 2.   In order to place a device on the market, importers shall verify that: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) a manufacturer is identified and that an authorised representative in accordance with Article 11 has been designated by the manufacturer; (c) the device is labelled in accordance with this Regulation and accompanied by the required instructions for use; (d) where applicable, a UDI has been assigned by the manufacturer in accordance with Article 27. Where an importer considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not place the device on the market until it has been brought into conformity and shall inform the manufacturer and the manufacturer's authorised representative. Where the importer considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which the importer is established. 3.   Importers shall indicate on the device or on its packaging or in a document accompanying the device their name, registered trade name or registered trade mark, their registered place of business and the address at which they can be contacted, so that their location can be established. They shall ensure that any additional label does not obscure any information on the label provided by the manufacturer. 4.   Importers shall verify that the device is registered in the electronic system in accordance with Article 29. Importers shall add their details to the registration in accordance with Article 31. 5.   Importers shall ensure that, while a device is under their responsibility, storage or transport conditions do not jeopardise its compliance with the general safety and performance requirements set out in Annex I and shall comply with the conditions set by the manufacturer, where available. 6.   Importers shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and provide the manufacturer, authorised representative and distributors with any information requested by them, in order to allow them to investigate complaints. 7.   Importers who consider or have reason to believe that a device which they have placed on the market is not in conformity with this Regulation shall immediately inform the manufacturer and its authorised representative. Importers shall co-operate with the manufacturer, the manufacturer's authorised representative and the competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or recall it is taken. Where the device presents a serious risk, they shall also immediately inform the competent authorities of the Member States in which they made the device available and, if applicable, the notified body that issued a certificate in accordance with Article 56 for the device in question, giving details, in particular, of the non-compliance and of any corrective action taken. 8.   Importers who have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device which they have placed on the market shall immediately forward this information to the manufacturer and its authorised representative. 9.   Importers shall, for the period referred to in Article 10(8), keep a copy of the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56. 10.   Importers shall cooperate with competent authorities, at the latters' request, on any action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market. Importers, upon request by a competent authority of the Member State in which the importer has its registered place of business, shall provide samples of the device free of charge or, where that is impracticable, grant access to the device. Article 14 General obligations of distributors 1.   When making a device available on the market, distributors shall, in the context of their activities, act with due care in relation to the requirements applicable. 2.   Before making a device available on the market, distributors shall verify that all of the following requirements are met: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) the device is accompanied by the information to be supplied by the manufacturer in accordance with Article 10(11); (c) for imported devices, the importer has complied with the requirements set out in Article 13(3); (d) that, where applicable, a UDI has been assigned by the manufacturer. In order to meet the requirements referred to in points (a), (b) and (d) of the first subparagraph the distributor may apply a sampling method that is representative of the devices supplied by that distributor. Where a distributor considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not make the device available on the market until it has been brought into conformity, and shall inform the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. Where the distributor considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which it is established. 3.   Distributors shall ensure that, while the device is under their responsibility, storage or transport conditions comply with the conditions set by the manufacturer. 4.   Distributors that consider or have reason to believe that a device which they have made available on the market is not in conformity with this Regulation shall immediately inform the manufacturer and, where applicable, the manufacturer's authorised representative and the importer. Distributors shall co-operate with the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer, and with competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or to recall it, as appropriate, is taken. Where the distributor considers or has reason to believe that the device presents a serious risk, it shall also immediately inform the competent authorities of the Member States in which it made the device available, giving details, in particular, of the non-compliance and of any corrective action taken. 5.   Distributors that have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device they have made available, shall immediately forward this information to the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. They shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and keep the manufacturer and, where available, the authorised representative and the importer informed of such monitoring and provide them with any information upon their request. 6.   Distributors shall, upon request by a competent authority, provide it with all the information and documentation that is at their disposal and is necessary to demonstrate the conformity of a device. Distributors shall be considered to have fulfilled the obligation referred to in the first subparagraph when the manufacturer or, where applicable, the authorised representative for the device in question provides the required information. Distributors shall cooperate with competent authorities, at their request, on any action taken to eliminate the risks posed by devices which they have made available on the market. Distributors, upon request by a competent authority, shall provide free samples of the device or, where that is impracticable, grant access to the device. Article 15 Person responsible for regulatory compliance 1.   Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom-made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. 2.   Micro and small enterprises within the meaning of Commission Recommendation 2003/361/EC (36) shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal. 3.   The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; (b) the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date; (c) the post-market surveillance obligations are complied with in accordance with Article 10(10); (d) the reporting obligations referred to in Articles 87 to 91 are fulfilled; (e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV is issued. 4.   If a number of persons are jointly responsible for regulatory compliance in accordance with paragraphs 1, 2 and 3, their respective areas of responsibility shall be stipulated in writing. 5.   The person responsible for regulatory compliance shall suffer no disadvantage within the manufacturer's organisation in relation to the proper fulfilment of his or her duties, regardless of whether or not they are employees of the organisation. 6.   Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Article 16 Cases in which obligations of manufacturers apply to importers, distributors or other persons 1.   A distributor, importer or other natural or legal person shall assume the obligations incumbent on manufacturers if it does any of the following: (a) makes available on the market a device under its name, registered trade name or registered trade mark, except in cases where a distributor or importer enters into an agreement with a manufacturer whereby the manufacturer is identified as such on the label and is responsible for meeting the requirements placed on manufacturers in this Regulation; (b) changes the intended purpose of a device already placed on the market or put into service; (c) modifies a device already placed on the market or put into service in such a way that compliance with the applicable requirements may be affected. The first subparagraph shall not apply to any person who, while not considered a manufacturer as defined in point (30) of Article 2, assembles or adapts for an individual patient a device already on the market without changing its intended purpose. 2.   For the purposes of point (c) of paragraph 1, the following shall not be considered to be a modification of a device that could affect its compliance with the applicable requirements: (a) provision, including translation, of the information supplied by the manufacturer, in accordance with Section 23 of Annex I, relating to a device already placed on the market and of further information which is necessary in order to market the device in the relevant Member State; (b) changes to the outer packaging of a device already placed on the market, including a change of pack size, if the repackaging is necessary in order to market the device in the relevant Member State and if it is carried out in such conditions that the original condition of the device cannot be affected by it. In the case of devices placed on the market in sterile condition, it shall be presumed that the original condition of the device is adversely affected if the packaging that is necessary for maintaining the sterile condition is opened, damaged or otherwise negatively affected by the repackaging. 3.   A distributor or importer that carries out any of the activities mentioned in points (a) and (b) of paragraph 2 shall indicate on the device or, where that is impracticable, on its packaging or in a document accompanying the device, the activity carried out together with its name, registered trade name or registered trade mark, registered place of business and the address at which it can be contacted, so that its location can be established. Distributors and importers shall ensure that they have in place a quality management system that includes procedures which ensure that the translation of information is accurate and up-to-date, and that the activities mentioned in points (a) and (b) of paragraph 2 are performed by a means and under conditions that preserve the original condition of the device and that the packaging of the repackaged device is not defective, of poor quality or untidy. The quality management system shall cover, inter alia, procedures ensuring that the distributor or importer is informed of any corrective action taken by the manufacturer in relation to the device in question in order to respond to safety issues or to bring it into conformity with this Regulation. 4.   At least 28 days prior to making the relabelled or repackaged device available on the market, distributors or importers carrying out any of the activities mentioned in points (a) and (b) of paragraph 2 shall inform the manufacturer and the competent authority of the Member State in which they plan to make the device available of the intention to make the relabelled or repackaged device available and, upon request, shall provide the manufacturer and the competent authority with a sample or mock-up of the relabelled or repackaged device, including any translated label and instructions for use. Within the same period of 28 days, the distributor or importer shall submit to the competent authority a certificate, issued by a notified body designated for the type of devices that are subject to activities mentioned in points (a) and (b) of paragraph 2, attesting that the quality management system of the distributer or importer complies with the requirements laid down in paragraph 3. Article 17 Single-use devices and their reprocessing 1.   Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 2.   Any natural or legal person who reprocesses a single-use device to make it suitable for further use within the Union shall be considered to be the manufacturer of the reprocessed device and shall assume the obligations incumbent on manufacturers laid down in this Regulation, which include obligations relating to the traceability of the reprocessed device in accordance with Chapter III of this Regulation. The reprocessor of the device shall be considered to be a producer for the purpose of Article 3(1) of Directive 85/374/EEC. 3.   By way of derogation from paragraph 2, as regards single-use devices that are reprocessed and used within a health institution, Member States may decide not to apply all of the rules relating to manufacturers' obligations laid down in this Regulation provided that they ensure that: (a) the safety and performance of the reprocessed device is equivalent to that of the original device and the requirements in points (a), (b), (d), (e), (f), (g) and (h) of Article 5(5) are complied with; (b) the reprocessing is performed in accordance with CS detailing the requirements concerning: — risk management, including the analysis of the construction and material, related properties of the device (reverse engineering) and procedures to detect changes in the design of the original device as well as of its planned application after reprocessing, — the validation of procedures for the entire process, including cleaning steps, — the product release and performance testing, — the quality management system, — the reporting of incidents involving devices that have been reprocessed, and — the traceability of reprocessed devices. Member States shall encourage, and may require, health institutions to provide information to patients on the use of reprocessed devices within the health institution and, where appropriate, any other relevant information on the reprocessed devices that patients are treated with. Member States shall notify the Commission and the other Member States of the national provisions introduced pursuant to this paragraph and the grounds for introducing them. The Commission shall keep the information publicly available. 4.   Member States may choose to apply the provisions referred to in paragraph 3 also as regards single-use devices that are reprocessed by an external reprocessor at the request of a health institution, provided that the reprocessed device in its entirety is returned to that health institution and the external reprocessor complies with the requirements referred to in points (a) and (b) of paragraph 3. 5.   The Commission shall adopt, in accordance with Article 9(1), the necessary CS referred to in point (b) of paragraph 3 by 26 May 2020. Those CS shall be consistent with the latest scientific evidence and shall address the application of the general requirements on safety and performance laid down in in this Regulation. In the event that those CS are not adopted by 26 May 2020, reprocessing shall be performed in accordance with any relevant harmonised standards and national provisions that cover the aspects outlined in point (b) of paragraph 3. Compliance with CS or, in the absence of CS, with any relevant harmonised standards and national provisions, shall be certified by a notified body. 6.   Only single-use devices that have been placed on the market in accordance with this Regulation, or prior to 26 May 2020 in accordance with Directive 93/42/EEC, may be reprocessed. 7.   Only reprocessing of single-use devices that is considered safe according to the latest scientific evidence may be carried out. 8.   The name and address of the legal or natural person referred to in paragraph 2 and the other relevant information referred to in Section 23 of Annex I shall be indicated on the label and, where applicable, in the instructions for use of the reprocessed device. The name and address of the manufacturer of the original single-use device shall no longer appear on the label, but shall be mentioned in the instructions for use of the reprocessed device. 9.   A Member State that permits reprocessing of single-use devices may maintain or introduce national provisions that are stricter than those laid down in this Regulation and which restrict or prohibit, within its territory, the following: (a) the reprocessing of single-use devices and the transfer of single-use devices to another Member State or to a third country with a view to their reprocessing; (b) the making available or further use of reprocessed single-use devices. Member States shall notify the Commission and the other Member States of those national provisions. The Commission shall make such information publicly available. 10.   The Commission shall by 27 May 2024 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. On the basis of that report, the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 18 Implant card and information to be supplied to the patient with an implanted device 1.   The manufacturer of an implantable device shall provide together with the device the following: (a) information allowing the identification of the device, including the device name, serial number, lot number, the UDI, the device model, as well as the name, address and the website of the manufacturer; (b) any warnings, precautions or measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions; (c) any information about the expected lifetime of the device and any necessary follow-up; (d) any other information to ensure safe use of the device by the patient, including the information in point (u) of Section 23.4 of Annex I. The information referred to in the first subparagraph shall be provided, for the purpose of making it available to the particular patient who has been implanted with the device, by any means that allow rapid access to that information and shall be stated in the language(s) determined by the concerned Member State. The information shall be written in a way that is readily understood by a lay person and shall be updated where appropriate. Updates of the information shall be made available to the patient via the website mentioned in point (a) of the first subparagraph. In addition, the manufacturer shall provide the information referred to in point (a) of the first subparagraph on an implant card delivered with the device. 2.   Member States shall require health institutions to make the information referred to in paragraph 1 available, by any means that allow rapid access to that information, to any patients who have been implanted with the device, together with the implant card, which shall bear their identity. 3.   The following implants shall be exempted from the obligations laid down in this Article: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors. The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend this list by adding other types of implants to it or by removing implants therefrom. Article 19 EU declaration of conformity 1.   The EU declaration of conformity shall state that the requirements specified in this Regulation have been fulfilled in relation to the device that is covered. The manufacturer shall continuously update the EU declaration of conformity. The EU declaration of conformity shall, as a minimum, contain the information set out in Annex IV and shall be translated into an official Union language or languages required by the Member State(s) in which the device is made available. 2.   Where, concerning aspects not covered by this Regulation, devices are subject to other Union legislation which also requires an EU declaration of conformity by the manufacturer that fulfilment of the requirements of that legislation has been demonstrated, a single EU declaration of conformity shall be drawn up in respect of all Union acts applicable to the device. The declaration shall contain all the information required for identification of the Union legislation to which the declaration relates. 3.   By drawing up the EU declaration of conformity, the manufacturer shall assume responsibility for compliance with the requirements of this Regulation and all other Union legislation applicable to the device. 4.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the EU declaration of conformity set out in Annex IV in the light of technical progress. Article 20 CE marking of conformity 1.   Devices, other than custom-made or investigational devices, considered to be in conformity with the requirements of this Regulation shall bear the CE marking of conformity, as presented in Annex V. 2.   The CE marking shall be subject to the general principles set out in Article 30 of Regulation (EC) No 765/2008. 3.   The CE marking shall be affixed visibly, legibly and indelibly to the device or its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE marking shall be affixed to the packaging. The CE marking shall also appear in any instructions for use and on any sales packaging. 4.   The CE marking shall be affixed before the device is placed on the market. It may be followed by a pictogram or any other mark indicating a special risk or use. 5.   Where applicable, the CE marking shall be followed by the identification number of the notified body responsible for the conformity assessment procedures set out in Article 52. The identification number shall also be indicated in any promotional material which mentions that a device fulfils the requirements for CE marking. 6.   Where devices are subject to other Union legislation which also provides for the affixing of the CE marking, the CE marking shall indicate that the devices also fulfil the requirements of that other legislation. Article 21 Devices for special purposes 1.   Member States shall not create obstacles to: (a) investigational devices being supplied to an investigator for the purpose of a clinical investigation if they meet the conditions laid down in Articles 62 to 80 and Article 82, in the implementing acts adopted pursuant to Article 81 and in Annex XV; (b) custom-made devices being made available on the market if Article 52(8) and Annex XIII have been complied with. The devices referred to in the first subparagraph shall not bear the CE marking, with the exception of the devices referred to in Article 74. 2.   Custom-made devices shall be accompanied by the statement referred to in Section 1 of Annex XIII, which shall be made available to the particular patient or user identified by name, an acronym or a numerical code. Member States may require that the manufacturer of a custom-made device submit to the competent authority a list of such devices which have been made available in their territory. 3.   At trade fairs, exhibitions, demonstrations or similar events, Member States shall not create obstacles to the showing of devices which do not comply with this Regulation, provided a visible sign clearly indicates that such devices are intended for presentation or demonstration purposes only and cannot be made available until they have been brought into compliance with this Regulation. Article 22 Systems and procedure packs 1.   Natural or legal persons shall draw up a statement if they combine devices bearing a CE marking with the following other devices or products, in a manner that is compatible with the intended purpose of the devices or other products and within the limits of use specified by their manufacturers, in order to place them on the market as a system or procedure pack: (a) other devices bearing the CE marking; (b) in vitro diagnostic medical devices bearing the CE marking in conformity with Regulation (EU) 2017/746; (c) other products which are in conformity with legislation that applies to those products only where they are used within a medical procedure or their presence in the system or procedure pack is otherwise justified. 2.   In the statement made pursuant to paragraph 1, the natural or legal person concerned shall declare that: (a) they verified the mutual compatibility of the devices and, if applicable other products, in accordance with the manufacturers' instructions and have carried out their activities in accordance with those instructions; (b) they packaged the system or procedure pack and supplied relevant information to users incorporating the information to be supplied by the manufacturers of the devices or other products which have been put together; (c) the activity of combining devices and, if applicable, other products as a system or procedure pack was subject to appropriate methods of internal monitoring, verification and validation. 3.   Any natural or legal person who sterilises systems or procedure packs referred to in paragraph 1 for the purpose of placing them on the market shall, at their choice, apply one of the procedures set out in Annex IX or the procedure set out in Part A of Annex XI. The application of those procedures and the involvement of the notified body shall be limited to the aspects of the procedure relating to ensuring sterility until the sterile packaging is opened or damaged. The natural or legal person shall draw up a statement declaring that sterilisation has been carried out in accordance with the manufacturer's instructions. 4.   Where the system or procedure pack incorporates devices which do not bear the CE marking or where the chosen combination of devices is not compatible in view of their original intended purpose, or where the sterilisation has not been carried out in accordance with the manufacturer's instructions, the system or procedure pack shall be treated as a device in its own right and shall be subject to the relevant conformity assessment procedure pursuant to Article 52. The natural or legal person shall assume the obligations incumbent on manufacturers. 5.   The systems or procedure packs referred to in paragraph 1 of this Article shall not themselves bear an additional CE marking but they shall bear the name, registered trade name or registered trade mark of the person referred to in paragraphs 1 and 3 of this Article as well as the address at which that person can be contacted, so that the person's location can be established. Systems or procedure packs shall be accompanied by the information referred to in Section 23 of Annex I. The statement referred to in paragraph 2 of this Article shall be kept at the disposal of the competent authorities, after the system or procedure pack has been put together, for the period that is applicable under Article 10(8) to the devices that have been combined. Where those periods differ, the longest period shall apply. Article 23 Parts and components 1.   Any natural or legal person who makes available on the market an item specifically intended to replace an identical or similar integral part or component of a device that is defective or worn in order to maintain or restore the function of the device without changing its performance or safety characteristics or its intended purpose, shall ensure that the item does not adversely affect the safety and performance of the device. Supporting evidence shall be kept available for the competent authorities of the Member States. 2.   An item that is intended specifically to replace a part or component of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation. Article 24 Free movement Except where otherwise provided for in this Regulation, Member States shall not refuse, prohibit or restrict the making available on the market or putting into service within their territory of devices which comply with the requirements of this Regulation. CHAPTER III IDENTIFICATION AND TRACEABILITY OF DEVICES, REGISTRATION OF DEVICES AND OF ECONOMIC OPERATORS, SUMMARY OF SAFETY AND CLINICAL PERFORMANCE, EUROPEAN DATABASE ON MEDICAL DEVICES Article 25 Identification within the supply chain 1.   Distributors and importers shall co-operate with manufacturers or authorised representatives to achieve an appropriate level of traceability of devices. 2.   Economic operators shall be able to identify the following to the competent authority, for the period referred to in Article 10(8): (a) any economic operator to whom they have directly supplied a device; (b) any economic operator who has directly supplied them with a device; (c) any health institution or healthcare professional to which they have directly supplied a device. Article 26 Medical devices nomenclature To facilitate the functioning of the European database on medical devices (‘Eudamed’) as referred to in Article 33, the Commission shall ensure that an internationally recognised medical devices nomenclature is available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. The Commission shall also endeavour to ensure that that nomenclature is available to other stakeholders free of charge, where reasonably practicable. Article 27 Unique Device Identification system 1.   The Unique Device Identification system (‘UDI system’) described in Part C of Annex VI shall allow the identification and facilitate the traceability of devices, other than custom-made and investigational devices, and shall consist of the following: (a) production of a UDI that comprises the following: (i) a UDI device identifier (‘UDI-DI’) specific to a manufacturer and a device, providing access to the information laid down in Part B of Annex VI; (ii) a UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI; (b) placing of the UDI on the label of the device or on its packaging; (c) storage of the UDI by economic operators, health institutions and healthcare professionals, in accordance with the conditions laid down in paragraphs 8 and 9 of this Article respectively; (d) establishment of an electronic system for Unique Device Identification (‘UDI database’) in accordance with Article 28. 2.   The Commission shall, by means of implementing acts, designate one or several entities to operate a system for assignment of UDIs pursuant to this Regulation (‘issuing entity’). That entity or those entities shall satisfy all of the following criteria: (a) the entity is an organisation with legal personality; (b) its system for the assignment of UDIs is adequate to identify a device throughout its distribution and use in accordance with the requirements of this Regulation; (c) its system for the assignment of UDIs conforms to the relevant international standards; (d) the entity gives access to its system for the assignment of UDIs to all interested users in accordance with a set of predetermined and transparent terms and conditions; (e) the entity undertakes to do the following: (i) operate its system for the assignment of UDIs for at least 10 years after its designation; (ii) make available to the Commission and to the Member States, upon request, information concerning its system for the assignment of UDIs; (iii) remain in compliance with the criteria for designation and the terms of designation. When designating issuing entities, the Commission shall endeavour to ensure that UDI carriers, as defined in Part C of Annex VI, are universally readable regardless of the system used by the issuing entity, with a view to minimising financial and administrative burdens for economic operators and health institutions. 3.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall assign to the device and, if applicable, to all higher levels of packaging, a UDI created in compliance with the rules of the issuing entity designated by the Commission in accordance with paragraph 2. Before a device, other than a custom-made or investigational device, is placed on the market the manufacturer shall ensure that the information referred to in Part B of Annex VI of the device in question are correctly submitted and transferred to the UDI database referred to in Article 28. 4.   UDI carriers shall be placed on the label of the device and on all higher levels of packaging. Higher levels of packaging shall not be understood to include shipping containers. 5.   The UDI shall be used for reporting serious incidents and field safety corrective actions in accordance with Article 87. 6.   The Basic UDI-DI, as defined in Part C of Annex VI, of the device shall appear on the EU declaration of conformity referred to in Article 19. 7.   As part of the technical documentation referred to in Annex II, the manufacturer shall keep up-to-date a list of all UDIs that it has assigned. 8.   Economic operators shall store and keep, preferably by electronic means, the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to: — class III implantable devices; — the devices, categories or groups of devices determined by a measure referred to in point (a) of paragraph 11. 9.   Health institutions shall store and keep preferably by electronic means the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to class III implantable devices. For devices other than class III implantable devices, Member States shall encourage, and may require, health institutions to store and keep, preferably by electronic means, the UDI of the devices with which they have been supplied. Member States shall encourage, and may require, healthcare professionals to store and keep preferably by electronic means, the UDI of the devices with which they have been supplied with. 10.   The Commission is empowered to adopt delegated acts in accordance with Article 115: (a) amending the list of information set out in Part B of Annex VI in the light of technical progress; and (b) amending Annex VI in the light of international developments and technical progress in the field of Unique Device Identification. 11.   The Commission may, by means of implementing acts, specify the detailed arrangements and the procedural aspects for the UDI system with a view to ensuring its harmonised application in relation to any of the following: (a) determining the devices, categories or groups of devices to which the obligation laid down in paragraph 8 is to apply; (b) specifying the data to be included in the UDI-PI of specific devices or device groups; The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). 12.   When adopting the measures referred to in paragraph 11, the Commission shall take into account all of the following: (a) confidentiality and data protection as referred to in Articles 109 and 110 respectively; (b) the risk-based approach; (c) the cost-effectiveness of the measures; (d) the convergence of UDI systems developed at international level; (e) the need to avoid duplications in the UDI system; (f) the needs of the healthcare systems of the Member States, and where possible, compatibility with other medical device identification systems that are used by stakeholders. Article 28 UDI database 1.   The Commission, after consulting the MDCG shall set up and manage a UDI database to validate, collate, process and make available to the public the information mentioned in Part B of Annex VI. 2.   When designing the UDI database, the Commission shall take into account the general principles set out in Section 5 of Part C of Annex VI. The UDI database shall be designed in particular such that no UDI-PIs and no commercially confidential product information can be included therein. 3.   The core data elements to be provided to the UDI database, referred to in Part B of Annex VI, shall be accessible to the public free of charge. 4.   The technical design of the UDI database shall ensure maximum accessibility to information stored therein, including multi-user access and automatic uploads and downloads of that information. The Commission shall provide for technical and administrative support to manufacturers and other users of the UDI database. Article 29 Registration of devices 1.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall, in accordance with the rules of the issuing entity referred to in Article 27(2), assign a Basic UDI-DI as defined in Part C of Annex VI to the device and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 2.   Before placing on the market a system or procedure pack pursuant to Article 22(1) and (3), that is not a custom-made device, the natural or legal person responsible shall assign to the system or procedure pack, in compliance with the rules of the issuing entity, a Basic UDI-DI and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that system or procedure pack. 3.   For devices that are the subject of a conformity assessment as referred to in Article 52(3) and in the second and third subparagraphs of Article 52(4), the assignment of a Basic UDI-DI referred to in paragraph 1 of this Article shall be done before the manufacturer applies to a notified body for that assessment. For the devices referred to in the first subparagraph, the notified body shall include a reference to the Basic UDI-DI on the certificate issued in accordance with point (a) of Section 4 of Chapter I of Annex XII and confirm in Eudamed that the information referred to in Section 2.2 of Part A of Annex VI is correct. After the issuing of the relevant certificate and before placing the device on the market, the manufacturer shall provide the Basic UDI-DI to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 4.   Before placing a device on the market, other than a custom-made device, the manufacturer shall enter or if, already provided, verify in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and shall thereafter keep the information updated. Article 30 Electronic system for registration of economic operators 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to create the single registration number referred to in Article 31(2) and to collate and process information that is necessary and proportionate to identify the manufacturer and, where applicable, the authorised representative and the importer. The details regarding the information to be provided to that electronic system by the economic operators are laid down in Section 1 of Part A of Annex VI. 2.   Member States may maintain or introduce national provisions on registration of distributors of devices which have been made available on their territory. 3.   Within two weeks of placing a device, other than a custom-made device, on the market, importers shall verify that the manufacturer or authorised representative has provided to the electronic system the information referred to in paragraph 1. Where applicable, importers shall inform the relevant authorised representative or manufacturer if the information referred to in paragraph 1 is not included or is incorrect. Importers shall add their details to the relevant entry/entries. Article 31 Registration of manufacturers, authorised representatives and importers 1.   Before placing a device, other than a custom-made device, on the market, manufacturers, authorised representatives and importers shall, in order to register, submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already registered in accordance with this Article. In cases where the conformity assessment procedure requires the involvement of a notified body pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI shall be provided to that electronic system before applying to the notified body. 2.   After having verified the data entered pursuant to paragraph 1, the competent authority shall obtain a single registration number (‘SRN’) from the electronic system referred to in Article 30 and issue it to the manufacturer, the authorised representative or the importer. 3.   The manufacturer shall use the SRN when applying to a notified body for conformity assessment and for accessing Eudamed in order to fulfil its obligations under Article 29. 4.   Within one week of any change occurring in relation to the information referred to in paragraph 1 of this Article, the economic operator shall update the data in the electronic system referred to in Article 30. 5.   Not later than one year after submission of the information in accordance with paragraph 1, and every second year thereafter, the economic operator shall confirm the accuracy of the data. In the event of a failure to do so within six months of those deadlines, any Member State may take appropriate corrective measures within its territory until that economic operator complies with that obligation. 6.   Without prejudice to the economic operator's responsibility for the data, the competent authority shall verify the confirmed data referred to in Section 1 of Part A of Annex VI. 7.   The data entered pursuant to paragraph 1 of this Article in the electronic system referred to in Article 30 shall be accessible to the public. 8.   The competent authority may use the data to charge the manufacturer, the authorised representative or the importer a fee pursuant to Article 111. Article 32 Summary of safety and clinical performance 1.   For implantable devices and for class III devices, other than custom-made or investigational devices, the manufacturer shall draw up a summary of safety and clinical performance. The summary of safety and clinical performance shall be written in a way that is clear to the intended user and, if relevant, to the patient and shall be made available to the public via Eudamed. The draft of the summary of safety and clinical performance shall be part of the documentation to be submitted to the notified body involved in the conformity assessment pursuant to Article 52 and shall be validated by that body. After its validation, the notified body shall upload the summary to Eudamed. The manufacturer shall mention on the label or instructions for use where the summary is available. 2.   The summary of safety and clinical performance shall include at least the following aspects: (a) the identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN; (b) the intended purpose of the device and any indications, contraindications and target populations; (c) a description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intended to be used in combination with the device; (d) possible diagnostic or therapeutic alternatives; (e) reference to any harmonised standards and CS applied; (f) the summary of clinical evaluation as referred to in Annex XIV, and relevant information on post-market clinical follow-up; (g) suggested profile and training for users; (h) information on any residual risks and any undesirable effects, warnings and precautions. 3.   The Commission may, by means of implementing acts, set out the form and the presentation of the data elements to be included in the summary of safety and clinical performance. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). Article 33 European database on medical devices 1.   The Commission, after consulting the MDCG, shall set up, maintain and manage the European database on medical devices (‘Eudamed’) for the following purposes: (a) to enable the public to be adequately informed about devices placed on the market, the corresponding certificates issued by notified bodies and about the relevant economic operators; (b) to enable unique identification of devices within the internal market and to facilitate their traceability; (c) to enable the public to be adequately informed about clinical investigations and to enable sponsors of clinical investigations to comply with obligations under Articles 62 to 80, Article 82, and any acts adopted pursuant to Article 81; (d) to enable manufacturers to comply with the information obligations laid down in Articles 87 to 90 or in any acts adopted pursuant to Article 91; (e) to enable the competent authorities of the Member States and the Commission to carry out their tasks relating to this Regulation on a well-informed basis and to enhance the cooperation between them. 2.   Eudamed shall include the following electronic systems: (a) the electronic system for registration of devices referred to in Article 29(4); (b) the UDI-database referred to in Article 28; (c) the electronic system on registration of economic operators referred to in Article 30; (d) the electronic system on notified bodies and on certificates referred to in Article 57; (e) the electronic system on clinical investigations referred to in Article 73; (f) the electronic system on vigilance and post-market surveillance referred to in Article 92; (g) the electronic system on market surveillance referred to in Article 100. 3.   When designing Eudamed the Commission shall give due consideration to compatibility with national databases and national web-interfaces to allow for import and export of data. 4.   The data shall be entered into Eudamed by the Member States, notified bodies, economic operators and sponsors as specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall provide for technical and administrative support to users of Eudamed. 5.   All the information collated and processed by Eudamed shall be accessible to the Member States and to the Commission. The information shall be accessible to notified bodies, economic operators, sponsors and the public to the extent specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall ensure that public parts of Eudamed are presented in a user-friendly and easily-searchable format. 6.   Eudamed shall contain personal data only insofar as necessary for the electronic systems referred to in paragraph 2 of this Article to collate and process information in accordance with this Regulation. Personal data shall be kept in a form which permits identification of data subjects for periods no longer than those referred to in Article 10(8). 7.   The Commission and the Member States shall ensure that data subjects may effectively exercise their rights to information, of access, to rectification and to object in accordance with Regulation (EC) No 45/2001 and Directive 95/46/EC, respectively. They shall also ensure that data subjects may effectively exercise the right of access to data relating to them, and the right to have inaccurate or incomplete data corrected and erased. Within their respective responsibilities, the Commission and the Member States shall ensure that inaccurate and unlawfully processed data are deleted, in accordance with the applicable legislation. Corrections and deletions shall be carried out as soon as possible, but no later than 60 days after a request is made by a data subject. 8.   The Commission shall, by means of implementing acts, lay down the detailed arrangements necessary for the setting up and maintenance of Eudamed. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). When adopting those implementing acts, the Commission shall ensure that, as far as possible, the system is developed in such a way as to avoid having to enter the same information twice within the same module or in different modules of the system. 9.   In relation to its responsibilities under this Article and the processing of personal data involved therein, the Commission shall be considered to be the controller of Eudamed and its electronic systems. Article 34 Functionality of Eudamed 1.   The Commission shall, in collaboration with the MDCG, draw up the functional specifications for Eudamed. The Commission shall draw up a plan for the implementation of those specifications by 26 May 2018. That plan shall seek to ensure that Eudamed is fully functional at a date that allows the Commission to publish the notice referred to in paragraph 3 of this Article by 25 March 2020 and that all other relevant deadlines laid down in Article 123 of this Regulation and in Article 113 of Regulation (EU) 2017/746 are met. 2.   The Commission shall, on the basis of an independent audit report, inform the MDCG when it has verified that Eudamed has achieved full functionality and Eudamed meets the functional specifications drawn up pursuant to paragraph 1. 3.   The Commission shall, after consultation with the MDCG and when it is satisfied that the conditions referred to in paragraph 2 have been fulfilled, publish a notice to that effect in the Official Journal of the European Union. CHAPTER IV NOTIFIED BODIES Article 35 Authorities responsible for notified bodies 1.   Any Member State that intends to designate a conformity assessment body as a notified body, or has designated a notified body, to carry out conformity assessment activities under this Regulation shall appoint an authority (‘authority responsible for notified bodies’), which may consist of separate constituent entities under national law and shall be responsible for setting up and carrying out the necessary procedures for the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, including subcontractors and subsidiaries of those bodies. 2.   The authority responsible for notified bodies shall be established, organised and operated so as to safeguard the objectivity and impartiality of its activities and to avoid any conflicts of interests with conformity assessment bodies. 3.   The authority responsible for notified bodies shall be organised in a manner such that each decision relating to designation or notification is taken by personnel different from those who carried out the assessment. 4.   The authority responsible for notified bodies shall not perform any activities that notified bodies perform on a commercial or competitive basis. 5.   The authority responsible for notified bodies shall safeguard the confidential aspects of the information it obtains. However, it shall exchange information on notified bodies with other Member States, the Commission and, when required, with other regulatory authorities. 6.   The authority responsible for notified bodies shall have a sufficient number of competent personnel permanently available for the proper performance of its tasks. Where the authority responsible for notified bodies is a different authority from the national competent authority for medical devices, it shall ensure that the national authority responsible for medical devices is consulted on relevant matters. 7.   Member States shall make publicly available general information on their measures governing the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, and on changes which have a significant impact on such tasks. 8.   The authority responsible for notified bodies shall participate in the peer-review activities provided for in Article 48. Article 36 Requirements relating to notified bodies 1.   Notified bodies shall fulfil the tasks for which they are designated in accordance with this Regulation. They shall satisfy the organisational and general requirements and the quality management, resource and process requirements that are necessary to fulfil those tasks. In particular, notified bodies shall comply with Annex VII. In order to meet the requirements referred to in the first subparagraph, notified bodies shall have permanent availability of sufficient administrative, technical and scientific personnel in accordance with Section 3.1.1 of Annex VII and personnel with relevant clinical expertise in accordance with Section 3.2.4 of Annex VII, where possible employed by the notified body itself. The personnel referred to in Sections 3.2.3 and 3.2.7 of Annex VII shall be employed by the notified body itself and shall not be external experts or subcontractors. 2.   Notified bodies shall make available and submit upon request all relevant documentation, including the manufacturer's documentation, to the authority responsible for notified bodies to allow it to conduct its assessment, designation, notification, monitoring and surveillance activities and to facilitate the assessment outlined in this Chapter. 3.   In order to ensure the uniform application of the requirements set out in Annex VII, the Commission may adopt implementing acts, to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 37 Subsidiaries and subcontracting 1.   Where a notified body subcontracts specific tasks connected with conformity assessment or has recourse to a subsidiary for specific tasks connected with conformity assessment, it shall verify that the subcontractor or the subsidiary meets the applicable requirements set out in Annex VII and shall inform the authority responsible for notified bodies accordingly. 2.   Notified bodies shall take full responsibility for the tasks performed on their behalf by subcontractors or subsidiaries. 3.   Notified bodies shall make publicly available a list of their subsidiaries. 4.   Conformity assessment activities may be subcontracted or carried out by a subsidiary provided that the legal or natural person that applied for conformity assessment has been informed accordingly. 5.   Notified bodies shall keep at the disposal of the authority responsible for notified bodies all relevant documents concerning the verification of the qualifications of the subcontractor or the subsidiary and the work carried out by them under this Regulation. Article 38 Application by conformity assessment bodies for designation 1.   Conformity assessment bodies shall submit an application for designation to the authority responsible for notified bodies. 2.   The application shall specify the conformity assessment activities as defined in this Regulation, and the types of devices for which the body is applying to be designated, and shall be supported by documentation demonstrating compliance with Annex VII. In respect of the organisational and general requirements and the quality management requirements set out in Sections 1 and 2 of Annex VII, a valid accreditation certificate and the corresponding evaluation report delivered by a national accreditation body in accordance with Regulation (EC) No 765/2008 may be submitted and shall be taken into consideration during the assessment described in Article 39. However, the applicant shall make available all the documentation referred to in the first subparagraph to demonstrate compliance with those requirements upon request. 3.   The notified body shall update the documentation referred to in paragraph 2 whenever relevant changes occur, in order to enable the authority responsible for notified bodies to monitor and verify continuous compliance with all the requirements set out in Annex VII. Article 39 Assessment of the application 1.   The authority responsible for notified bodies shall within 30 days check that the application referred to in Article 38 is complete and shall request the applicant to provide any missing information. Once the application is complete that authority shall send it to the Commission. The authority responsible for notified bodies shall review the application and supporting documentation in accordance with its own procedures and shall draw up a preliminary assessment report. 2.   The authority responsible for notified bodies shall submit the preliminary assessment report to the Commission which shall immediately transmit it to the MDCG. 3.   Within 14 days of the submission referred to in paragraph 2 of this Article, the Commission, in conjunction with the MDCG, shall appoint a joint assessment team made up of three experts, unless the specific circumstances require a different number of experts, chosen from the list referred to in Article 40(2). One of the experts shall be a representative of the Commission who shall coordinate the activities of the joint assessment team. The other two experts shall come from Member States other than the one in which the applicant conformity assessment body is established. The joint assessment team shall be comprised of experts who are competent to assess the conformity assessment activities and the types of devices which are the subject of the application or, in particular when the assessment procedure is initiated in accordance with Article 47(3), to ensure that the specific concern can be appropriately assessed. 4.   Within 90 days of its appointment, the joint assessment team shall review the documentation submitted with the application in accordance with Article 38. The joint assessment team may provide feedback to, or require clarification from, the authority responsible for notified bodies on the application and on the planned on-site assessment. The authority responsible for notified bodies together with the joint assessment team shall plan and conduct an on-site assessment of the applicant conformity assessment body and, where relevant, of any subsidiary or subcontractor, located inside or outside the Union, to be involved in the conformity assessment process. The on-site assessment of the applicant body shall be led by the authority responsible for notified bodies. 5.   Findings regarding non-compliance of an applicant conformity assessment body with the requirements set out in Annex VII shall be raised during the assessment process and discussed between the authority responsible for notified bodies and the joint assessment team with a view to reaching consensus and resolving any diverging opinions, with respect to the assessment of the application. At the end of the on-site assessment, the authority responsible for notified bodies shall list for the applicant conformity assessment body the non-compliances resulting from the assessment and summarise the assessment by the joint assessment team. Within a specified timeframe, the applicant conformity assessment body shall submit to the national authority a corrective and preventive action plan to address the non-compliances. 6.   The joint assessment team shall document any remaining diverging opinions with respect to the assessment within 30 days of completion of the on-site assessment and send them to the authority responsible for notified bodies. 7.   The authority responsible for notified bodies shall following receipt of a corrective and preventive action plan from the applicant body assess whether non-compliances identified during the assessment have been appropriately addressed. This plan shall indicate the root cause of the identified non-compliances and shall include a timeframe for implementation of the actions therein. The authority responsible for notified bodies shall having confirmed the corrective and preventive action plan forward it and its opinion thereon to the joint assessment team. The joint assessment team may request of the authority responsible for notified bodies further clarification and modifications. The authority responsible for notified bodies shall draw up its final assessment report which shall include: — the result of the assessment, — confirmation that the corrective and preventive actions have been appropriately addressed and, where required, implemented, — any remaining diverging opinion with the joint assessment team, and, where applicable, — the recommended scope of designation. 8.   The authority responsible for notified bodies shall submit its final assessment report and, if applicable, the draft designation to the Commission, the MDCG and the joint assessment team. 9.   The joint assessment team shall provide a final opinion regarding the assessment report prepared by the authority responsible for notified bodies and, if applicable, the draft designation within 21 days of receipt of those documents to the Commission, which shall immediately submit that final opinion to the MDCG. Within 42 days of receipt of the opinion of the joint assessment team, the MDCG shall issue a recommendation with regard to the draft designation, which the authority responsible for notified bodies shall duly take into consideration for its decision on the designation of the notified body. 10.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements specifying procedures and reports for the application for designation referred to in Article 38 and the assessment of the application set out in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 40 Nomination of experts for joint assessment of applications for notification 1.   The Member States and the Commission shall nominate experts qualified in the assessment of conformity assessment bodies in the field of medical devices to participate in the activities referred to in Articles 39 and 48. 2.   The Commission shall maintain a list of the experts nominated pursuant to paragraph 1 of this Article, together with information on their specific field of competence and expertise. That list shall be made available to Member States competent authorities through the electronic system referred to in Article 57. Article 41 Language requirements All documents required pursuant to Articles 38 and 39 shall be drawn up in a language or languages which shall be determined by the Member State concerned. Member States, in applying the first paragraph, shall consider accepting and using a commonly understood language in the medical field, for all or part of the documentation concerned. The Commission shall provide translations of the documentation pursuant to Articles 38 and 39, or parts thereof into an official Union language, such as is necessary for that documentation to be readily understood by the joint assessment team appointed in accordance with Article 39(3). Article 42 Designation and notification procedure 1.   Member States may only designate conformity assessment bodies for which the assessment pursuant to Article 39 was completed and which comply with Annex VII. 2.   Member States shall notify the Commission and the other Member States of the conformity assessment bodies they have designated, using the electronic notification tool within the database of notified bodies developed and managed by the Commission (NANDO). 3.   The notification shall clearly specify, using the codes referred to in paragraph 13 of this Article, the scope of the designation indicating the conformity assessment activities as defined in this Regulation and the types of devices which the notified body is authorised to assess and, without prejudice to Article 44, any conditions associated with the designation. 4.   The notification shall be accompanied by the final assessment report of the authority responsible for notified bodies, the final opinion of the joint assessment team referred to in Article 39(9) and the recommendation of the MDCG. Where the notifying Member State does not follow the recommendation of the MDCG, it shall provide a duly substantiated justification. 5.   The notifying Member State shall, without prejudice to Article 44, inform the Commission and the other Member States of any conditions associated with the designation and provide documentary evidence regarding the arrangements in place to ensure that the notified body will be monitored regularly and will continue to satisfy the requirements set out in Annex VII. 6.   Within 28 days of the notification referred to in paragraph 2, a Member State or the Commission may raise written objections, setting out its arguments, with regard either to the notified body or to its monitoring by the authority responsible for notified bodies. Where no objection is raised, the Commission shall publish in NANDO the notification within 42 days of its having been notified as referred to in paragraph 2. 7.   When a Member State or the Commission raises objections in accordance with paragraph 6, the Commission shall bring the matter before the MDCG within 10 days of the expiry of the period referred to in paragraph 6. After consulting the parties involved, the MDCG shall give its opinion at the latest within 40 days of the matter having been brought before it. Where the MDCG is of the opinion that the notification can be accepted, the Commission shall publish in NANDO the notification within 14 days. 8.   Where the MDCG, after having been consulted in accordance with paragraph 7, confirms the existing objection or raises another objection, the notifying Member State shall provide a written response to the MDCG opinion within 40 days of its receipt. The response shall address the objections raised in the opinion, and set out the reasons for the notifying Member State's decision to designate or not designate the conformity assessment body. 9.   Where the notifying Member State decides to uphold its decision to designate the conformity assessment body, having given its reasons in accordance with paragraph 8, the Commission shall publish in NANDO the notification within 14 days of being informed thereof. 10.   When publishing the notification in NANDO, the Commission shall also add to the electronic system referred to in Article 57 the information relating to the notification of the notified body along with the documents mentioned in paragraph 4 of this Article and the opinion and responses referred to in paragraphs 7 and 8 of this Article. 11.   The designation shall become valid the day after the notification is published in NANDO. The published notification shall state the scope of lawful conformity assessment activity of the notified body. 12.   The conformity assessment body concerned may perform the activities of a notified body only after the designation has become valid in accordance with paragraph 11. 13.   The Commission shall by 26 November 2017, by means of implementing acts, draw up a list of codes and corresponding types of devices for the purpose of specifying the scope of the designation of notified bodies. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). The Commission, after consulting the MDCG, may update this list based, inter alia, on information arising from the coordination activities described in Article 48. Article 43 Identification number and list of notified bodies 1.   The Commission shall assign an identification number to each notified body for which the notification becomes valid in accordance with Article 42(11). It shall assign a single identification number even when the body is notified under several Union acts. If they are successfully designated in accordance with this Regulation, bodies notified pursuant to Directives 90/385/EEC and 93/42/EEC shall retain the identification number assigned to them pursuant to those Directives. 2.   The Commission shall make the list of the bodies notified under this Regulation, including the identification numbers that have been assigned to them and the conformity assessment activities as defined in this Regulation and the types of devices for which they have been notified, accessible to the public in NANDO. It shall also make this list available on the electronic system referred to in Article 57. The Commission shall ensure that the list is kept up to date. Article 44 Monitoring and re-assessment of notified bodies 1.   Notified bodies shall, without delay, and at the latest within 15 days, inform the authority responsible for notified bodies of relevant changes which may affect their compliance with the requirements set out in Annex VII or their ability to conduct the conformity assessment activities relating to the devices for which they have been designated. 2.   The authorities responsible for notified bodies shall monitor the notified bodies established on their territory and their subsidiaries and subcontractors to ensure ongoing compliance with the requirements and the fulfilment of its obligations set out in this Regulation. Notified bodies shall, upon request by their authority responsible for notified bodies, supply all relevant information and documents, required to enable the authority, the Commission and other Member States to verify compliance. 3.   Where the Commission or the authority of a Member State submits a request to a notified body established on the territory of another Member State relating to a conformity assessment carried out by that notified body, it shall send a copy of that request to the authority responsible for notified bodies of that other Member State. The notified body concerned shall respond without delay and within 15 days at the latest to the request. The authority responsible for notified bodies of the Member State in which the body is established shall ensure that requests submitted by authorities of any other Member State or by the Commission are resolved by the notified body unless there is a legitimate reason for not doing so in which case the matter may be referred to the MDCG. 4.   At least once a year, the authorities responsible for notified bodies shall re-assess whether the notified bodies established on their respective territory and, where appropriate, the subsidiaries and subcontractors under the responsibility of those notified bodies still satisfy the requirements and fulfil their obligations set out in Annex VII. That review shall include an on-site audit of each notified body and, where necessary, of its subsidiaries and subcontractors. The authority responsible for notified bodies shall conduct its monitoring and assessment activities according to an annual assessment plan to ensure that it can effectively monitor the continued compliance of the notified body with the requirements of this Regulation. That plan shall provide a reasoned schedule for the frequency of assessment of the notified body and, in particular, associated subsidiaries and subcontractors. The authority shall submit its annual plan for monitoring or assessment for each notified body for which it is responsible to the MDCG and to the Commission. 5.   The monitoring of notified bodies by the authority responsible for notified bodies shall include observed audits of notified body personnel, including where necessary any personnel from subsidiaries and subcontractors, as that personnel is in the process of conducting quality management system assessments at a manufacturer's facility. 6.   The monitoring of notified bodies conducted by the authority responsible for notified bodies shall consider data arising from market surveillance, vigilance and post-market surveillance to help guide its activities. The authority responsible for notified bodies shall provide for a systematic follow-up of complaints and other information, including from other Member States, which may indicate non-fulfilment of the obligations by a notified body or its deviation from common or best practice. 7.   The authority responsible for notified bodies may in addition to regular monitoring or on-site assessments conduct short-notice, unannounced or ‘for-cause’ reviews if needed to address a particular issue or to verify compliance. 8.   The authority responsible for notified bodies shall review the assessments by notified bodies of manufacturers' technical documentation, in particular the clinical evaluation documentation as further outlined in Article 45. 9.   The authority responsible for notified bodies shall document and record any findings regarding non-compliance of the notified body with the requirements set out in Annex VII and shall monitor the timely implementation of corrective and preventive actions. 10.   Three years after notification of a notified body, and again every fourth year thereafter, a complete re-assessment to determine whether the notified body still satisfies the requirements set out in Annex VII shall be conducted by the authority responsible for notified bodies of the Member State in which the body is established and by a joint assessment team appointed for the purpose of the procedure described in Articles 38 and 39. 11.   The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend paragraph 10 to modify the frequency at which the complete re-assessment referred to in that paragraph is to be carried out. 12.   The Member States shall report to the Commission and to the MDCG, at least once a year, on their monitoring and on-site assessment activities regarding notified bodies and, where applicable, subsidiaries and subcontractors. The report shall provide details of the outcome of those activities, including activities pursuant to paragraph 7, and shall be treated as confidential by the MDCG and the Commission; however it shall contain a summary which shall be made publicly available. The summary of the report shall be uploaded to the electronic system referred to in Article 57. Article 45 Review of notified body assessment of technical documentation and clinical evaluation documentation 1.   The authority responsible for notified bodies, as part of its ongoing monitoring of notified bodies, shall review an appropriate number of notified body assessments of manufacturers' technical documentation, in particular the clinical evaluation documentation as referred to in points (c) and (d) of Section 6.1 of Annex II to verify the conclusions drawn by the notified body based on the information presented by the manufacturer. The reviews by the authority responsible for notified bodies shall be conducted both off-site and on-site. 2.   The sampling of files to be reviewed in accordance with paragraph 1 shall be planned and representative of the types and risk of devices certified by the notified body, in particular high-risk devices, and be appropriately justified and documented in a sampling plan, which shall be made available by the authority responsible for notified bodies to the MDCG upon request. 3.   The authority responsible for notified bodies shall review whether the assessment by the notified body was conducted appropriately and shall check the procedures used, associated documentation and the conclusions drawn by the notified body. Such checking shall include the technical documentation and clinical evaluation documentation of the manufacturer upon which the notified body has based its assessment. Such reviews shall be conducted utilising CS. 4.   Those reviews shall also form part of the re-assessment of notified bodies in accordance with Article 44(10) and the joint assessment activities referred to in Article 47(3). The reviews shall be conducted utilising appropriate expertise. 5.   Based on the reports of the reviews and assessments by the authority responsible for notified bodies or joint assessment teams, on input from the market surveillance, vigilance and post-market surveillance activities described in Chapter VII, on the continuous monitoring of technical progress, or on the identification of concerns and emerging issues concerning the safety and performance of devices, the MDCG may recommend that the sampling, carried out under this Article, cover a greater or lesser proportion of the technical documentation and clinical evaluation documentation assessed by a notified body. 6.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements, associated documents for, and coordination of, the review of assessments of technical documentation and clinical evaluation documentation, as referred to in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 46 Changes to designations and notifications 1.   The authority responsible for notified bodies shall notify the Commission and the other Member States of any relevant changes to the designation of a notified body. The procedures described in Article 39 and in Article 42 shall apply to extensions of the scope of the designation. For changes to the designation other than extensions of its scope, the procedures laid down in the following paragraphs shall apply. 2.   The Commission shall immediately publish the amended notification in NANDO. The Commission shall immediately enter information on the changes to the designation of the notified body in the electronic system referred to in Article 57. 3.   Where a notified body decides to cease its conformity assessment activities it shall inform the authority responsible for notified bodies and the manufacturers concerned as soon as possible and in the case of a planned cessation one year before ceasing its activities. The certificates may remain valid for a temporary period of nine months after cessation of the notified body's activities on condition that another notified body has confirmed in writing that it will assume responsibilities for the devices covered by those certificates. The new notified body shall complete a full assessment of the devices affected by the end of that period before issuing new certificates for those devices. Where the notified body has ceased its activity, the authority responsible for notified bodies shall withdraw the designation. 4.   Where a authority responsible for notified bodies has ascertained that a notified body no longer meets the requirements set out in Annex VII, or that it is failing to fulfil its obligations or has not implemented the necessary corrective measures, the authority shall suspend, restrict, or fully or partially withdraw the designation, depending on the seriousness of the failure to meet those requirements or fulfil those obligations. A suspension shall not exceed a period of one year, renewable once for the same period. The authority responsible for notified bodies shall immediately inform the Commission and the other Member States of any suspension, restriction or withdrawal of a designation. 5.   Where its designation has been suspended, restricted, or fully or partially withdrawn, the notified body shall inform the manufacturers concerned at the latest within 10 days. 6.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall take appropriate steps to ensure that the files of the notified body concerned are kept and make them available to authorities in other Member States responsible for notified bodies and to authorities responsible for market surveillance at their request. 7.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall: (a) assess the impact on the certificates issued by the notified body; (b) submit a report on its findings to the Commission and the other Member States within three months of having notified the changes to the designation; (c) require the notified body to suspend or withdraw, within a reasonable period of time determined by the authority, any certificates which were unduly issued to ensure the safety of devices on the market; (d) enter into the electronic system referred to in Article 57 information in relation to certificates of which it has required their suspension or withdrawal; (e) inform the competent authority for medical devices of the Member State in which the manufacturer has its registered place of business through the electronic system referred to in Article 57 of the certificates for which it has required suspension or withdrawal. That competent authority shall take the appropriate measures, where necessary to avoid a potential risk to the health or safety of patients, users or others. 8.   With the exception of certificates unduly issued, and where a designation has been suspended or restricted, the certificates shall remain valid in the following circumstances: (a) the authority responsible for notified bodies has confirmed, within one month of the suspension or restriction, that there is no safety issue in relation to certificates affected by the suspension or restriction, and the authority responsible for notified bodies has outlined a timeline and actions anticipated to remedy the suspension or restriction; or (b) the authority responsible for notified bodies has confirmed that no certificates relevant to the suspension will be issued, amended or re-issued during the course of the suspension or restriction, and states whether the notified body has the capability of continuing to monitor and remain responsible for existing certificates issued for the period of the suspension or restriction. In the event that the authority responsible for notified bodies determines that the notified body does not have the capability to support existing certificates issued, the manufacturer shall provide, to the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business, within three months of the suspension or restriction, a written confirmation that another qualified notified body is temporarily assuming the functions of the notified body to monitor and remain responsible for the certificates during the period of suspension or restriction. 9.   With the exception of certificates unduly issued, and where a designation has been withdrawn, the certificates shall remain valid for a period of nine months in the following circumstances: (a) where the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business has confirmed that there is no safety issue associated with the devices in question; and (b) another notified body has confirmed in writing that it will assume immediate responsibilities for those devices and will have completed assessment of them within twelve months of the withdrawal of the designation. In the circumstances referred to in the first subparagraph, the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its place of business may extend the provisional validity of the certificates for further periods of three months, which altogether shall not exceed twelve months. The authority or the notified body assuming the functions of the notified body affected by the change of designation shall immediately inform the Commission, the other Member States and the other notified bodies thereof. Article 47 Challenge to the competence of notified bodies 1.   The Commission, in conjunction with the MDCG, shall investigate all cases where concerns have been brought to its attention regarding the continued fulfilment by a notified body, or of one or more of its subsidiaries or subcontractors, of the requirements set out in Annex VII or the obligations to which they are subject. It shall ensure that the relevant authority responsible for notified bodies is informed and is given an opportunity to investigate those concerns. 2.   The notifying Member State shall provide the Commission, on request, with all information regarding the designation of the notified body concerned. 3.   The Commission, in conjunction with the MDCG, may initiate, as applicable, the assessment procedure described in Article 39(3) and (4), where there is reasonable concern about the ongoing compliance of a notified body or a subsidiary or subcontractor of the notified body with the requirements set out in Annex VII and where the investigation by the authority responsible for notified bodies is not deemed to have fully addressed the concerns or upon request of the authority responsible for notified bodies. The reporting and outcome of that assessment shall follow the principles of Article 39. Alternatively, depending on the severity of the issue, the Commission, in conjunction with the MDCG, may request that the authority responsible for notified bodies allow the participation of up to two experts from the list established pursuant to Article 40 in an on-site assessment as part of the planned monitoring and assessment activities in accordance with Article 44 and as outlined in the annual assessment plan described in Article 44(4). 4.   Where the Commission ascertains that a notified body no longer meets the requirements for its designation, it shall inform the notifying Member State accordingly and request it to take the necessary corrective measures, including the suspension, restriction or withdrawal of the designation if necessary. Where the Member State fails to take the necessary corrective measures, the Commission may, by means of implementing acts, suspend, restrict or withdraw the designation. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). It shall notify the Member State concerned of its decision and update NANDO and the electronic system referred to in Article 57. 5.   The Commission shall ensure that all confidential information obtained in the course of its investigations is treated accordingly. Article 48 Peer review and exchange of experience between authorities responsible for notified bodies 1.   The Commission shall provide for the organisation of exchange of experience and coordination of administrative practice between the authorities responsible for notified bodies. Such exchange shall cover elements including: (a) development of best practice documents relating to the activities of the authorities responsible for notified bodies; (b) development of guidance documents for notified bodies in relation to the implementation of this Regulation; (c) training and qualification of the experts referred to in Article 40; (d) monitoring of trends relating to changes to notified body designations and notifications and trends in certificate withdrawals and transfers between notified bodies; (e) monitoring of the application and applicability of scope codes referred to in Article 42(13); (f) development of a mechanism for peer reviews between authorities and the Commission; (g) methods of communication to the public on the monitoring and surveillance activities of authorities and the Commission on notified bodies. 2.   The authorities responsible for notified bodies shall participate in a peer review every third year through the mechanism developed pursuant to paragraph 1 of this Article. Such reviews shall normally be conducted in parallel with the on-site joint assessments described in Article 39. Alternatively, an authority may make the choice of having such reviews take place as part of its monitoring activities referred to in Article 44. 3.   The Commission shall participate in the organisation and provide support to the implementation of the peer review mechanism. 4.   The Commission shall compile an annual summary report of the peer review activities, which shall be made publicly available. 5.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements and related documents for the peer review mechanism and training and qualification as referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 49 Coordination of notified bodies The Commission shall ensure that appropriate coordination and cooperation between notified bodies is put in place and operated in the form of a coordination group of notified bodies in the field of medical devices, including in vitro diagnostic medical devices. This group shall meet on a regular basis and at least annually. The bodies notified under this Regulation shall participate in the work of that group. The Commission may establish the specific arrangements for the functioning of the coordination group of notified bodies. Article 50 List of standard fees Notified bodies shall establish lists of their standard fees for the conformity assessment activities that they carry out and shall make those lists publicly available. CHAPTER V CLASSIFICATION AND CONFORMITY ASSESSMENT SECTION 1 Classification Article 51 Classification of devices 1.   Devices shall be divided into classes I, IIa, IIb and III, taking into account the intended purpose of the devices and their inherent risks. Classification shall be carried out in accordance with Annex VIII. 2.   Any dispute between the manufacturer and the notified body concerned, arising from the application of Annex VIII, shall be referred for a decision to the competent authority of the Member State in which the manufacturer has its registered place of business. In cases where the manufacturer has no registered place of business in the Union and has not yet designated an authorised representative, the matter shall be referred to the competent authority of the Member State in which the authorised representative referred to in the last indent of point (b) of the second paragraph of Section 2.2 of Annex IX has its registered place of business. Where the notified body concerned is established in a Member State other than that of the manufacturer, the competent authority shall adopt its decision after consultation with the competent authority of the Member State that designated the notified body. The competent authority of the Member State in which the manufacturer has its registered place of business shall notify the MDCG and the Commission of its decision. The decision shall be made available upon request. 3.   At the request of a Member State the Commission shall after consulting the MDCG, decide, by means of implementing acts, on the following: (a) application of Annex VIII to a given device, or category or group of devices, with a view to determining the classification of such devices; (b) that a device, or category or group of devices, shall for reasons of public health based on new scientific evidence, or based on any information which becomes available in the course of the vigilance and market surveillance activities be reclassified, by way of derogation from Annex VIII. 4.   The Commission may also, on its own initiative and after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in points (a) and (b) of paragraph 3. 5.   In order to ensure the uniform application of Annex VIII, and taking account of the relevant scientific opinions of the relevant scientific committees, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. 6.   The implementing acts referred to in paragraphs 3, 4 and 5 of this Article shall be adopted in accordance with the examination procedure referred to in Article 114(3). SECTION 2 Conformity assessment Article 52 Conformity assessment procedures 1.   Prior to placing a device on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 2.   Prior to putting into service a device that is not placed on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 3.   Manufacturers of class III devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Annex X coupled with a conformity assessment as specified in Annex XI. 4.   Manufacturers of class IIb devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device per generic device group. However, for class IIb implantable devices, except sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors, the assessment of the technical documentation as specified in Section 4 of Annex IX shall apply for every device. Alternatively, the manufacturer may choose to apply a conformity assessment based on type examination as specified in Annex X coupled with a conformity assessment based on product conformity verification as specified in Annex XI. 5.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in the second subparagraph of paragraph 4 of this Article, being used in other class IIb implantable devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend that list by adding other types of class IIb implantable devices to that list or removing devices therefrom. 6.   Manufacturers of class IIa devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device for each category of devices. Alternatively, the manufacturer may choose to draw up the technical documentation set out in Annexes II and III coupled with a conformity assessment as specified in Section 10 or Section 18 of Annex XI. The assessment of the technical documentation shall apply for at least one representative device for each category of devices. 7.   Manufacturers of class I devices, other than custom-made or investigational devices, shall declare the conformity of their products by issuing the EU declaration of conformity referred to in Article 19 after drawing up the technical documentation set out in Annexes II and III. If those devices are placed on the market in sterile condition, have a measuring function or are reusable surgical instruments, the manufacturer shall apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI. However, the involvement of the notified body in those procedures shall be limited: (a) in the case of devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions; (b) in the case of devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements; (c) in the case of reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use. 8.   Manufacturers of custom-made devices shall follow the procedure set out in Annex XIII and draw up the statement set out in Section 1 of that Annex before placing such devices on the market. In addition to the procedure applicable pursuant to the first subparagraph, manufacturers of class III custom-made implantable devices shall be subject to the conformity assessment as specified in Chapter I of Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Part A of Annex XI. 9.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices referred to in the first subparagraph of Article 1(8), the procedure specified in Section 5.2 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 10.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices that are covered by this Regulation in accordance with point (f) or (g) of Article 1(6) and with the first subparagraph of Article 1(10), the procedure specified in Section 5.3 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 11.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7, in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the procedure specified in Section 5.4 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 12.   The Member State in which the notified body is established may require that all or certain documents, including the technical documentation, audit, assessment and inspection reports, relating to the procedures referred to in paragraphs 1 to 7 and 9 to 11 be made available in an official Union language(s) determined by that Member State. In the absence of such requirement, those documents shall be available in any official Union language acceptable to the notified body. 13.   Investigational devices shall be subject to the requirements set out in Articles 62 to 81. 14.   The Commission may, by means of implementing acts, specify detailed arrangements and procedural aspects with a view to ensuring the harmonised application of the conformity assessment procedures by the notified bodies for any of the following aspects: (a) the frequency and the sampling basis of the assessment of the technical documentation on a representative basis as set out in the third paragraph of Section 2.3 and in Section 3.5 of Annex IX in the case of class IIa and class IIb devices, and in Section 10.2 of Annex XI in the case of class IIa devices; (b) the minimum frequency of unannounced on-site audits and sample tests to be conducted by notified bodies in accordance with Section 3.4 of Annex IX, taking into account the risk-class and the type of device; (c) the physical, laboratory or other tests to be carried out by notified bodies in the context of sample tests, assessment of the technical documentation and type examination in accordance with Sections 3.4 and 4.3 of Annex IX, Section 3 of Annex X and Section 15 of Annex XI. The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 53 Involvement of notified bodies in conformity assessment procedures 1.   Where the conformity assessment procedure requires the involvement of a notified body, the manufacturer may apply to a notified body of its choice, provided that the chosen notified body is designated for conformity assessment activities related to the types of devices concerned. The manufacturer may not lodge an application in parallel with another notified body for the same conformity assessment procedure. 2.   The notified body concerned shall, by means of the electronic system referred to in Article 57, inform the other notified bodies of any manufacturer that withdraws its application prior to the notified body's decision regarding the conformity assessment. 3.   When applying to a notified body under paragraph 1, manufacturers shall declare whether they have withdrawn an application with another notified body prior to the decision of that notified body and provide information about any previous application for the same conformity assessment that has been refused by another notified body. 4.   The notified body may require any information or data from the manufacturer, which is necessary in order to properly conduct the chosen conformity assessment procedure. 5.   Notified bodies and the personnel of notified bodies shall carry out their conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific field and shall be free from all pressures and inducements, particularly financial, which might influence their judgement or the results of their conformity assessment activities, especially as regards persons or groups with an interest in the results of those activities. Article 54 Clinical evaluation consultation procedure for certain class III and class IIb devices 1.   In addition to the procedures applicable pursuant to Article 52, a notified body shall also follow the procedure regarding clinical evaluation consultation as specified in Section 5.1 of Annex IX or as referred to in Section 6 of Annex X, as applicable, when performing a conformity assessment of the following devices: (a) class III implantable devices, and (b) class IIb active devices intended to administer and/or remove a medicinal product, as referred to in Section 6.4 of Annex VIII (Rule 12). 2.   The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not adversely affect the benefit-risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device. 3.   The notified body shall notify the competent authorities, the authority responsible for notified bodies and the Commission through the electronic system referred to in Article 57 of whether or not the procedure referred to in paragraph 1 of this Article is to be applied. That notification shall be accompanied by the clinical evaluation assessment report. 4.   The Commission shall draw up an annual overview of devices which have been subject to the procedure specified in Section 5.1 of Annex IX and referred to in Section 6 of Annex X. The annual overview shall include the notifications in accordance with paragraph 3 of this Article and point (e) of Section 5.1 of Annex IX and a listing of the cases where the notified body did not follow the advice from the expert panel. The Commission shall submit this overview to the European Parliament, to the Council and to the MDCG. 5.   The Commission shall by 27 May 2025 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. The report shall take into account the annual overviews and any available relevant recommendations from the MDCG. On the basis of that report the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 55 Mechanism for scrutiny of conformity assessments of certain class III and class IIb devices 1.   A notified body shall notify the competent authorities of certificates it has granted to devices for which the conformity assessment has been performed pursuant to Article 54(1). Such notification shall take place through the electronic system referred to in Article 57 and shall include the summary of safety and clinical performance pursuant to Article 32, the assessment report by the notified body, the instructions for use referred to in Section 23.4 of Annex I, and, where applicable, the scientific opinion of the expert panels referred to in Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. In the case of divergent views between the notified body and the expert panels, a full justification shall also be included. 2.   A competent authority and, where applicable, the Commission may, based on reasonable concerns apply further procedures in accordance with Article 44, 45, 46, 47 or 94 and, where deemed necessary, take appropriate measures in accordance with Articles 95 and 97. 3.   The MDCG and, where applicable, the Commission, may, based on reasonable concerns, request scientific advice from the expert panels in relation to the safety and performance of any device. Article 56 Certificates of conformity 1.   The certificates issued by the notified bodies in accordance with Annexes IX, X and XI shall be in an official Union language determined by the Member State in which the notified body is established or otherwise in an official Union language acceptable to the notified body. The minimum content of the certificates shall be as set out in Annex XII. 2.   The certificates shall be valid for the period they indicate, which shall not exceed five years. On application by the manufacturer, the validity of the certificate may be extended for further periods, each not exceeding five years, based on a re-assessment in accordance with the applicable conformity assessment procedures. Any supplement to a certificate shall remain valid as long as the certificate which it supplements is valid. 3.   Notified bodies may impose restrictions to the intended purpose of a device to certain groups of patients or require manufacturers to undertake specific PMCF studies pursuant to Part B of Annex XIV. 4.   Where a notified body finds that the requirements of this Regulation are no longer met by the manufacturer, it shall, taking account of the principle of proportionality, suspend or withdraw the certificate issued or impose any restrictions on it unless compliance with such requirements is ensured by appropriate corrective action taken by the manufacturer within an appropriate deadline set by the notified body. The notified body shall give the reasons for its decision. 5.   The notified body shall enter in the electronic system referred to in Article 57 any information regarding certificates issued, including amendments and supplements thereto, and regarding suspended, reinstated, withdrawn or refused certificates and restrictions imposed on certificates. Such information shall be accessible to the public. 6.   In the light of technical progress, the Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the certificates set out in Annex XII. Article 57 Electronic system on notified bodies and on certificates of conformity 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to collate and process the following information: (a) the list of subsidiaries referred to in Article 37(3); (b) the list of experts referred to in Article 40(2); (c) the information relating to the notification referred to in Article 42(10) and the amended notifications referred to in Article 46(2); (d) the list of notified bodies referred to in Article 43(2); (e) the summary of the report referred to in Article 44(12); (f) the notifications for conformity assessments and certificates referred to in Articles 54(3) and 55(1); (g) withdrawal or refusals of applications for the certificates as referred to in Article 53(2) and Section 4.3 of Annex VII; (h) the information regarding certificates referred to in Article 56(5); (i) the summary of safety and clinical performance referred to in Article 32. 2.   The information collated and processed by the electronic system shall be accessible to the competent authorities of the Member States, to the Commission, where appropriate to the notified bodies and where provided elsewhere in this regulation or in Regulation (EU) 2017/746 to the public. Article 58 Voluntary change of notified body 1.   In cases where a manufacturer terminates its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device, the detailed arrangements for the change of notified body shall be clearly defined in an agreement between the manufacturer, the incoming notified body and, where practicable the outgoing notified body. That agreement shall cover at least the following aspects: (a) the date on which the certificates issued by the outgoing notified body become invalid; (b) the date until which the identification number of the outgoing notified body may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the date after which the conformity assessment tasks of the outgoing notified body is assigned to the incoming notified body; (e) the last serial number or lot number for which the outgoing notified body is responsible. 2.   The outgoing notified body shall withdraw the certificates it has issued for the device concerned on the date on which they become invalid. Article 59 Derogation from the conformity assessment procedures 1.   By way of derogation from Article 52, any competent authority may authorise, on a duly justified request, the placing on the market or putting into service within the territory of the Member State concerned, of a specific device for which the procedures referred to in that Article have not been carried out but use of which is in the interest of public health or patient safety or health. 2.   The Member State shall inform the Commission and the other Member States of any decision to authorise the placing on the market or putting into service of a device in accordance with paragraph 1 where such authorisation is granted for use other than for a single patient. 3.   Following a notification pursuant to paragraph 2 of this Article, the Commission, in exceptional cases relating to public health or patient safety or health, may, by means of implementing acts, extend for a limited period of time the validity of an authorisation granted by a Member State in accordance with paragraph 1 of this Article to the territory of the Union and set the conditions under which the device may be placed on the market or put into service. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). On duly justified imperative grounds of urgency relating to the health and safety of humans, the Commission shall adopt immediately applicable implementing acts in accordance with the procedure referred to in Article 114(4). Article 60 Certificate of free sale 1.   For the purpose of export and upon request by a manufacturer or an authorised representative, the Member State in which the manufacturer or the authorised representative has its registered place of business shall issue a certificate of free sale declaring that the manufacturer or the authorised representative, as applicable, has its registered place of business on its territory and that the device in question bearing the CE marking in accordance with this Regulation may be marketed in the Union. The certificate of free sale shall set out the Basic UDI-DI of the device as provided to the UDI database under Article 29. Where a notified body has issued a certificate pursuant to Article 56, the certificate of free sale shall set out the unique number identifying the certificate issued by the notified body, as referred to in Section 3 of Chapter II of Annex XII. 2.   The Commission may, by means of implementing acts, establish a model for certificates of free sale, taking into account international practice as regards the use of certificates of free sale. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). CHAPTER VI CLINICAL EVALUATION AND CLINICAL INVESTIGATIONS Article 61 Clinical evaluation 1.   Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III. The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV. 2.   For all class III devices and for the class IIb devices referred to in point (b) of Article 54(1), the manufacturer may, prior to its clinical evaluation and/or investigation, consult an expert panel as referred to in Article 106, with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation. The manufacturer shall give due consideration to the views expressed by the expert panel. Such consideration shall be documented in the clinical evaluation report referred to in paragraph 12 of this Article. The manufacturer may not invoke any rights to the views expressed by the expert panel with regard to any future conformity assessment procedure. 3.   A clinical evaluation shall follow a defined and methodologically sound procedure based on the following: (a) a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied: — it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate, in accordance with Section 3 of Annex XIV, and — the data adequately demonstrate compliance with the relevant general safety and performance requirements; (b) a critical evaluation of the results of all available clinical investigations, taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV; and (c) a consideration of currently available alternative treatment options for that purpose, if any. 4.   In the case of implantable devices and class III devices, clinical investigations shall be performed, except if: — the device has been designed by modifications of a device already marketed by the same manufacturer, — the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and — the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device. In addition, clinical investigations need not be performed in the cases referred to in paragraph 6. 5.   A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph: — the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and — the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body. 6.   The requirement to perform clinical investigations pursuant to paragraph 4 shall not apply to implantable devices and class III devices: (a) which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation: — is based on sufficient clinical data, and — is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available; or (b) that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific CS, where such a CS is available. 7.   Cases in which paragraph 4 is not applied by virtue of paragraph 6 shall be justified in the clinical evaluation report by the manufacturer and in the clinical evaluation assessment report by the notified body. 8.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in point (b) of paragraph 6 of this Article, being used in other devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list of exempted devices referred to in the second subparagraph of Article 52(4) and in point (b) of paragraph 6 of this Article, by adding other types of implantable or class III devices to that list or removing devices therefrom. 9.   In the case of the products without an intended medical purpose listed in Annex XVI, the requirement to demonstrate a clinical benefit in accordance with this Chapter and Annexes XIV and XV shall be understood as a requirement to demonstrate the performance of the device. Clinical evaluations of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified. 10.   Without prejudice to paragraph 4, where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation referred to in Annex II why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation, to be adequate. 11.   The clinical evaluation and its documentation shall be updated throughout the life cycle of the device concerned with clinical data obtained from the implementation of the manufacturer's PMCF plan in accordance with Part B of Annex XIV and the post-market surveillance plan referred to in Article 84. For class III devices and implantable devices, the PMCF evaluation report and, if indicated, the summary of safety and clinical performance referred to in Article 32 shall be updated at least annually with such data. 12.   The clinical evaluation, its results and the clinical evidence derived from it shall be documented in a clinical evaluation report as referred to in Section 4 of Annex XIV, which, except for custom-made devices, shall be part of the technical documentation referred to in Annex II relating to the device concerned. 13.   Where necessary to ensure the uniform application of Annex XIV, the Commission may, having due regard to technical and scientific progress, adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 62 General requirements regarding clinical investigations conducted to demonstrate conformity of devices 1.   Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and of Articles 63 to 80, the acts adopted pursuant to Article 81, and Annex XV, where carried out as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes: (a) to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer; (b) to establish and verify the clinical benefits of a device as specified by its manufacturer; (c) to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device. 2.   Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor. Member States may choose not to apply the first subparagraph to clinical investigations to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical investigation who shall be the addressee for all communications with the sponsor provided for in this Regulation. 3.   Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust. Clinical investigations shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by ethics committees are compatible with the procedures set out in this Regulation for the assessment of the application for authorisation of a clinical investigation. At least one lay person shall participate in the ethical review. 4.   A clinical investigation as referred to in paragraph 1 may be conducted only where all of the following conditions are met: (a) the clinical investigation is the subject of an authorisation by the Member State(s) in which the clinical investigation is to be conducted, in accordance with this Regulation, unless otherwise stated; (b) an ethics committee, set up in accordance with national law, has not issued a negative opinion in relation to the clinical investigation, which is valid for that entire Member State under its national law; (c) the sponsor, or its legal representative or a contact person pursuant to paragraph 2, is established in the Union; (d) vulnerable populations and subjects are appropriately protected in accordance with Articles 64 to 68; (e) the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored; (f) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has given informed consent in accordance with Article 63; (g) the subject or, where the subject is not able to give informed consent, his or her legally designated representative, has been provided with the contact details of an entity where further information can be received in case of need; (h) the rights of the subject to physical and mental integrity, to privacy and to the protection of the data concerning him or her in accordance with Directive 95/46/EC are safeguarded; (i) the clinical investigation has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are specifically defined in the clinical investigation plan and constantly monitored; (j) the medical care provided to the subjects is the responsibility of an appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner or any other person entitled by national law to provide the relevant patient care under clinical investigation conditions; (k) no undue influence, including that of a financial nature, is exerted on the subject, or, where applicable, on his or her legally designated representatives, to participate in the clinical investigation; (l) the investigational device(s) in question conform(s) to the applicable general safety and performance requirements set out in Annex I apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, technical and biological safety testing and pre-clinical evaluation, as well as provisions in the field of occupational safety and accident prevention, taking into consideration the state of the art; (m) the requirements of Annex XV are fulfilled. 5.   Any subject, or, where the subject is not able to give informed consent, his or her legally designated representative, may, without any resulting detriment and without having to provide any justification, withdraw from the clinical investigation at any time by revoking his or her informed consent. Without prejudice to Directive 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and the use of data obtained based on informed consent before its withdrawal. 6.   The investigator shall be a person exercising a profession which is recognised in the Member State concerned as qualifying for the role of investigator on account of having the necessary scientific knowledge and experience in patient care. Other personnel involved in conducting a clinical investigation shall be suitably qualified, by education, training or experience in the relevant medical field and in clinical research methodology, to perform their tasks. 7.   The facilities where the clinical investigation is to be conducted shall be suitable for the clinical investigation and shall be similar to the facilities where the device is intended to be used. Article 63 Informed consent 1.   Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document or the record, as appropriate, by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical investigation. 2.   Information given to the subject or, where the subject is not able to give informed consent, his or her legally designated representative for the purposes of obtaining his or her informed consent shall: (a) enable the subject or his or her legally designated representative to understand: (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical investigations; (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her right to refuse to participate in and the right to withdraw from the clinical investigation at any time without any resulting detriment and without having to provide any justification; (iii) the conditions under which the clinical investigations is to be conducted, including the expected duration of the subject's participation in the clinical investigation; and (iv) the possible treatment alternatives, including the follow-up measures if the participation of the subject in the clinical investigation is discontinued; (b) be kept comprehensive, concise, clear, relevant, and understandable to the subject or his or her legally designated representative; (c) be provided in a prior interview with a member of the investigating team who is appropriately qualified under national law; (d) include information about the applicable damage compensation system referred to in Article 69; and (e) include the Union-wide unique single identification number of the clinical investigation referred to in Article 70(1) and information about the availability of the clinical investigation results in accordance with paragraph 6 of this Article. 3.   The information referred to in paragraph 2 shall be prepared in writing and be available to the subject or, where the subject is not able to give informed consent, his or her legally designated representative. 4.   In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information. 5.   In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood the information. 6.   The subject shall be informed that a clinical investigation report and a summary presented in terms understandable to the intended user will be made available pursuant to Article 77(5) in the electronic system on clinical investigations referred to in Article 73 irrespective of the outcome of the clinical investigation, and shall be informed, to the extent possible, when they have become available. 7.   This Regulation is without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical investigation. Article 64 Clinical investigations on incapacitated subjects 1.   In the case of incapacitated subjects who have not given, or have not refused to give, informed consent before the onset of their incapacity, a clinical investigation may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the incapacitated subjects have received the information referred to in Article 63(2) in a way that is adequate in view of their capacity to understand it; (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to subjects or their legally designated representatives, except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical investigations on persons able to give informed consent, or by other research methods; (f) the clinical investigation relates directly to a medical condition from which the subject suffers; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the incapacitated subject outweighing the risks and burdens involved. 2.   The subject shall as far as possible take part in the informed consent procedure. Article 65 Clinical investigations on minors A clinical investigation on minors may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the minors have received the information referred to in Article 63(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children; (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is intended to investigate treatments for a medical condition that only occurs in minors or the clinical investigation is essential with respect to minors to validate data obtained in clinical investigations on persons able to give informed consent or by other research methods; (f) the clinical investigation either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the minor subject outweighing the risks and burdens involved; (h) the minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity; (i) if during a clinical investigation the minor reaches the age of legal competence to give informed consent as defined in national law, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical investigation. Article 66 Clinical investigations on pregnant or breastfeeding women A clinical investigation on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the clinical investigation has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; (b) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse impact on the health of the child; (c) no incentives or financial inducements are given to the subject except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation. Article 67 Additional national measures Member States may maintain additional measures regarding persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical investigations, or persons in residential care institutions. Article 68 Clinical investigations in emergency situations 1.   By way of derogation from point (f) of Article 62(4), from points (a) and (b) of Article 64(1) and from points (a) and (b) of Article 65, informed consent to participate in a clinical investigation may be obtained, and information on the clinical investigation may be given, after the decision to include the subject in the clinical investigation, provided that that decision is taken at the time of the first intervention on the subject, in accordance with the clinical investigation plan for that clinical investigation and that all of the following conditions are fulfilled: (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical investigation; (b) there are scientific grounds to expect that participation of the subject in the clinical investigation will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition; (c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative; (d) the investigator certifies that he or she is not aware of any objections to participate in the clinical investigation previously expressed by the subject; (e) the clinical investigation relates directly to the subject's medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical investigation is of such a nature that it may be conducted exclusively in emergency situations; (f) the clinical investigation poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition. 2.   Following an intervention pursuant to paragraph 1 of this Article, informed consent in accordance with Article 63 shall be sought to continue the participation of the subject in the clinical investigation, and information on the clinical investigation shall be given, in accordance with the following requirements: (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 63(2) shall be given as soon as possible to the subject and to his or her legally designated representative; (b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever can be done sooner, and the information referred to in Article 63(2) shall be given as soon as possible to the subject or his or her legally designated representative, as applicable. For the purposes of point (b) where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical investigation shall be obtained from the subject as soon as he or she is capable of giving informed consent. 3.   If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical investigation. Article 69 Damage compensation 1.   Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical investigation conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk. 2.   The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State in which the clinical investigation is conducted. Article 70 Application for clinical investigations 1.   The sponsor of a clinical investigation shall submit an application to the Member State(s) in which the clinical investigation is to be conducted (referred to for the purposes of this Article as ‘Member State concerned’) accompanied by the documentation referred to in Chapter II of Annex XV. The application shall be submitted by means of the electronic system referred to in Article 73, which shall generate a Union-wide unique single identification number for the clinical investigation, which shall be used for all relevant communication in relation to that clinical investigation. Within 10 days of it receiving the application, the Member State concerned shall notify the sponsor as to whether the clinical investigation falls within the scope of this Regulation and as to whether the application dossier is complete in accordance with Chapter II of Annex XV. 2.   Within one week of any change occurring in relation to the documentation referred to in Chapter II of Annex XV, the sponsor shall update the relevant data in the electronic system referred to in Article 73 and make that change to the documentation clearly identifiable. The Member State concerned shall be notified of the update by means of that electronic system. 3.   Where the Member State concerned finds that the clinical investigation applied for does not fall within the scope of this Regulation or that the application dossier is not complete, it shall inform the sponsor thereof and shall set a time limit of maximum 10 days for the sponsor to comment or to complete the application by means of the electronic system referred to in Article 73. The Member State concerned may extend this period by a maximum of 20 days where appropriate. Where the sponsor has not provided comments nor completed the application within the time limit referred to in the first subparagraph, the application shall be deemed to have lapsed. Where the sponsor considers the application does fall under the scope of this Regulation and/or is complete but the Member State concerned does not, the application shall be considered to have been rejected. The Member State concerned shall provide for an appeal procedure in respect of such refusal. The Member State concerned shall notify the sponsor within five days of receipt of the comments or of the requested additional information, whether the clinical investigation is considered as falling within the scope of this Regulation and the application is complete. 4.   The Member State concerned may also extend the period referred to in paragraph 1 and 3 each by a further five days. 5.   For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the periods referred to in paragraphs 1, 3 and 4 respectively. 6.   During the period when the application is being assessed, the Member State may request additional information from the sponsor. The expiry of the period laid down in point (b) of paragraph 7 shall be suspended from the date of the first request until such time as the additional information has been received. 7.   The sponsor may start the clinical investigation in the following circumstances: (a) in the case of investigational class I devices or in the case of non-invasive class IIa and class IIb devices, unless otherwise stated by national law, immediately after the validation date of the application pursuant to paragraph 5, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation; (b) in the case of investigational devices, other than those referred to in point (a), as soon as the Member State concerned has notified the sponsor of its authorisation, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation. The Member State shall notify the sponsor of the authorisation within 45 days of the validation date referred to in paragraph 5. The Member State may extend this period by a further 20 days for the purpose of consulting with experts. 8.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress and global regulatory developments, the requirements laid down in Chapter II of Annex XV. 9.   In order to ensure the uniform application of the requirements laid down in Chapter II of Annex XV, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 71 Assessment by Member States 1.   Member States shall ensure that the persons validating and assessing the application, or deciding on it, do not have conflicts of interest, are independent of the sponsor, the investigators involved and of natural or legal persons financing the clinical investigation, as well as free of any other undue influence. 2.   Member States shall ensure that the assessment is done jointly by an appropriate number of persons who collectively have the necessary qualifications and experience. 3.   Member States shall assess whether the clinical investigation is designed in such a way that potential remaining risks to subjects or third persons, after risk minimization, are justified, when weighed against the clinical benefits to be expected. They shall, while taking into account applicable CS or harmonised standards, examine in particular: (a) the demonstration of compliance of the investigational device(s) with the applicable general safety and performance requirements, apart from the aspects covered by the clinical investigation, and whether, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, assurance of technical and biological safety testing and pre-clinical evaluation; (b) whether the risk-minimisation solutions employed by the sponsor are described in harmonised standards and, in those cases where the sponsor does not use harmonised standards, whether the risk-minimisation solutions provide a level of protection that is equivalent to that provided by harmonised standards; (c) whether the measures planned for the safe installation, putting into service and maintenance of the investigational device are adequate; (d) the reliability and robustness of the data generated in the clinical investigation, taking account of statistical approaches, design of the investigation and methodological aspects, including sample size, comparator and endpoints; (e) whether the requirements of Annex XV are met; (f) in the case of devices for sterile use, evidence of the validation of the manufacturer's sterilisation procedures or information on the reconditioning and sterilisation procedures which have to be conducted by the investigation site; (g) the demonstration of the safety, quality and usefulness of any components of animal or human origin or of substances, which may be considered medicinal products in accordance with Directive 2001/83/EC. 4.   Member States shall refuse the authorisation of the clinical investigation if: (a) the application dossier submitted pursuant to Article 70(1) remains incomplete; (b) the device or the submitted documents, especially the investigation plan and the investigator's brochure, do not correspond to the state of scientific knowledge, and the clinical investigation, in particular, is not suitable for providing evidence for the safety, performance characteristics or benefit of the device on subjects or patients, (c) the requirements of Article 62 are not met, or (d) any assessment under paragraph 3 is negative. Member States shall provide for an appeal procedure in respect of a refusal pursuant to the first subparagraph. Article 72 Conduct of a clinical investigation 1.   The sponsor and the investigator shall ensure that the clinical investigation is conducted in accordance with the approved clinical investigation plan. 2.   In order to verify that the rights, safety and well-being of subjects are protected, that the reported data are reliable and robust, and that the conduct of the clinical investigation is in compliance with the requirements of this Regulation, the sponsor shall ensure adequate monitoring of the conduct of a clinical investigation. The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics of the clinical investigation including the following: (a) the objective and methodology of the clinical investigation; and (b) the degree of deviation of the intervention from normal clinical practice. 3.   All clinical investigation information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable law on personal data protection. 4.   Appropriate technical and organisational measures shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves transmission over a network. 5.   Member States shall inspect, at an appropriate level, investigation site(s) to check that clinical investigations are conducted in accordance with the requirements of this Regulation and with the approved investigation plan. 6.   The sponsor shall establish a procedure for emergency situations which enables the immediate identification and, where necessary, an immediate recall of the devices used in the investigation. Article 73 Electronic system on clinical investigations 1.   The Commission shall, in collaboration with the Member States, set up, manage and maintain an electronic system: (a) to create the single identification numbers for clinical investigations referred to in Article 70(1); (b) to be used as an entry point for the submission of all applications or notifications for clinical investigations referred to in Articles 70, 74, 75 and 78 and for all other submission of data, or processing of data in this context; (c) for the exchange of information relating to clinical investigations in accordance with this Regulation between the Member States and between them and the Commission including the exchange of information referred to in Articles 70 and 76; (d) for information to be provided by the sponsor in accordance with Article 77, including the clinical investigation report and its summary as required in paragraph 5 of that Article; (e) for reporting on serious adverse events and device deficiencies and related updates referred to in Article 80. 2.   When setting up the electronic system referred in paragraph 1 of this Article, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council (37) as concerns combined clinical investigations of devices with a clinical trial under that Regulation. 3.   The information referred to in point (c) of paragraph 1 shall only be accessible to the Member States and the Commission. The information referred to in the other points of that paragraph shall be accessible to the public, unless, for all or parts of that information, confidentiality of the information is justified on any of the following grounds: (a) protection of personal data in accordance with Regulation (EC) No 45/2001; (b) protection of commercially confidential information, especially in the investigators brochure, in particular through taking into account the status of the conformity assessment for the device, unless there is an overriding public interest in disclosure; (c) effective supervision of the conduct of the clinical investigation by the Member State(s) concerned. 4.   No personal data of subjects shall be publicly available. 5.   The user interface of the electronic system referred to in paragraph 1 shall be available in all official languages of the Union. Article 74 Clinical investigations regarding devices bearing the CE marking 1.   Where a clinical investigation is to be conducted to further assess, within the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), (‘PMCF investigation’), and where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned at least 30 days prior to its commencement by means of the electronic system referred to in Article 73. The sponsor shall include the documentation referred to in Chapter II of Annex XV as part of the notification. Points (b) to (k) and (m) of Article 62(4), Article 75, Article 76, Article 77, Article 80(5) and the relevant provisions of Annex XV shall apply to PMCF investigations. 2.   Where a clinical investigation is to be conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), Articles 62 to 81 shall apply. Article 75 Substantial modifications to clinical investigations 1.   If a sponsor intends to introduce modifications to a clinical investigation that are likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation, it shall notify, within one week, by means of the electronic system referred to in Article 73 the Member State(s) in which the clinical investigation is being or is to be conducted of the reasons for and the nature of those modifications. The sponsor shall include an updated version of the relevant documentation referred to in Chapter II of Annex XV as part of the notification. Changes to the relevant documentation shall be clearly identifiable. 2.   The Member State shall assess any substantial modification to the clinical investigation in accordance with the procedure laid down in Article 71. 3.   The sponsor may implement the modifications referred to in paragraph 1 at the earliest 38 days after the notification referred to in that paragraph, unless: (a) the Member State in which the clinical investigation is being or is to be conducted has notified the sponsor of its refusal based on the grounds referred to in Article 71(4) or on considerations of public health, subject and user safety or health, of public policy, or (b) an ethics committee in that Member State has issued a negative opinion in relation to the substantial modification to the clinical investigation, which, in accordance with national law, is valid for that entire Member State. 4.   The Member State(s) concerned may extend the period referred to in paragraph 3 by a further seven days, for the purpose of consulting with experts. Article 76 Corrective measures to be taken by Member States and information exchange between Member States 1.   Where a Member State in which a clinical investigation is being or is to be conducted has grounds for considering that the requirements set out in this Regulation are not met, it may take at least any of the following measures on its territory: (a) revoke the authorisation for the clinical investigation; (b) suspend or terminate the clinical investigation; (c) require the sponsor to modify any aspect of the clinical investigation. 2.   Before the Member State concerned takes any of the measures referred to in paragraph 1 it shall, except where immediate action is required, ask the sponsor or the investigator or both for their opinion. That opinion shall be delivered within seven days. 3.   Where a Member State has taken a measure referred to in paragraph 1 of this Article or has refused a clinical investigation, or has been notified by the sponsor of the early termination of a clinical investigation on safety grounds, that Member State shall communicate the corresponding decision and the grounds therefor to all Member States and the Commission by means of the electronic system referred to in Article 73. 4.   Where an application is withdrawn by the sponsor prior to a decision by a Member State, that information shall be made available through the electronic system referred to in Article 73 to all Member States and the Commission. Article 77 Information from the sponsor at the end of a clinical investigation or in the event of a temporary halt or early termination 1.   If the sponsor has temporarily halted a clinical investigation or has terminated a clinical investigation early, it shall inform within 15 days the Member State in which that clinical investigation has been temporarily halted or terminated early, through the electronic system referred to in Article 73, of the temporary halt or early termination, providing a justification. In the event that the sponsor has temporarily halted or terminated early the clinical investigation on safety grounds, it shall inform all Member States in which that clinical investigation is being conducted thereof within 24 hours. 2.   The end of a clinical investigation shall be deemed to coincide with the last visit of the last subject unless another point in time for such end is set out in the clinical investigation plan. 3.   The sponsor shall notify each Member State in which a clinical investigation was being conducted of the end of that clinical investigation in that Member State. That notification shall be made within 15 days of the end of the clinical investigation in relation to that Member State. 4.   If an investigation is conducted in more than one Member State, the sponsor shall notify all Member States in which that clinical investigation was conducted of the end of the clinical investigation in all Member States. That notification shall be made within 15 days of that end of the clinical investigation. 5.   Irrespective of the outcome of the clinical investigation, within one year of the end of the clinical investigation or within three months of the early termination or temporary halt, the sponsor shall submit to the Member States in which a clinical investigation was conducted a clinical investigation report as referred to in Section 2.8 of Chapter I and Section 7 of Chapter III of Annex XV. The clinical investigation report shall be accompanied by a summary presented in terms that are easily understandable to the intended user. Both the report and summary shall be submitted by the sponsor by means of the electronic system referred to in Article 73. Where, for scientific reasons, it is not possible to submit the clinical investigation report within one year of the end of the investigation, it shall be submitted as soon as it is available. In such case, the clinical investigation plan referred to in Section 3 of Chapter II of Annex XV shall specify when the results of the clinical investigation are going to be available, together with a justification. 6.   The Commission shall issue guidelines regarding the content and structure of the summary of the clinical investigation report. In addition, the Commission may issue guidelines for the formatting and sharing of raw data, for cases where the sponsor decides to share raw data on a voluntary basis. Those guidelines may take as a basis and adapt, where possible, existing guidelines for sharing of raw data in the field of clinical investigations. 7.   The summary and the clinical investigation report referred to in paragraph 5 of this Article shall become publicly accessible through the electronic system referred to in Article 73, at the latest when the device is registered in accordance with Article 29 and before it is placed on the market. In cases of early termination or temporary halt, the summary and the report shall become publicly accessible immediately after submission. If the device is not registered in accordance with Article 29 within one year of the summary and the report having been entered into the electronic system pursuant to paragraph 5 of this Article, they shall become publicly accessible at that point in time. Article 78 Coordinated assessment procedure for clinical investigations 1.   By means of the electronic system referred to in Article 73, the sponsor of a clinical investigation to be conducted in more than one Member State may submit, for the purpose of Article 70, a single application that, upon receipt, is transmitted electronically to all Member States in which the clinical investigation is to be conducted. 2.   The sponsor shall propose in the single application referred to in paragraph 1 that one of the Member States in which the clinical investigation is to be conducted acts as coordinating Member State. The Member States in which the clinical investigation is to be conducted shall, within six days of submission of the application, agree on one of them taking the role of the coordinating Member State. If they do not agree on a coordinating Member State, the coordinating Member State proposed by the sponsor shall assume that role. 3.   Under the direction of the coordinating Member State referred to in paragraph 2, the Member States concerned shall coordinate their assessment of the application, in particular of the documentation referred to in Chapter II of Annex XV. However, the completeness of the documentation referred to in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV shall be assessed separately by each Member State concerned in accordance with Article 70(1) to (5). 4.   With regard to documentation other than that referred to in the second subparagraph of paragraph 3, the coordinating Member State shall: (a) within six days of receipt of the single application, notify the sponsor that it is the coordinating Member State (‘notification date’); (b) for the purpose of the validation of the application, take into account any considerations submitted within seven days of the notification date by any Member State concerned; (c) within 10 days of the notification date, assess whether the clinical investigation falls within the scope of this Regulation and whether the application is complete, and shall notify the sponsor accordingly. Article 70(1) and (3) to (5) shall apply to the coordinating Member State in relation to that assessment; (d) establish the results of its assessment in a draft assessment report to be transmitted within 26 days of the validation date to the Member States concerned. By day 38 after the validation date, the other Member States concerned shall transmit their comments and proposals on the draft assessment report and the underlying application to the coordinating Member State which shall take due account of those comments and proposals in its finalisation of the final assessment report, to be transmitted within 45 days of the validation date to the sponsor and the other Member States concerned. The final assessment report shall be taken into account by all Member States concerned when deciding on the sponsor's application in accordance with Article 70(7). 5.   As regards the assessment of the documentation referred to in the second subparagraph of paragraph 3, each Member State concerned may request, on a single occasion, additional information from the sponsor. The sponsor shall submit the requested additional information within the period set by the Member State concerned, which shall not exceed 12 days from the receipt of the request. The expiry of the last deadline pursuant to point (d) of paragraph 4 shall be suspended from the date of the request until such time as the additional information has been received. 6.   For class IIb and class III devices, the coordinating Member State may also extend the periods referred to in paragraph 4 by a further 50 days, for the purpose of consulting with experts. 7.   The Commission may, by means of implementing acts, further specify the procedures and timescales for coordinated assessments to be taken into account by Member States concerned when deciding on the sponsor's application. Such implementing acts may also set out the procedures and timescales for coordinated assessment in the case of substantial modifications pursuant to paragraph 12 of this Article, in the case of reporting of adverse events pursuant to Article 80(4) and in the case of clinical investigations of combination products between medical devices and medicinal products, where the latter are under a concurrent coordinated assessment of a clinical trial under Regulation (EU) No 536/2014. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 8.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the conduct of the clinical investigation is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of all Member States concerned. Notwithstanding the first subparagraph, a Member State concerned may only disagree with the conclusion of the coordinating Member State concerning the area of coordinated assessment on the following grounds: (a) when it considers that participation in the clinical investigation would lead to a subject receiving treatment inferior to that received in normal clinical practice in that Member State concerned; (b) infringement of national law; or (c) considerations as regards subject safety and data reliability and robustness submitted under point (b) of paragraph 4. Where one of the Member States concerned disagrees with the conclusion on the basis of the second subparagraph of this paragraph, it shall communicate its disagreement, together with a detailed justification, through the electronic system referred to in Article 73, to the Commission, to all other Member States concerned and to the sponsor. 9.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the clinical investigation is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned. 10.   A Member State concerned shall refuse to authorise a clinical investigation if it disagrees with the conclusion of the coordinating Member State as regards any of the grounds referred to in the second subparagraph of paragraph 8, or if it finds, on duly justified grounds, that the aspects addressed in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV are not complied with, or where an ethics committee has issued a negative opinion in relation to that clinical investigation, which is valid, in accordance with national law, for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal. 11.   Each Member State concerned shall notify the sponsor through the electronic system referred to in Article 73 as to whether the clinical investigation is authorised, whether it is authorised subject to conditions, or whether authorisation has been refused. Notification shall be done by way of one single decision within five days of the transmission, pursuant to point (d) of paragraph 4, by the coordinating Member State of the final assessment report. Where an authorisation of a clinical investigation is subject to conditions, those conditions may only be such that, by their nature, they cannot be fulfilled at the time of that authorisation. 12.   Any substantial modifications as referred to in Article 75 shall be notified to the Member States concerned by means of the electronic system referred to in Article 73. Any assessment as to whether there are grounds for disagreement as referred to in the second subparagraph of paragraph 8 of this Article shall be carried out under the direction of the coordinating Member State, except for substantial modifications concerning Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV, which shall be assessed separately by each Member State concerned. 13.   The Commission shall provide administrative support to the coordinating Member State in the accomplishment of its tasks under this Chapter. 14.   The procedure set out in this Article shall, until 27 May 2027, be applied only by those of the Member States in which the clinical investigation is to be conducted which have agreed to apply it. After 27 May 2027, all Member States shall be required to apply that procedure. Article 79 Review of coordinated assessment procedure By 27 May 2026, the Commission shall submit to the European Parliament and to the Council a report on experience gained from the application of Article 78 and, if necessary, propose a review of Article 78(14) and point (h) of Article 123(3). Article 80 Recording and reporting of adverse events that occur during clinical investigations 1.   The sponsor shall fully record all of the following: (a) any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation; (b) any serious adverse event; (c) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (d) any new findings in relation to any event referred to in points (a) to (c). 2.   The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of the following by means of the electronic system referred to in Article 73: (a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; (b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (c) any new findings in relation to any event referred to in points (a) and (b). The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the sponsor may submit an initial report that is incomplete followed up by a complete report. Upon request by any Member State in which the clinical investigation is being conducted, the sponsor shall provide all information referred to in paragraph 1. 3.   The sponsor shall also report to the Member States in which the clinical investigation is being conducted any event referred to in paragraph 2 of this Article that occurred in third countries in which a clinical investigation is performed under the same clinical investigation plan as the one applying to a clinical investigation covered by this Regulation by means of the electronic system referred to in Article 73. 4.   In the case of a clinical investigation for which the sponsor has used the single application referred to in Article 78, the sponsor shall report any event as referred to in paragraph 2 of this Article by means of the electronic system referred to in Article 73. Upon receipt, this report shall be transmitted electronically to all Member States in which the clinical investigation is being conducted. Under the direction of the coordinating Member State referred to in Article 78(2), the Member States shall coordinate their assessment of serious adverse events and device deficiencies to determine whether to modify, suspend or terminate the clinical investigation or whether to revoke the authorisation for that clinical investigation. This paragraph shall not affect the rights of the other Member States to perform their own evaluation and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating Member State and the Commission shall be kept informed of the outcome of any such evaluation and the adoption of any such measures. 5.   In the case of PMCF investigations referred to in Article 74(1), the provisions on vigilance laid down in Articles 87 to 90 and in the acts adopted pursuant to Article 91 shall apply instead of this Article. 6.   Notwithstanding paragraph 5, this Article shall apply where a causal relationship between the serious adverse event and the preceding investigational procedure has been established. Article 81 Implementing acts The Commission may, by means of implementing acts, establish the detailed arrangements and procedural aspects necessary for the implementation of this Chapter as regards the following: (a) harmonised electronic forms for the application for clinical investigations and their assessment as referred to in Articles 70 and 78, taking into account specific categories or groups of devices; (b) the functioning of the electronic system referred to in Article 73; (c) harmonised electronic forms for the notification of PMCF investigations as referred to in Article 74(1), and of substantial modifications as referred to in Article 75; (d) the exchange of information between Member States as referred to in Article 76; (e) harmonised electronic forms for the reporting of serious adverse events and device deficiencies as referred to in Article 80; (f) the timelines for the reporting of serious adverse events and device deficiencies, taking into account the severity of the event to be reported as referred to in Article 80; (g) uniform application of the requirements regarding the clinical evidence or data needed to demonstrate compliance with the general safety and performance requirements set out in Annex I. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 82 Requirements regarding other clinical investigations 1.   Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), shall comply with the provisions of Article 62 (2) and (3), points (b), (c), (d), (f), (h), and (l) of Article 62(4) and Article 62(6). 2.   In order to protect the rights, safety, dignity and well-being of subjects and the scientific and ethical integrity of clinical investigations not performed for any of the purposes listed in Article 62(1), each Member State shall define any additional requirements for such investigations, as appropriate for each Member State concerned. CHAPTER VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE SECTION 1 Post-market surveillance Article 83 Post-market surveillance system of the manufacturer 1.   For each device, manufacturers shall plan, establish, document, implement, maintain and update a post-market surveillance system in a manner that is proportionate to the risk class and appropriate for the type of device. That system shall be an integral part of the manufacturer's quality management system referred to in Article 10(9). 2.   The post-market surveillance system shall be suited to actively and systematically gathering, recording and analysing relevant data on the quality, performance and safety of a device throughout its entire lifetime, and to drawing the necessary conclusions and to determining, implementing and monitoring any preventive and corrective actions. 3.   Data gathered by the manufacturer's post-market surveillance system shall in particular be used: (a) to update the benefit-risk determination and to improve the risk management as referred to in Chapter I of Annex I; (b) to update the design and manufacturing information, the instructions for use and the labelling; (c) to update the clinical evaluation; (d) to update the summary of safety and clinical performance referred to in Article 32; (e) for the identification of needs for preventive, corrective or field safety corrective action; (f) for the identification of options to improve the usability, performance and safety of the device; (g) when relevant, to contribute to the post-market surveillance of other devices; and (h) to detect and report trends in accordance with Article 88. The technical documentation shall be updated accordingly. 4.   If, in the course of the post-market surveillance, a need for preventive or corrective action or both is identified, the manufacturer shall implement the appropriate measures and inform the competent authorities concerned and, where applicable, the notified body. Where a serious incident is identified or a field safety corrective action is implemented, it shall be reported in accordance with Article 87. Article 84 Post-market surveillance plan The post-market surveillance system referred to in Article 83 shall be based on a post-market surveillance plan, the requirements for which are set out in Section 1.1 of Annex III. For devices other than custom-made devices, the post-market surveillance plan shall be part of the technical documentation specified in Annex II. Article 85 Post-market surveillance report Manufacturers of class I devices shall prepare a post-market surveillance report summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. The report shall be updated when necessary and made available to the competent authority upon request. Article 86 Periodic safety update report 1.   Manufacturers of class IIa, class IIb and class III devices shall prepare a periodic safety update report (‘PSUR’) for each device and where relevant for each category or group of devices summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. Throughout the lifetime of the device concerned, that PSUR shall set out: (a) the conclusions of the benefit-risk determination; (b) the main findings of the PMCF; and (c) the volume of sales of the device and an estimate evaluation of the size and other characteristics of the population using the device and, where practicable, the usage frequency of the device. Manufacturers of class IIb and class III devices shall update the PSUR at least annually. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. Manufacturers of class IIa devices shall update the PSUR when necessary and at least every two years. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. For custom-made devices, the PSUR shall be part of the documentation referred to in Section 2 of Annex XIII. 2.   For class III devices or implantable devices, manufacturers shall submit PSURs by means of the electronic system referred to in Article 92 to the notified body involved in the conformity assessment in accordance with Article 52. The notified body shall review the report and add its evaluation to that electronic system with details of any action taken. Such PSURs and the evaluation by the notified body shall be made available to competent authorities through that electronic system. 3.   For devices other than those referred to in paragraph 2, manufacturers shall make PSURs available to the notified body involved in the conformity assessment and, upon request, to competent authorities. SECTION 2 Vigilance Article 87 Reporting of serious incidents and field safety corrective actions 1.   Manufacturers of devices made available on the Union market, other than investigational devices, shall report, to the relevant competent authorities, in accordance with Articles 92(5) and (7), the following: (a) any serious incident involving devices made available on the Union market, except expected side-effects which are clearly documented in the product information and quantified in the technical documentation and are subject to trend reporting pursuant to Article 88; (b) any field safety corrective action in respect of devices made available on the Union market, including any field safety corrective action undertaken in a third country in relation to a device which is also legally made available on the Union market, if the reason for the field safety corrective action is not limited to the device made available in the third country. The reports referred to in the first subparagraph shall be submitted through the electronic system referred to in Article 92. 2.   As a general rule, the period for the reporting referred to in paragraph 1 shall take account of the severity of the serious incident. 3.   Manufacturers shall report any serious incident as referred to in point (a) of paragraph 1 immediately after they have established the causal relationship between that incident and their device or that such causal relationship is reasonably possible and not later than 15 days after they become aware of the incident. 4.   Notwithstanding paragraph 3, in the event of a serious public health threat the report referred to in paragraph 1 shall be provided immediately, and not later than 2 days after the manufacturer becomes aware of that threat. 5.   Notwithstanding paragraph 3, in the event of death or an unanticipated serious deterioration in a person's state of health the report shall be provided immediately after the manufacturer has established or as soon as it suspects a causal relationship between the device and the serious incident but not later than 10 days after the date on which the manufacturer becomes aware of the serious incident. 6.   Where necessary to ensure timely reporting, the manufacturer may submit an initial report that is incomplete followed up by a complete report. 7.   If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report within the timeframe required in accordance with paragraphs 2 to 5. 8.   Except in cases of urgency in which the manufacturer needs to undertake field safety corrective action immediately, the manufacturer shall, without undue delay, report the field safety corrective action referred to in point (b) of paragraph 1 in advance of the field safety corrective action being undertaken. 9.   For similar serious incidents that occur with the same device or device type and for which the root cause has been identified or a field safety corrective action implemented or where the incidents are common and well documented, the manufacturer may provide periodic summary reports instead of individual serious incident reports, on condition that the coordinating competent authority referred to in Article 89(9), in consultation with the competent authorities referred to in point (a) of Article 92(8), has agreed with the manufacturer on the format, content and frequency of the periodic summary reporting. Where a single competent authority is referred to in points (a) and (b) of Article 92(8), the manufacturer may provide periodic summary reports following agreement with that competent authority. 10.   The Member States shall take appropriate measures such as organising targeted information campaigns, to encourage and enable healthcare professionals, users and patients to report to the competent authorities suspected serious incidents referred to in point (a) of paragraph 1. The competent authorities shall record centrally at national level reports they receive from healthcare professionals, users and patients. 11.   Where a competent authority of a Member State obtains such reports on suspected serious incidents referred to in point (a) of paragraph 1 from healthcare professionals, users or patients, it shall take the necessary steps to ensure that the manufacturer of the device concerned is informed of the suspected serious incident without delay. Where the manufacturer of the device concerned considers that the incident is a serious incident, it shall provide a report in accordance with paragraphs 1 to 5 of this Article on that serious incident to the competent authority of the Member State in which that serious incident occurred and shall take the appropriate follow-up action in accordance with Article 89. Where the manufacturer of the device concerned considers that the incident is not a serious incident or is an expected undesirable side-effect, which will be covered by trend reporting in accordance with Article 88, it shall provide an explanatory statement. If the competent authority does not agree with the conclusion of the explanatory statement, it may require the manufacturer to provide a report in accordance with paragraphs 1 to 5 of this Article and require it to ensure that appropriate follow-up action is taken in accordance with Article 89. Article 88 Trend reporting 1.   Manufacturers shall report, by means of the electronic system referred to in Article 92, any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side-effects that could have a significant impact on the benefit-risk analysis referred to in Sections 1 and 5 of Annex I and which have led or may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. The significant increase shall be established in comparison to the foreseeable frequency or severity of such incidents in respect of the device, or category or group of devices, in question during a specific period as specified in the technical documentation and product information. The manufacturer shall specify how to manage the incidents referred to in the first subparagraph and the methodology used for determining any statistically significant increase in the frequency or severity of such incidents, as well as the observation period, in the post-market surveillance plan referred to in Article 84. 2.   The competent authorities may conduct their own assessments on the trend reports referred to in paragraph 1 and require the manufacturer to adopt appropriate measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. Each competent authority shall inform the Commission, the other competent authorities and the notified body that issued the certificate, of the results of such assessment and of the adoption of such measures. Article 89 Analysis of serious incidents and field safety corrective actions 1.   Following the reporting of a serious incident pursuant to Article 87(1), the manufacturer shall, without delay, perform the necessary investigations in relation to the serious incident and the devices concerned. This shall include a risk assessment of the incident and field safety corrective action taking into account criteria as referred to in paragraph 3 of this Article as appropriate. The manufacturer shall co-operate with the competent authorities and where relevant with the notified body concerned during the investigations referred to in the first subparagraph and shall not perform any investigation which involves altering the device or a sample of the batch concerned in a way which may affect any subsequent evaluation of the causes of the incident, prior to informing the competent authorities of such action. 2.   Member States shall take the necessary steps to ensure that any information regarding a serious incident that has occurred within their territory, or a field safety corrective action that has been or is to be undertaken within their territory, and that is brought to their knowledge in accordance with Article 87 is evaluated centrally at national level by their competent authority, if possible together with the manufacturer, and, where relevant, the notified body concerned. 3.   In the context of the evaluation referred to in paragraph 2, the competent authority shall evaluate the risks arising from the reported serious incident and evaluate any related field safety corrective actions, taking into account the protection of public health and criteria such as causality, detectability and probability of recurrence of the problem, frequency of use of the device, probability of occurrence of direct or indirect harm, the severity of that harm, the clinical benefit of the device, intended and potential users, and population affected. The competent authority shall also evaluate the adequacy of the field safety corrective action envisaged or undertaken by the manufacturer and the need for, and kind of, any other corrective action, in particular taking into account the principle of inherent safety contained in Annex I. Upon request by the national competent authority, manufacturers shall provide all documents necessary for the risk assessment. 4.   The competent authority shall monitor the manufacturer's investigation of a serious incident. Where necessary, a competent authority may intervene in a manufacturer's investigation or initiate an independent investigation. 5.   The manufacturer shall provide a final report to the competent authority setting out its findings from the investigation by means of the electronic system referred to in Article 92. The report shall set out conclusions and where relevant indicate corrective actions to be taken. 6.   In the case of devices referred to in the first subparagraph of Article 1(8) and where the serious incident or field safety corrective action may be related to a substance which, if used separately, would be considered to be a medicinal product, the evaluating competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall, inform the national competent authority or the EMA, depending on which issued the scientific opinion on that substance under Article 52(9), of that serious incident or field safety corrective action. In the case of devices covered by this Regulation in accordance with point (g) of Article 1(6) and where the serious incident or field safety corrective action may be related to the derivatives of tissues or cells of human origin utilised for the manufacture of the device, and in the case of devices falling under this Regulation pursuant to Article 1(10), the competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall inform the competent authority for human tissues and cells that was consulted by the notified body in accordance with Article 52(10). 7.   After carrying out the evaluation in accordance with paragraph 3 of this Article, the evaluating competent authority shall, through the electronic system referred to in Article 92, inform, without delay, the other competent authorities of the corrective action taken or envisaged by the manufacturer or required of it to minimise the risk of recurrence of the serious incident, including information on the underlying events and the outcome of its assessment. 8.   The manufacturer shall ensure that information about the field safety corrective action taken is brought without delay to the attention of users of the device in question by means of a field safety notice. The field safety notice shall be edited in an official Union language or languages determined by the Member State in which the field safety corrective action is taken. Except in cases of urgency, the content of the draft field safety notice shall be submitted to the evaluating competent authority or, in the cases referred to in paragraph 9, to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice shall be consistent in all Member States. The field safety notice shall allow the correct identification of the device or devices involved, in particular by including the relevant UDIs, and the correct identification, in particular, by including the SRN, if already issued, of the manufacturer that has undertaken the field safety corrective action. The field safety notice shall explain, in a clear manner, without understating the level of risk, the reasons for the field safety corrective action with reference to the device malfunction and associated risks for patients, users or other persons, and shall clearly indicate all the actions to be taken by users. The manufacturer shall enter the field safety notice in the electronic system referred to in Article 92 through which that notice shall be accessible to the public. 9.   The competent authorities shall actively participate in a procedure in order to coordinate their assessments referred to in paragraph 3 in the following cases: (a) where there is concern regarding a particular serious incident or cluster of serious incidents relating to the same device or type of device of the same manufacturer in more than one Member State; (b) where the appropriateness of a field safety corrective action that is proposed by a manufacturer in more than one Member State is in question. That coordinated procedure shall cover the following: — designation of a coordinating competent authority on a case by case basis, when required; — defining the coordinated assessment process, including the tasks and responsibilities of the coordinating competent authority and the involvement of other competent authorities. Unless otherwise agreed between the competent authorities, the coordinating competent authority shall be the competent authority of the Member State in which the manufacturer has its registered place of business. The coordinating competent authority shall, through the electronic system referred to in Article 92, inform the manufacturer, the other competent authorities and the Commission that it has assumed the role of coordinating authority. 10.   The designation of a coordinating competent authority shall not affect the rights of the other competent authorities to perform their own assessment and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating competent authority and the Commission shall be kept informed of the outcome of any such assessment and the adoption of any such measures. 11.   The Commission shall provide administrative support to the coordinating competent authority in the accomplishment of its tasks under this Chapter. Article 90 Analysis of vigilance data The Commission shall, in collaboration with the Member States, put in place systems and processes to actively monitor the data available in the electronic system referred to in Article 92, in order to identify trends, patterns or signals in the data that may reveal new risks or safety concerns. Where a previously unknown risk is identified or the frequency of an anticipated risk significantly and adversely changes the benefit-risk determination, the competent authority or, where appropriate, the coordinating competent authority shall inform the manufacturer, or where applicable the authorised representative, which shall then take the necessary corrective actions. Article 91 Implementing acts The Commission may, by means of implementing acts, and after consultation of the MDCG, adopt the detailed arrangements and procedural aspects necessary for the implementation of Articles 85 to 90 and 92 as regards the following: (a) the typology of serious incidents and field safety corrective actions in relation to specific devices, or categories or groups of devices; (b) the reporting of serious incidents and field safety corrective actions and field safety notices, and the provision of periodic summary reports, post-market surveillance reports, PSURs and trend reports by manufacturers as referred to in Articles 85, 86, 87, 88 and 89 respectively; (c) standard structured forms for electronic and non-electronic reporting, including a minimum data set for reporting of suspected serious incidents by healthcare professionals, users and patients; (d) timelines for the reporting of field safety corrective actions, and for the provision by manufacturers of periodic summary reports and trend reports, taking into account the severity of the incident to be reported as referred to in Article 87; (e) harmonised forms for the exchange of information between competent authorities as referred to in Article 89; (f) procedures for the designation of a coordinating competent authority; the coordinated evaluation process, including tasks and responsibilities of the coordinating competent authority and involvement of other competent authorities in this process. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 92 Electronic system on vigilance and on post-market surveillance 1.   The Commission shall, in collaboration with the Member States, set up and manage an electronic system to collate and process the following information: (a) the reports by manufacturers on serious incidents and field safety corrective actions referred to in Article 87(1) and Article 89(5); (b) the periodic summary reports by manufacturers referred to in Article 87(9); (c) the reports by manufacturers on trends referred to in Article 88; (d) the PSURs referred to in Article 86; (e) the field safety notices by manufacturers referred to in Article 89(8); (f) the information to be exchanged between the competent authorities of the Member States and between them and the Commission in accordance with Article 89(7) and (9). That electronic system shall include relevant links to the UDI database. 2.   The information referred to in paragraph 1 of this Article shall be made available through the electronic system to the competent authorities of the Member States and to the Commission. The notified bodies shall also have access to that information to the extent that it relates to devices for which they issued a certificate in accordance with Article 53. 3.   The Commission shall ensure that healthcare professionals and the public have appropriate levels of access to the electronic system referred to in paragraph 1. 4.   On the basis of arrangements between the Commission and competent authorities of third countries or international organisations, the Commission may grant those competent authorities or international organisations access to the electronic system referred to in paragraph 1 at the appropriate level. Those arrangements shall be based on reciprocity and make provision for confidentiality and data protection equivalent to those applicable in the Union. 5.   The reports on serious incidents referred to in point (a) of Article 87(1) shall be automatically transmitted, upon receipt, via the electronic system referred to in paragraph 1 of this Article, to the competent authority of the Member State in which the incident occurred. 6.   The trend reports referred to in Article 88(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the Member State in which the incidents occurred. 7.   The reports on field safety corrective actions referred to in point (b) of Article 87(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the following Member States: (a) the Member States in which the field safety corrective action is being or is to be undertaken; (b) the Member State in which the manufacturer has its registered place of business. 8.   The periodic summary reports referred to in Article 87(9) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authority of: (a) the Member State or Member States participating in the coordination procedure in accordance with Article 89(9) and which have agreed on the periodic summary report; (b) the Member State in which the manufacturer has its registered place of business. 9.   The information referred to in paragraphs 5 to 8 of this Article shall be automatically transmitted, upon receipt, through the electronic system referred to in paragraph 1 of this Article, to the notified body that issued the certificate for the device in question in accordance with Article 56. SECTION 3 Market surveillance Article 93 Market surveillance activities 1.   The competent authorities shall perform appropriate checks on the conformity characteristics and performance of devices including, where appropriate, a review of documentation and physical or laboratory checks on the basis of adequate samples. The competent authorities shall, in particular, take account of established principles regarding risk assessment and risk management, vigilance data and complaints. 2.   The competent authorities shall draw up annual surveillance activity plans and allocate a sufficient number of material and competent human resources in order to carry out those activities taking into account the European market surveillance programme developed by the MDCG pursuant to Article 105 and local circumstances. 3.   In order to fulfil the obligations laid down in paragraph 1, the competent authorities: (a) may require economic operators to, inter alia, make available the documentation and information necessary for the purpose of carrying out the authorities' activities and, where justified, to provide the necessary samples of devices or access to devices free of charge; and (b) shall carry out both announced and, if necessary, unannounced inspections of the premises of economic operators, as well as suppliers and/or subcontractors, and, where necessary, at the facilities of professional users. 4.   The competent authorities shall prepare an annual summary of the results of their surveillance activities and make it accessible to other competent authorities by means of the electronic system referred to in Article 100. 5.   The competent authorities may confiscate, destroy or otherwise render inoperable devices that present an unacceptable risk or falsified devices where they deem it necessary to do so in the interests of the protection of public health. 6.   Following each inspection carried out for the purposes referred to in paragraph 1, the competent authority shall draw up a report on the findings of the inspection that concern compliance with the legal and technical requirements applicable under this Regulation. The report shall set out any corrective actions needed. 7.   The competent authority which carried out the inspection shall communicate the content of the report referred to in paragraph 6 of this Article to the economic operator that has been the subject of the inspection. Before adopting the final report, the competent authority shall give that economic operator the opportunity to submit comments. That final inspection report shall be entered in the electronic system provided for in Article 100. 8.   The Member States shall review and assess the functioning of their market surveillance activities. Such reviews and assessments shall be carried out at least every four years and the results thereof shall be communicated to the other Member States and the Commission. Each Member State shall make a summary of the results accessible to the public by means of the electronic system referred to in Article 100. 9.   The competent authorities of the Member States shall coordinate their market surveillance activities, cooperate with each other and share with each other and with the Commission the results thereof, to provide for a harmonised and high level of market surveillance in all Member States. Where appropriate, the competent authorities of the Member States shall agree on work-sharing, joint market surveillance activities and specialisation. 10.   Where more than one authority in a Member State is responsible for market surveillance and external border controls, those authorities shall cooperate with each other, by sharing information relevant to their role and functions. 11.   Where appropriate, the competent authorities of the Member States shall cooperate with the competent authorities of third countries with a view to exchanging information and technical support and promoting activities relating to market surveillance. Article 94 Evaluation of devices suspected of presenting an unacceptable risk or other non-compliance Where the competent authorities of a Member State, based on data obtained by vigilance or market surveillance activities or on other information, have reason to believe that a device: (a) may present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health; or (b) otherwise does not comply with the requirements laid down in this Regulation, they shall carry out an evaluation of the device concerned covering all requirements laid down in this Regulation relating to the risk presented by the device, or to any other non-compliance of the device. The relevant economic operators shall cooperate with the competent authorities. Article 95 Procedure for dealing with devices presenting an unacceptable risk to health and safety 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities find that the device presents an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall without delay require the manufacturer of the devices concerned, its authorised representative and all other relevant economic operators to take all appropriate and duly justified corrective action to bring the device into compliance with the requirements of this Regulation relating to the risk presented by the device and, in a manner that is proportionate to the nature of the risk, to restrict the making available of the device on the market, to subject the making available of the device to specific requirements, to withdraw the device from the market, or to recall it, within a reasonable period that is clearly defined and communicated to the relevant economic operator. 2.   The competent authorities shall, without delay, notify the Commission, the other Member States and, where a certificate has been issued in accordance with Article 56 for the device concerned, the notified body that issued that certificate, of the results of the evaluation and of the actions which they have required the economic operators to take, by means of the electronic system referred to in Article 100. 3.   The economic operators as referred to in paragraph 1 shall, without delay, ensure that all appropriate corrective action is taken throughout the Union in respect of all the devices concerned that they have made available on the market. 4.   Where the economic operator as referred to in paragraph 1 does not take adequate corrective action within the period referred to in paragraph 1, the competent authorities shall take all appropriate measures to prohibit or restrict the making available of the device on their national market, to withdraw the device from that market or to recall it. The competent authorities shall notify the Commission, the other Member States and the notified body referred to in paragraph 2 of this Article, without delay, of those measures, by means of the electronic system referred to in Article 100. 5.   The notification referred to in paragraph 4 shall include all available details, in particular the data necessary for the identification and tracing of the non-compliant device, the origin of the device, the nature of and the reasons for the non-compliance alleged and the risk involved, the nature and duration of the national measures taken and the arguments put forward by the relevant economic operator. 6.   Member States other than the Member State initiating the procedure shall, without delay, inform the Commission and the other Member States, by means of the electronic system referred to in Article 100, of any additional relevant information at their disposal relating to the non-compliance of the device concerned and of any measures adopted by them in relation to the device concerned. In the event of disagreement with the notified national measure, they shall, without delay, inform the Commission and the other Member States of their objections, by means of the electronic system referred to in Article 100. 7.   Where, within two months of receipt of the notification referred to in paragraph 4, no objection has been raised by either a Member State or the Commission in respect of any measures taken by a Member State, those measures shall be deemed to be justified. In that case, all Member States shall ensure that corresponding appropriate restrictive or prohibitive measures, including withdrawing, recalling or limiting the availability of the device on their national market, are taken without delay in respect of the device concerned. Article 96 Procedure for evaluating national measures at Union level 1.   Where, within two months of receipt of the notification referred to in Article 95(4), objections are raised by a Member State against a measure taken by another Member State, or where the Commission considers the measure to be contrary to Union law, the Commission shall, after consulting the competent authorities concerned and, where necessary, the economic operators concerned, evaluate that national measure. On the basis of the results of that evaluation, the Commission may decide, by means of implementing acts, whether or not the national measure is justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Where the Commission considers the national measure to be justified as referred to in paragraph 1 of this Article, the second subparagraph of Article 95(7) shall apply. If the Commission considers the national measure to be unjustified, the Member State concerned shall withdraw the measure. Where the Commission does not adopt a decision pursuant to paragraph 1 of this Article within eight months of receipt of the notification referred to in Article 95(4), the national measure shall be considered to be justified. 3.   Where a Member State or the Commission considers that the risk to health and safety emanating from a device cannot be mitigated satisfactorily by means of measures taken by the Member State or Member States concerned, the Commission, at the request of a Member State or on its own initiative, may take, by means of implementing acts, the necessary and duly justified measures to ensure the protection of health and safety, including measures restricting or prohibiting the placing on the market and putting into service of the device concerned. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 97 Other non-compliance 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities of a Member State find that a device does not comply with the requirements laid down in this Regulation but does not present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall require the relevant economic operator to bring the non-compliance concerned to an end within a reasonable period that is clearly defined and communicated to the economic operator and that is proportionate to the non-compliance. 2.   Where the economic operator does not bring the non-compliance to an end within the period referred to in paragraph 1 of this Article, the Member State concerned shall, without delay, take all appropriate measures to restrict or prohibit the product being made available on the market or to ensure that it is recalled or withdrawn from the market. That Member State shall inform the Commission and the other Member States, without delay, of those measures, by means of the electronic system referred to in Article 100. 3.   In order to ensure the uniform application of this Article, the Commission may, by means of implementing acts, specify appropriate measures to be taken by competent authorities to address given types of non-compliance. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 98 Preventive health protection measures 1.   Where a Member State, after having performed an evaluation which indicates a potential risk related to a device or a specific category or group of devices, considers that, in order to protect the health and safety of patients, users or other persons or other aspects of public health, the making available on the market or putting into service of a device or a specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled, it may take any necessary and justified measures. 2.   The Member State referred to in paragraph 1 shall immediately notify the Commission and all other Member States, giving the reasons for its decision, by means of the electronic system referred to in Article 100. 3.   The Commission, in consultation with the MDCG and, where necessary, the economic operators concerned, shall assess the national measures taken. The Commission may decide, by means of implementing acts, whether the national measures are justified or not. In the absence of a Commission decision within six months of their notification, the national measures shall be considered to be justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 4.   Where the assessment referred to in paragraph 3 of this Article demonstrates that the making available on the market or putting into service of a device, specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled in all Member States in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission may adopt implementing acts to take the necessary and duly justified measures. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 99 Good administrative practice 1.   Any measure adopted by the competent authorities of the Member States pursuant to Articles 95 to 98 shall state the exact grounds on which it is based. Where such a measure is addressed to a specific economic operator, the competent authority shall notify without delay the economic operator concerned of that measure, and shall at the same time inform that economic operator of the remedies available under the law or the administrative practice of the Member State concerned and of the time limits to which such remedies are subject. Where the measure is of general applicability, it shall be appropriately published. 2.   Except in cases where immediate action is necessary for reasons of unacceptable risk to human health or safety, the economic operator concerned shall be given the opportunity to make submissions to the competent authority within an appropriate period of time that is clearly defined before any measure is adopted. Where action has been taken without the economic operator having had the opportunity to make submissions as referred to in the first subparagraph, it shall be given the opportunity to make submissions as soon as possible and the action taken shall be reviewed promptly thereafter. 3.   Any measure adopted shall be immediately withdrawn or amended upon the economic operator's demonstrating that it has taken effective corrective action and that the device is in compliance with the requirements of this Regulation. 4.   Where a measure adopted pursuant to Articles 95 to 98 concerns a device for which a notified body has been involved in the conformity assessment, the competent authorities shall by means of the electronic system referred to in Article 100 inform the relevant notified body and the authority responsible for the notified body of the measure taken. Article 100 Electronic system on market surveillance 1.   The Commission, in collaboration with the Member States, shall set up and manage an electronic system to collate and process the following information: (a) summaries of the results of the surveillance activities referred to in Article 93(4); (b) the final inspection report referred to in Article 93(7); (c) information in relation to devices presenting an unacceptable risk to health and safety as referred to in Article 95(2), (4) and (6); (d) information in relation to non-compliance of products as referred to in Article 97(2); (e) information in relation to the preventive health protection measures referred to in Article 98(2); (f) summaries of the results of the reviews and assessments of the market surveillance activities of the Member States referred to in 93(8). 2.   The information referred to in paragraph 1 of this Article shall be immediately transmitted through the electronic system to all competent authorities concerned and, where applicable, to the notified body that issued a certificate in accordance with Article 56 for the device concerned and be accessible to the Member States and to the Commission. 3.   Information exchanged between Member States shall not be made public where to do so might impair market surveillance activities and co-operation between Member States. CHAPTER VIII COOPERATION BETWEEN MEMBER STATES, MEDICAL DEVICE COORDINATION GROUP, EXPERT LABORATORIES, EXPERT PANELS AND DEVICE REGISTERS Article 101 Competent authorities The Member States shall designate the competent authority or authorities responsible for the implementation of this Regulation. They shall entrust their authorities with the powers, resources, equipment and knowledge necessary for the proper performance of their tasks pursuant to this Regulation. The Member States shall communicate the names and contact details of the competent authorities to the Commission which shall publish a list of competent authorities. Article 102 Cooperation 1.   The competent authorities of the Member States shall cooperate with each other and with the Commission. The Commission shall provide for the organisation of exchanges of information necessary to enable this Regulation to be applied uniformly. 2.   Member States shall, with the support of the Commission, participate, where appropriate, in initiatives developed at international level with the aim of ensuring cooperation between regulatory authorities in the field of medical devices. Article 103 Medical Device Coordination Group 1.   A Medical Device Coordination Group (‘MDCG’) is hereby established. 2.   Each Member State shall appoint to the MDCG, for a three-year term which may be renewed, one member and one alternate each with expertise in the field of medical devices, and one member and one alternate with expertise in the field of in vitro diagnostic medical devices. A Member State may choose to appoint only one member and one alternate, each with expertise in both fields. The members of the MDCG shall be chosen for their competence and experience in the field of medical devices and in vitro diagnostic medical devices. They shall represent the competent authorities of the Member States. The names and affiliation of members shall be made public by the Commission. The alternates shall represent and vote for the members in their absence. 3.   The MDCG shall meet at regular intervals and, where the situation requires, upon request by the Commission or a Member State. The meetings shall be attended either by the members appointed for their role and expertise in the field of medical devices, or by the members appointed for their expertise in the field of in vitro diagnostic medical devices, or by the members appointed for their expertise in both fields, or their alternates, as appropriate. 4.   The MDCG shall use its best endeavours to reach consensus. If such consensus cannot be reached, the MDCG shall decide by a majority of its members. Members with diverging positions may request that their positions and the grounds on which they are based be recorded in the MDCG's position. 5.   The MDCG shall be chaired by a representative of the Commission. The chair shall not take part in votes of the MDCG. 6.   The MDCG may invite, on a case-by-case basis, experts and other third parties to attend meetings or provide written contributions. 7.   The MDCG may establish standing or temporary sub-groups. Where appropriate, organisations representing the interests of the medical device industry, healthcare professionals, laboratories, patients and consumers at Union level shall be invited to such sub-groups in the capacity of observers. 8.   The MDCG shall establish its rules of procedure which shall, in particular, lay down procedures for the following: — the adoption of opinions or recommendations or other positions, including in cases of urgency; — the delegation of tasks to reporting and co-reporting members; — the implementation of Article 107 regarding conflict of interests; — the functioning of sub-groups. 9.   The MDCG shall have the tasks laid down in Article 105 of this Regulation and Article 99 of Regulation (EU) 2017/746. Article 104 Support by the Commission The Commission shall support the functioning of the cooperation between national competent authorities. It shall, in particular, provide for the organisation of exchanges of experience between the competent authorities and provide technical, scientific and logistic support to the MDCG and its sub-groups. It shall organise the meetings of the MDCG and its sub-groups, participate in those meetings and ensure the appropriate follow-up. Article 105 Tasks of the MDCG Under this Regulation, the MDCG shall have the following tasks: (a) to contribute to the assessment of applicant conformity assessment bodies and notified bodies pursuant to the provisions set out in Chapter IV; (b) to advise the Commission, at its request, in matters concerning the coordination group of notified bodies as established pursuant to Article 49; (c) to contribute to the development of guidance aimed at ensuring effective and harmonised implementation of this Regulation, in particular regarding the designation and monitoring of notified bodies, application of the general safety and performance requirements and conduct of clinical evaluations and investigations by manufacturers, assessment by notified bodies and vigilance activities; (d) to contribute to the continuous monitoring of technical progress and assessment of whether the general safety and performance requirements laid down in this Regulation and Regulation (EU) 2017/746 are adequate to ensure safety and performance of devices, and thereby contribute to identifying whether there is a need to amend Annex I to this Regulation; (e) to contribute to the development of device standards, of CS and of scientific guidelines, including product specific guidelines, on clinical investigation of certain devices in particular implantable devices and class III devices; (f) to assist the competent authorities of the Member States in their coordination activities in particular in the fields of classification and the determination of the regulatory status of devices, clinical investigations, vigilance and market surveillance including the development and maintenance of a framework for a European market surveillance programme with the objective of achieving efficiency and harmonisation of market surveillance in the Union, in accordance with Article 93; (g) to provide advice, either on its own initiative or at request of the Commission, in the assessment of any issue related to the implementation of this Regulation; (h) to contribute to harmonised administrative practice with regard to devices in the Member States. Article 106 Provision of scientific, technical and clinical opinions and advice 1.   The Commission shall, by means of implementing acts and in consultation with the MDCG, make provision for expert panels to be designated for the assessment of the clinical evaluation in relevant medical fields as referred to in paragraph 9 of this Article and to provide views in accordance with Article 48(6) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices and, where necessary, for categories or groups of devices, or for specific hazards relating to categories or groups of devices, observing the principles of highest scientific competence, impartiality, independence and transparency. The same principles shall apply where the Commission decides to appoint expert laboratories in accordance with paragraph 7 of this Article. 2.   Expert panels and expert laboratories may be designated in areas where the Commission, in consultation with the MDCG, has identified a need for the provision of consistent scientific, technical and/or clinical advice or laboratory expertise in relation to the implementation of this Regulation. Expert panels and expert laboratories may be appointed on a standing or temporary basis. 3.   Expert panels shall consist of advisors appointed by the Commission on the basis of up-to-date clinical, scientific or technical expertise in the field and with a geographical distribution that reflects the diversity of scientific and clinical approaches in the Union. The Commission shall determine the number of members of each panel in accordance with the requisite needs. The members of expert panels shall perform their tasks with impartiality and objectivity. They shall neither seek nor take instructions from notified bodies or manufacturers. Each member shall draw up a declaration of interests, which shall be made publicly available. The Commission shall establish systems and procedures to actively manage and prevent potential conflicts of interest. 4.   Expert panels shall take into account relevant information provided by stakeholders including patients' organisations and healthcare professionals when preparing their scientific opinions. 5.   The Commission, following consultation with the MDCG, may appoint advisors to expert panels following publication in the Official Journal of the European Union and on the Commission website following a call for expressions of interest. Depending on the type of task and the need for specific expertise, advisors may be appointed to the expert panels for a maximum period of three years and their appointment may be renewed. 6.   The Commission, following consultation with the MDCG, may include advisors on a central list of available experts who, whilst not being formally appointed to a panel, are available to provide advice and to support the work of the expert panel as needed. That list shall be published on the Commission website. 7.   The Commission may, by means of implementing acts and following consultation with the MDCG, designate expert laboratories, on the basis of their expertise in: — physico-chemical characterisation, or — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical biological and toxicological testing of specific devices, categories or groups of devices. The Commission shall only designate expert laboratories for which a Member State or the Joint Research Centre has submitted an application for designation. 8.   Expert laboratories shall satisfy the following criteria: (a) have adequate and appropriately qualified staff with adequate knowledge and experience in the field of the devices for which they are designated; (b) possess the necessary equipment to carry out the tasks assigned to them; (c) have the necessary knowledge of international standards and best practices; (d) have an appropriate administrative organisation and structure; (e) ensure that their staff observe the confidentiality of information and data obtained in carrying out their tasks. 9.   Expert panels appointed for clinical evaluation in relevant medical fields shall fulfil the tasks provided for in Article 54(1) and Article 61(2) and Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. 10.   Expert panels and expert laboratories may have the following tasks, depending on the requisite needs: (a) to provide scientific, technical and clinical assistance to the Commission and the MDCG in relation to the implementation of this Regulation; (b) to contribute to the development and maintenance of appropriate guidance and CS for: — clinical investigations, — clinical evaluation and PMCF, — performance studies, — performance evaluation and post-market performance follow-up, — physico-chemical characterisation, and — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing for specific devices, or a category or group of devices, or for specific hazards related to a category or group of devices; (c) to develop and review clinical evaluation guidance and performance evaluation guidance for performance of conformity assessment in line with the state of the art with regard to clinical evaluation, performance evaluation, physico-chemical characterisation, and microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing; (d) to contribute to the development of standards at international level, ensuring that such standards reflect the state of the art; (e) to provide opinions in response to consultations by manufacturers in accordance with Article 61(2), notified bodies and Member States in accordance with paragraphs 11 to 13 of this Article. (f) to contribute to identification of concerns and emerging issues on the safety and performance of medical devices; (g) to provide views in accordance with Article 48(4) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices. 11.   The Commission, shall facilitate the access of Member States and notified bodies and manufacturers to advice provided by expert panels and expert laboratories concerning, inter alia, the criteria for an appropriate data set for assessment of the conformity of a device, in particular with regard to the clinical data required for clinical evaluation, with regard to physico-chemical characterisation, and with regard to microbiological, biocompatibility, mechanical, electrical, electronic and non-clinical toxicological testing. 12.   When adopting its scientific opinion in accordance with paragraph 9, the members of the expert panels shall use their best endeavours to reach consensus. If consensus cannot be reached, the expert panels shall decide by a majority of their members, and the scientific opinion shall mention the divergent positions and the grounds on which they are based. The Commission shall publish the scientific opinion and advice delivered in accordance with paragraphs 9 and 11 of this Article, ensuring consideration of aspects of confidentiality as set out in Article 109. The clinical evaluation guidance referred to in point (c) of paragraph 10 shall be published following consultation with the MDCG. 13.   The Commission may require manufacturers and notified bodies to pay fees for the advice provided by expert panels and expert laboratories. The structure and the level of fees as well as the scale and structure of recoverable costs shall be adopted by the Commission by means of implementing acts, taking into account the objectives of the adequate implementation of this Regulation, protection of health and safety, support of innovation and cost-effectiveness and the necessity to achieve active participation in the expert panels. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 14.   The fees payable to the Commission in accordance with the procedure under paragraph 13 of this Article shall be set in a transparent manner and on the basis of the costs for the services provided. The fees payable shall be reduced in the case of a clinical evaluation consultation procedure initiated in accordance with point (c) of Section 5.1 of Annex IX involving a manufacturer who is a micro, small or medium-sized enterprise within the meaning of Recommendation 2003/361/EC. 15.   The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the tasks of expert panels and expert laboratories referred to in paragraph 10 of this Article. Article 107 Conflict of interests 1.   Members of the MDCG, its sub-groups, and members of expert panels and expert laboratories shall not have financial or other interests in the medical device industry which could affect their impartiality. They shall undertake to act in the public interest and in an independent manner. They shall declare any direct or indirect interests they may have in the medical device industry and update that declaration whenever a relevant change occurs. The declaration of interests shall be made publicly available on the Commission website. This Article shall not apply to the representatives of stakeholder organisations participating in the sub-groups of the MDCG. 2.   Experts and other third parties invited by the MDCG on a case-by-case basis shall declare any interests they may have in the issue in question. Article 108 Device registers and databanks The Commission and the Member States shall take all appropriate measures to encourage the establishment of registers and databanks for specific types of devices setting common principles to collect comparable information. Such registers and databanks shall contribute to the independent evaluation of the long-term safety and performance of devices, or the traceability of implantable devices, or all of such characteristics. CHAPTER IX CONFIDENTIALITY, DATA PROTECTION, FUNDING AND PENALTIES Article 109 Confidentiality 1.   Unless otherwise provided for in this Regulation and without prejudice to existing national provisions and practices in the Member States on confidentiality, all parties involved in the application of this Regulation shall respect the confidentiality of information and data obtained in carrying out their tasks in order to protect the following: (a) personal data, in accordance with Article 110; (b) commercially confidential information and trade secrets of a natural or legal person, including intellectual property rights; unless disclosure is in the public interest; (c) the effective implementation of this Regulation, in particular for the purpose of inspections, investigations or audits. 2.   Without prejudice to paragraph 1, information exchanged on a confidential basis between competent authorities and between competent authorities and the Commission shall not be disclosed without the prior agreement of the originating authority. 3.   Paragraphs 1 and 2 shall not affect the rights and obligations of the Commission, Member States and notified bodies with regard to exchange of information and the dissemination of warnings, nor the obligations of the persons concerned to provide information under criminal law. 4.   The Commission and Member States may exchange confidential information with regulatory authorities of third countries with which they have concluded bilateral or multilateral confidentiality arrangements. Article 110 Data protection 1.   Member States shall apply Directive 95/46/EC to the processing of personal data carried out in the Member States pursuant to this Regulation. 2.   Regulation (EC) No 45/2001 shall apply to the processing of personal data carried out by the Commission pursuant to this Regulation. Article 111 Levying of fees 1.   This Regulation shall be without prejudice to the possibility for Member States to levy fees for the activities set out in this Regulation, provided that the level of the fees is set in a transparent manner and on the basis of cost-recovery principles. 2.   Member States shall inform the Commission and the other Member States at least three months before the structure and level of fees is to be adopted. The structure and level of fees shall be made publicly available on request. Article 112 Funding of activities related to designation and monitoring of notified bodies The costs associated with joint assessment activities shall be covered by the Commission. The Commission shall, by means of implementing acts, lay down the scale and structure of recoverable costs and other necessary implementing rules. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 113 Penalties The Member States shall lay down the rules on penalties applicable for infringement of the provisions of this Regulation and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be effective, proportionate, and dissuasive. The Member States shall notify the Commission of those rules and of those measures by 25 February 2020 and shall notify it, without delay, of any subsequent amendment affecting them. CHAPTER X FINAL PROVISIONS Article 114 Committee procedure 1.   The Commission shall be assisted by a Committee on Medical Devices. That Committee shall be a committee within the meaning of Regulation (EU) No 182/2011. 2.   Where reference is made to this paragraph, Article 4 of Regulation (EU) No 182/2011 shall apply. 3.   Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply. Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third subparagraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply. 4.   Where reference is made to this paragraph, Article 8 of Regulation (EU) No 182/2011, in conjunction with Article 4 or 5 thereof, as appropriate, shall apply. Article 115 Exercise of the delegation 1.   The power to adopt delegated acts is conferred on the Commission subject to the conditions laid down in this Article. 2.   The power to adopt delegated acts referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall be conferred on the Commission for a period of five years from 25 May 2017. The Commission shall draw up a report in respect of the delegation of power not later than nine months before the end of the five-year period. The delegation of power shall be tacitly extended for periods of an identical duration, unless the European Parliament or the Council opposes such extension not later than three months before the end of each period. 3.   The delegation of power referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) may be revoked at any time by the European Parliament or by the Council. A decision to revoke shall put an end to the delegation of the power specified in that decision. It shall take effect the day following the publication of the decision in the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity of any delegated acts already in force. 4.   Before adopting a delegated act, the Commission shall consult experts designated by each Member State in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making. 5.   As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament and to the Council. 6.   A delegated act adopted pursuant to Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall enter into force only if no objection has been expressed either by the European Parliament or by the Council within a period of three months of notification of that act to the European Parliament and the Council or if, before the expiry of that period, the European Parliament and the Council have both informed the Commission that they will not object. That period shall be extended by three months at the initiative of the European Parliament or of the Council. Article 116 Separate delegated acts for different delegated powers The Commission shall adopt a separate delegated act in respect of each power delegated to it pursuant to this Regulation. Article 117 Amendment to Directive 2001/83/EC In Annex I to Directive 2001/83/EC, point 12 of Section 3.2. is replaced by the following: ‘(12) Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question. Article 118 Amendment to Regulation (EC) No 178/2002 In the third paragraph of Article 2 of Regulation (EC) No 178/2002, the following point is added: ‘(i) medical devices within the meaning of Regulation (EU) 2017/745 of the European Parliament and of the Council (*2). Article 119 Amendment to Regulation (EC) No 1223/2009 In Article 2 of Regulation (EC) No 1223/2009, the following paragraph is added: ‘4.   The Commission may, at the request of a Member State or on its own initiative, adopt the necessary measures to determine whether or not a specific product or group of products falls within the definition ‘cosmetic product’. Those measures shall be adopted in accordance with the regulatory procedure referred to in Article 32(2).’. Article 120 Transitional provisions 1.   From 26 May 2020, any publication of a notification in respect of a notified body in accordance with Directives 90/385/EEC and 93/42/EEC shall become void. 2.   Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC prior to 25 May 2017 shall remain valid until the end of the period indicated on the certificate, except for certificates issued in accordance with Annex 4 to Directive 90/385/EEC or Annex IV to Directive 93/42/EEC which shall become void at the latest on 27 May 2022. Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC from 25 May 2017 shall remain valid until the end of the period indicated on the certificate, which shall not exceed five years from its issuance. They shall however become void at the latest on 27 May 2024. 3.   By way of derogation from Article 5 of this Regulation, a device with a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC and which is valid by virtue of paragraph 2 of this Article may only be placed on the market or put into service provided that from the date of application of this Regulation it continues to comply with either of those Directives, and provided there are no significant changes in the design and intended purpose. However, the requirements of this Regulation relating to post-market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in those Directives. Without prejudice to Chapter IV and paragraph 1 of this Article, the notified body that issued the certificate referred to in the first subparagraph shall continue to be responsible for the appropriate surveillance in respect of all of the applicable requirements relating to the devices it has certified. 4.   Devices lawfully placed on the market pursuant to Directives 90/385/EEC and 93/42/EEC prior to 26 May 2020, and devices placed on the market from 26 May 2020 by virtue of a certificate as referred to in paragraph 2 of this Article, may continue to be made available on the market or put into service until 27 May 2025. 5.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, devices which comply with this Regulation may be placed on the market prior to 26 May 2020. 6.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, conformity assessment bodies which comply with this Regulation may be designated and notified prior 26 May 2020. Notified bodies which are designated and notified in accordance with this Regulation may carry out the conformity assessment procedures laid down in this Regulation and issue certificates in accordance with this Regulation prior to 26 May 2020. 7.   As regards devices subject to the consultation procedure laid down in Article 54, paragraph 5 of this Article shall apply provided that the necessary appointments to the MDCG and expert panels have been made. 8.   By way of derogation from Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC and Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, manufacturers, authorised representatives, importers and notified bodies which, during the period starting on the later of the dates referred to point (d) of Article 123(3) and ending 18 months later, comply with Article 29(4) and Article 56(5) of this Regulation shall be considered to comply with the laws and regulations adopted by Member States in accordance with, respectively, Article 10a of Directive 90/385/EEC or Article 14(1) and (2) of Directive 93/42/EEC and with, respectively, point (a) of Article 10b(1) of Directive 90/385/EEC or points (a) and (b) of Article 14a(1) of Directive 93/42/EEC as specified in Decision 2010/227/EU. 9.   Authorisations granted by the competent authorities of the Member States in accordance with Article 9(9) of Directive 90/385/EEC or Article 11(13) of Directive 93/42/EEC shall keep the validity indicated in the authorisation. 10.   Devices falling within the scope of this Regulation in accordance with points (f) and (g) of Article 1(6) which have been legally placed on the market or put into service in accordance with the rules in force in the Member States prior to 26 May 2020 may continue to be placed on the market and put into service in the Member States concerned. 11.   Clinical investigations which have started to be conducted in accordance with Article 10 of Directive 90/385/EEC or Article 15 of Directive 93/42/EEC prior to 26 May 2020 may continue to be conducted. As of 26 May 2020, however, the reporting of serious adverse events and device deficiencies shall be carried out in accordance with this Regulation. 12.   Until the Commission has designated, pursuant to Article 27(2), issuing entities, GS1, HIBCC and ICCBBA shall be considered to be designated issuing entities. Article 121 Evaluation By 27 May 2027, the Commission shall assess the application of this Regulation and produce an evaluation report on the progress towards achievement of the objectives contained herein including an assessment of the resources required to implement this Regulation. Special attention shall be given to the traceability of medical devices through the storage, pursuant to Article 27, of the UDI by economic operators, health institutions and health professionals. Article 122 Repeal Without prejudice to Articles 120(3) and (4) of this Regulation, and without prejudice to the obligations of the Member States and manufacturers as regards vigilance and to the obligations of manufacturers as regards the making available of documentation, under Directives 90/385/EEC and 93/42/EEC, those Directives are repealed with effect from 26 May 2020, with the exception of: — Articles 8 and 10, points (b) and (c) of Article 10b(1), Article 10b(2) and Article 10b(3) of Directive 90/385/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10, points (c) and (d) of Article 14a(1), Article 14a(2), Article 14a(3) and Article 15 of Directive 93/42/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; and — Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation. As regards the devices referred to in Article 120 (3) and (4) of this Regulation, the Directives referred to in the first paragraph shall continue to apply until 27 May 2025 to the extent necessary for the application of those paragraphs. Notwithstanding the first paragraph, Regulations (EU) No 207/2012 and (EU) No 722/2012 shall remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. References to the repealed Directives shall be understood as references to this Regulation and shall be read in accordance with the correlation table laid down in Annex XVII to this Regulation. Article 123 Entry into force and date of application 1.   This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union. 2.   It shall apply from 26 May 2020. 3.   By way of derogation from paragraph 2: (a) Articles 35 to 50 shall apply from 26 November 2017. However, from that date until 26 May 2020, the obligations on notified bodies pursuant to Articles 35 to 50 shall apply only to those bodies which submit an application for designation in accordance with Article 38; (b) Articles 101 and 103 shall apply from 26 November 2017; (c) Article 102 shall apply from 26 May 2018; (d) without prejudice to the obligations on the Commission pursuant to Article 34, where, due to circumstances that could not reasonably have been foreseen when drafting the plan referred to in Article 34(1), Eudamed is not fully functional on 26 May 2020, the obligations and requirements that relate to Eudamed shall apply from the date corresponding to six months after the date of publication of the notice referred to in Article 34(3). The provisions referred to in the preceding sentence are: — Article 29, — Article 31, — Article 32, — Article 33(4), — the second sentence of Article 40(2), — Article 42(10), — Article 43(2), — the second subparagraph of Article 44(12), — points (d) and (e) of Article 46(7), — Article 53(2), — Article 54(3), — Article 55(1), — Articles 70 to 77, — paragraphs 1 to 13 of Article 78, — Articles 79 to 82, — Article 86(2), — Articles 87 and 88, — Article 89(5) and (7), and the third subparagraph of Article 89(8), — Article 90, — Article 93(4), (7) and (8), — Article 95(2) and (4), — the last sentence of Article 97(2), — Article 99(4), — the second sentence of the first subparagraph of Article 120(3). Until Eudamed is fully functional, the corresponding provisions of Directives 90/385/EEC and 93/42/EEC shall continue to apply for the purpose of meeting the obligations laid down in the provisions listed in the first paragraph of this point regarding exchange of information including, and in particular, information regarding vigilance reporting, clinical investigations, registration of devices and economic operators, and certificate notifications. (e) Article 29(4) and Article 56(5) shall apply from 18 months after the later of the dates referred to in point (d); (f) for implantable devices and for class III devices Article 27(4) shall apply from 26 May 2021. For class IIa and class IIb devices Article 27(4) shall apply from 26 May 2023. For class I devices Article 27(4) shall apply from 26 May 2025; (g) for reusable devices that shall bear the UDI carrier on the device itself, Article 27(4) shall apply from two years after the date referred to in point (f) of this paragraph for the respective class of devices in that point; (h) The procedure set out in Article 78 shall apply from 26 May 2027, without prejudice to Article 78(14); (i) Article 120(12) shall apply from 26 May 2019. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Strasbourg, 5 April 2017. For the European Parliament The President A. TAJANI For the Council The President I. BORG (1)  Opinion of 14 February 2013 (OJ C 133, 9.5.2013, p. 52). (2)  Position of the European Parliament of 2 April 2014 (not yet published in the Official Journal) and position of the Council at first reading of 7 March 2017 (not yet published in the Official Journal). (3)  Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (OJ L 189, 20.7.1990, p. 17). (4)  Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ L 169, 12.7.1993, p. 1). (5)  Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety (OJ L 31, 1.2.2002, p. 1). (6)  Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (OJ L 342, 22.12.2009, p. 59). (7)  Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67). (8)  Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121). (9)  Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (OJ L 102, 7.4.2004, p. 48). (10)  Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components (OJ L 33, 8.2.2003, p. 30). (11)  Commission Recommendation 2011/696/EU of 18 October 2011 on the definition of nanomaterial (OJ L 275, 20.10.2011, p. 38). (12)  Directive 2014/30/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to electromagnetic compatibility (OJ L 96, 29.3.2014. p. 79). (13)  Council Directive 2013/59/Euratom of 5 December 2013 laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (OJ L 13, 17.1.2014, p. 1). (14)  Directive (EU) 2015/1535 of the European Parliament and of the Council of 9 September 2015 laying down a procedure for the provision of information in the field of technical regulations and of rules on Information Society services (OJ L 241, 17.9.2015, p. 1). (15)  Regulation (EU) No 1025/2012 of the European Parliament and of the Council of 25 October 2012 on European standardisation, amending Council Directives 89/686/EEC and 93/15/EEC and Directives 94/9/EC, 94/25/EC, 95/16/EC, 97/23/EC, 98/34/EC, 2004/22/EC, 2007/23/EC, 2009/23/EC and 2009/105/EC of the European Parliament and of the Council and repealing Council Decision 87/95/EEC and Decision No 1673/2006/EC of the European Parliament and of the Council (OJ L 316, 14.11.2012, p. 12). (16)  Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (OJ L 331, 7.12.1998, p. 1). (17)  Regulation (EC) No 765/2008 of the European Parliament and of the Council of 9 July 2008 setting out the requirements for accreditation and market surveillance relating to the marketing of products and repealing Regulation (EEC) No 339/93 (OJ L 218, 13.8.2008, p. 30). (18)  Decision No 768/2008/EC of the European Parliament and of the Council of 9 July 2008 on a common framework for the marketing of products, and repealing Council Decision 93/465/EEC (OJ L 218, 13.8.2008, p. 82). (19)  Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of the Member States concerning liability for defective products (OJ L 210, 7.8.1985, p. 29). (20)  Judgment of 28 July 2011 in Orifarm and Paranova, joined cases C-400/09 and C-207/10, ECLI:EU:C:2011:519. (21)  Commission Decision 2010/227/EU of 19 April 2010 on the European Databank for Medical Devices (OJ L 102, 23.4.2010, p. 45). (22)  Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995, p. 31). (23)  Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data (OJ L 8, 12.1.2001, p. 1). (24)  Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes (OJ L 276, 20.10.2010, p. 33). (25)  Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (see page 176 of this Official Journal). (26)   OJ L 123, 12.5.2016, p. 1. (27)  Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the rules and general principles concerning mechanisms for control by Member States of the Commission's exercise of implementing powers (OJ L 55, 28.2.2011, p. 13). (28)  Commission Regulation (EU) No 207/2012 of 9 March 2012 on electronic instructions for use of medical devices (OJ L 72, 10.3.2012, p. 28). (29)  Commission Regulation (EU) No 722/2012 of 8 August 2012 concerning particular requirements as regards the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and medical devices manufactured utilising tissues of animal origin (OJ L 212, 9.8.2012, p. 3). (30)  Commission Directive 2003/12/EC of 3 February 2003 on the reclassification of breast implants in the framework of Directive 93/42/EEC concerning medical devices (OJ L 28, 4.2.2003, p. 43). (31)  Commission Directive 2005/50/EC of 11 August 2005 on the reclassification of hip, knee and shoulder joint replacements in the framework of Council Directive 93/42/EEC concerning medical devices (OJ L 210, 12.8.2005, p. 41). (32)  Commission Implementing Regulation (EU) No 920/2013 of 24 September 2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices (OJ L 253, 25.9.2013, p. 8). (33)   OJ C 358, 7.12.2013, p. 10. (34)  Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1). (35)  Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24). (36)  Commission Recommendation 2003/361/ΕC of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises (OJ L 124, 20.5.2003, p. 36). (37)  Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1). ANNEXES I    General safety and performance requirements II    Technical documentation III    Technical documentation on post-market surveillance IV    EU declaration of conformity V    CE marking of conformity VI    Information to be submitted upon the registration of devices and economic operators in accordance with Articles 29(4) and 31; core data elements to be provided to the UDI database together with the UDI-DI in accordance with Articles 28 and 29;and the UDI system VII    Requirements to be met by notified bodies VIII    Classification rules IX    Conformity assessment based on a quality management system and assessment of the technical documentation X    Conformity assessment based on type examination XI    Conformity assessment based on product conformity verification XII    Certificates issued by a notified body XIII    Procedure for custom-made devices XIV    Clinical evaluation and post-market clinical follow-up XV    Clinical investigations XVI    List of groups of products without an intended medical purpose referred to in Article 1(2) XVII    Correlation table ANNEX I GENERAL SAFETY AND PERFORMANCE REQUIREMENTS CHAPTER I GENERAL REQUIREMENTS 1.   Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose. They shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. 2.   The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio. 3.   Manufacturers shall establish, implement, document and maintain a risk management system. Risk management shall be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. In carrying out risk management manufacturers shall: (a) establish and document a risk management plan for each device; (b) identify and analyse the known and foreseeable hazards associated with each device; (c) estimate and evaluate the risks associated with, and occurring during, the intended use and during reasonably foreseeable misuse; (d) eliminate or control the risks referred to in point (c) in accordance with the requirements of Section 4; (e) evaluate the impact of information from the production phase and, in particular, from the post-market surveillance system, on hazards and the frequency of occurrence thereof, on estimates of their associated risks, as well as on the overall risk, benefit-risk ratio and risk acceptability; and (f) based on the evaluation of the impact of the information referred to in point (e), if necessary amend control measures in line with the requirements of Section 4. 4.   Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art. To reduce risks, Manufacturers shall manage risks so that the residual risk associated with each hazard as well as the overall residual risk is judged acceptable. In selecting the most appropriate solutions, manufacturers shall, in the following order of priority: (a) eliminate or reduce risks as far as possible through safe design and manufacture; (b) where appropriate, take adequate protection measures, including alarms if necessary, in relation to risks that cannot be eliminated; and (c) provide information for safety (warnings/precautions/contra-indications) and, where appropriate, training to users. Manufacturers shall inform users of any residual risks. 5.   In eliminating or reducing risks related to use error, the manufacturer shall: (a) reduce as far as possible the risks related to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and (b) give consideration to the technical knowledge, experience, education, training and use environment, where applicable, and the medical and physical conditions of intended users (design for lay, professional, disabled or other users). 6.   The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer's instructions. 7.   Devices shall be designed, manufactured and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer. 8.   All known and foreseeable risks, and any undesirable side-effects, shall be minimised and be acceptable when weighed against the evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use. 9.   For the devices referred to in Annex XVI, the general safety requirements set out in Sections 1 and 8 shall be understood to mean that the device, when used under the conditions and for the purposes intended, does not present a risk at all or presents a risk that is no more than the maximum acceptable risk related to the product's use which is consistent with a high level of protection for the safety and health of persons. CHAPTER II REQUIREMENTS REGARDING DESIGN AND MANUFACTURE 10.   Chemical, physical and biological properties 10.1.   Devices shall be designed and manufactured in such a way as to ensure that the characteristics and performance requirements referred to in Chapter I are fulfilled. Particular attention shall be paid to: (a) the choice of materials and substances used, particularly as regards toxicity and, where relevant, flammability; (b) the compatibility between the materials and substances used and biological tissues, cells and body fluids, taking account of the intended purpose of the device and, where relevant, absorption, distribution, metabolism and excretion; (c) the compatibility between the different parts of a device which consists of more than one implantable part; (d) the impact of processes on material properties; (e) where appropriate, the results of biophysical or modelling research the validity of which has been demonstrated beforehand; (f) the mechanical properties of the materials used, reflecting, where appropriate, matters such as strength, ductility, fracture resistance, wear resistance and fatigue resistance; (g) surface properties; and (h) the confirmation that the device meets any defined chemical and/or physical specifications. 10.2.   Devices shall be designed, manufactured and packaged in such a way as to minimise the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure. 10.3.   Devices shall be designed and manufactured in such a way that they can be used safely with the materials and substances, including gases, with which they enter into contact during their intended use; if the devices are intended to administer medicinal products they shall be designed and manufactured in such a way as to be compatible with the medicinal products concerned in accordance with the provisions and restrictions governing those medicinal products and that the performance of both the medicinal products and of the devices is maintained in accordance with their respective indications and intended use. 10.4.   Substances 10.4.1.   Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine-disrupting properties for which there is scientific evidence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been adopted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established therein. 10.4.2.   Justification regarding the presence of CMR and/or endocrine-disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the substance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer-reviewed studies, scientific opinions from relevant scientific committees and an analysis of the availability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit-risk ratios of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3. and 10.4.4. 10.4.3.   Guidelines on phthalates For the purposes of Section 10.4., the Commission shall, as soon as possible and by 26 May 2018, provide the relevant scientific committee with a mandate to prepare guidelines that shall be ready before 26 May 2020. The mandate for the committee shall encompass at least a benefit-risk assessment of the presence of phthalates which belong to either of the groups of substances referred to in points (a) and (b) of Section 10.4.1. The benefit-risk assessment shall take into account the intended purpose and context of the use of the device, as well as any available alternative substances and alternative materials, designs or medical treatments. When deemed appropriate on the basis of the latest scientific evidence, but at least every five years, the guidelines shall be updated. 10.4.4.   Guidelines on other CMR and endocrine-disrupting substances Subsequently, the Commission shall mandate the relevant scientific committee to prepare guidelines as referred to in Section 10.4.3. also for other substances referred to in points (a) and (b) of Section 10.4.1., where appropriate. 10.4.5.   Labelling Where devices, parts thereof or materials used therein as referred to in Section 10.4.1. contain substances referred to in points (a) or (b) of Section 10.4.1. in a concentration above 0,1 % weight by weight (w/w), the presence of those substances shall be labelled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging, with the list of such substances. If the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials, information on residual risks for those patient groups and, if applicable, on appropriate precautionary measures shall be given in the instructions for use. 10.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used. 10.6.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks linked to the size and the properties of particles which are or can be released into the patient's or user's body, unless they come into contact with intact skin only. Special attention shall be given to nanomaterials. 11.   Infection and microbial contamination 11.1.   Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users and, where applicable, other persons. The design shall: (a) reduce as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries, (b) allow easy and safe handling, (c) reduce as far as possible any microbial leakage from the device and/or microbial exposure during use, and (d) prevent microbial contamination of the device or its content such as specimens or fluids. 11.2.   Where necessary devices shall be designed to facilitate their safe cleaning, disinfection, and/or re-sterilisation. 11.3.   Devices labelled as having a specific microbial state shall be designed, manufactured and packaged to ensure that they remain in that state when placed on the market and remain so under the transport and storage conditions specified by the manufacturer. 11.4.   Devices delivered in a sterile state shall be designed, manufactured and packaged in accordance with appropriate procedures, to ensure that they are sterile when placed on the market and that, unless the packaging which is intended to maintain their sterile condition is damaged, they remain sterile, under the transport and storage conditions specified by the manufacturer, until that packaging is opened at the point of use. It shall be ensured that the integrity of that packaging is clearly evident to the final user. 11.5.   Devices labelled as sterile shall be processed, manufactured, packaged and, sterilised by means of appropriate, validated methods. 11.6.   Devices intended to be sterilised shall be manufactured and packaged in appropriate and controlled conditions and facilities. 11.7.   Packaging systems for non-sterile devices shall maintain the integrity and cleanliness of the product and, where the devices are to be sterilised prior to use, minimise the risk of microbial contamination; the packaging system shall be suitable taking account of the method of sterilisation indicated by the manufacturer. 11.8.   The labelling of the device shall distinguish between identical or similar devices placed on the market in both a sterile and a non-sterile condition additional to the symbol used to indicate that devices are sterile. 12.   Devices incorporating a substance considered to be a medicinal product and devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body. 12.1.   In the case of devices referred to in the first subparagraph of Article 1(8), the quality, safety and usefulness of the substance which, if used separately, would be considered to be a medicinal product within the meaning of point (2) of Article 1 of Directive 2001/83/EC, shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC, as required by the applicable conformity assessment procedure under this Regulation. 12.2.   Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation. 13.   Devices incorporating materials of biological origin 13.1.   For devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable covered by this Regulation in accordance with point (g) of Article 1(6), the following shall apply: (a) donation, procurement and testing of the tissues and cells shall be done in accordance with Directive 2004/23/EC; (b) processing, preservation and any other handling of those tissues and cells or their derivatives shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process; (c) the traceability system for those devices shall be complementary and compatible with the traceability and data protection requirements laid down in Directive 2004/23/EC and in Directive 2002/98/EC. 13.2.   For devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable the following shall apply: (a) where feasible taking into account the animal species, tissues and cells of animal origin, or their derivatives, shall originate from animals that have been subjected to veterinary controls that are adapted to the intended use of the tissues. Information on the geographical origin of the animals shall be retained by manufacturers; (b) sourcing, processing, preservation, testing and handling of tissues, cells and substances of animal origin, or their derivatives, shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular safety with regard to viruses and other transmissible agents shall be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process, except when the use of such methods would lead to unacceptable degradation compromising the clinical benefit of the device; (c) in the case of devices manufactured utilising tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 the particular requirements laid down in that Regulation shall apply. 13.3.   For devices manufactured utilising non-viable biological substances other than those referred to in Sections 13.1 and 13.2, the processing, preservation, testing and handling of those substances shall be carried out so as to provide safety for patients, users and, where applicable, other persons, including in the waste disposal chain. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. 14.   Construction of devices and interaction with their environment 14.1.   If the device is intended for use in combination with other devices or equipment the whole combination, including the connection system shall be safe and shall not impair the specified performance of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the instructions for use. Connections which the user has to handle, such as fluid, gas transfer, electrical or mechanical coupling, shall be designed and constructed in such a way as to minimise all possible risks, such as misconnection. 14.2.   Devices shall be designed and manufactured in such a way as to remove or reduce as far as possible: (a) the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional and where appropriate ergonomic features; (b) risks connected with reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, temperature, variations in pressure and acceleration or radio signal interferences; (c) the risks associated with the use of the device when it comes into contact with materials, liquids, and substances, including gases, to which it is exposed during normal conditions of use; (d) the risks associated with the possible negative interaction between software and the IT environment within which it operates and interacts; (e) the risks of accidental ingress of substances into the device; (f) the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given; and (g) risks arising where maintenance or calibration are not possible (as with implants), from ageing of materials used or loss of accuracy of any measuring or control mechanism. 14.3.   Devices shall be designed and manufactured in such a way as to minimise the risks of fire or explosion during normal use and in single fault condition. Particular attention shall be paid to devices the intended use of which includes exposure to or use in association with flammable or explosive substances or substances which could cause combustion. 14.4.   Devices shall be designed and manufactured in such a way that adjustment, calibration, and maintenance can be done safely and effectively. 14.5.   Devices that are intended to be operated together with other devices or products shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe. 14.6   Any measurement, monitoring or display scale shall be designed and manufactured in line with ergonomic principles, taking account of the intended purpose, users and the environmental conditions in which the devices are intended to be used. 14.7.   Devices shall be designed and manufactured in such a way as to facilitate their safe disposal and the safe disposal of related waste substances by the user, patient or other person. To that end, manufacturers shall identify and test procedures and measures as a result of which their devices can be safely disposed after use. Such procedures shall be described in the instructions for use. 15.   Devices with a diagnostic or measuring function 15.1.   Diagnostic devices and devices with a measuring function, shall be designed and manufactured in such a way as to provide sufficient accuracy, precision and stability for their intended purpose, based on appropriate scientific and technical methods. The limits of accuracy shall be indicated by the manufacturer. 15.2.   The measurements made by devices with a measuring function shall be expressed in legal units conforming to the provisions of Council Directive 80/181/EEC (4). 16.   Protection against radiation 16.1.   General (a) Devices shall be designed, manufactured and packaged in such a way that exposure of patients, users and other persons to radiation is reduced as far as possible, and in a manner that is compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes. (b) The operating instructions for devices emitting hazardous or potentially hazardous radiation shall contain detailed information as to the nature of the emitted radiation, the means of protecting the patient and the user, and on ways of avoiding misuse and of reducing the risks inherent to installation as far as possible and appropriate. Information regarding the acceptance and performance testing, the acceptance criteria, and the maintenance procedure shall also be specified. 16.2.   Intended radiation (a) Where devices are designed to emit hazardous, or potentially hazardous, levels of ionizing and/or non-ionizing radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent to the emission, it shall be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility of relevant variable parameters within an acceptable tolerance. (b) Where devices are intended to emit hazardous, or potentially hazardous, ionizing and/or non-ionizing radiation, they shall be fitted, where possible, with visual displays and/or audible warnings of such emissions. 16.3.   Devices shall be designed and manufactured in such a way that exposure of patients, users and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. Where possible and appropriate, methods shall be selected which reduce the exposure to radiation of patients, users and other persons who may be affected. 16.4.   Ionising radiation (a) Devices intended to emit ionizing radiation shall be designed and manufactured taking into account the requirements of the Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation. (b) Devices intended to emit ionising radiation shall be designed and manufactured in such a way as to ensure that, where possible, taking into account the intended use, the quantity, geometry and quality of the radiation emitted can be varied and controlled, and, if possible, monitored during treatment. (c) Devices emitting ionising radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve an image and/or output quality that are appropriate to the intended medical purpose whilst minimising radiation exposure of the patient and user. (d) Devices that emit ionising radiation and are intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type, energy and, where appropriate, the quality of radiation. 17.   Electronic programmable systems — devices that incorporate electronic programmable systems and software that are devices in themselves 17.1.   Devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, shall be designed to ensure repeatability, reliability and performance in line with their intended use. In the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks or impairment of performance. 17.2.   For devices that incorporate software or for software that are devices in themselves, the software shall be developed and manufactured in accordance with the state of the art taking into account the principles of development life cycle, risk management, including information security, verification and validation. 17.3.   Software referred to in this Section that is intended to be used in combination with mobile computing platforms shall be designed and manufactured taking into account the specific features of the mobile platform (e.g. size and contrast ratio of the screen) and the external factors related to their use (varying environment as regards level of light or noise). 17.4.   Manufacturers shall set out minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. 18.   Active devices and devices connected to them 18.1.   For non-implantable active devices, in the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks. 18.2.   Devices where the safety of the patient depends on an internal power supply shall be equipped with a means of determining the state of the power supply and an appropriate warning or indication for when the capacity of the power supply becomes critical. If necessary, such warning or indication shall be given prior to the power supply becoming critical. 18.3.   Devices where the safety of the patient depends on an external power supply shall include an alarm system to signal any power failure. 18.4.   Devices intended to monitor one or more clinical parameters of a patient shall be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient's state of health. 18.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks of creating electromagnetic interference which could impair the operation of the device in question or other devices or equipment in the intended environment. 18.6.   Devices shall be designed and manufactured in such a way as to provide a level of intrinsic immunity to electromagnetic interference such that is adequate to enable them to operate as intended. 18.7.   Devices shall be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks to the patient, user or any other person, both during normal use of the device and in the event of a single fault condition in the device, provided the device is installed and maintained as indicated by the manufacturer. 18.8.   Devices shall be designed and manufactured in such a way as to protect, as far as possible, against unauthorised access that could hamper the device from functioning as intended. 19.   Particular requirements for active implantable devices 19.1.   Active implantable devices shall be designed and manufactured in such a way as to remove or minimize as far as possible: (a) risks connected with the use of energy sources with particular reference, where electricity is used, to insulation, leakage currents and overheating of the devices, (b) risks connected with medical treatment, in particular those resulting from the use of defibrillators or high-frequency surgical equipment, and (c) risks which may arise where maintenance and calibration are impossible, including: — excessive increase of leakage currents, — ageing of the materials used, — excess heat generated by the device, — decreased accuracy of any measuring or control mechanism. 19.2.   Active implantable devices shall be designed and manufactured in such a way as to ensure — if applicable, the compatibility of the devices with the substances they are intended to administer, and — the reliability of the source of energy. 19.3.   Active implantable devices and, if appropriate, their component parts shall be identifiable to allow any necessary measure to be taken following the discovery of a potential risk in connection with the devices or their component parts. 19.4.   Active implantable devices shall bear a code by which they and their manufacturer can be unequivocally identified (particularly with regard to the type of device and its year of manufacture); it shall be possible to read this code, if necessary, without the need for a surgical operation. 20.   Protection against mechanical and thermal risks 20.1.   Devices shall be designed and manufactured in such a way as to protect patients and users against mechanical risks connected with, for example, resistance to movement, instability and moving parts. 20.2.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. 20.3.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance. 20.4.   Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user or other person has to handle, shall be designed and constructed in such a way as to minimise all possible risks. 20.5.   Errors likely to be made when fitting or refitting certain parts which could be a source of risk shall be made impossible by the design and construction of such parts or, failing this, by information given on the parts themselves and/or their housings. The same information shall be given on moving parts and/or their housings where the direction of movement needs to be known in order to avoid a risk. 20.6.   Accessible parts of devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings shall not attain potentially dangerous temperatures under normal conditions of use. 21.   Protection against the risks posed to the patient or user by devices supplying energy or substances 21.1.   Devices for supplying the patient with energy or substances shall be designed and constructed in such a way that the amount to be delivered can be set and maintained accurately enough to ensure the safety of the patient and of the user. 21.2.   Devices shall be fitted with the means of preventing and/or indicating any inadequacies in the amount of energy delivered or substances delivered which could pose a danger. Devices shall incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy or substances from an energy and/or substance source. 21.3.   The function of the controls and indicators shall be clearly specified on the devices. Where a device bears instructions required for its operation or indicates operating or adjustment parameters by means of a visual system, such information shall be understandable to the user and, as appropriate, the patient. 22.   Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons 22.1.   Devices for use by lay persons shall be designed and manufactured in such a way that they perform appropriately for their intended purpose taking into account the skills and the means available to lay persons and the influence resulting from variation that can be reasonably anticipated in the lay person's technique and environment. The information and instructions provided by the manufacturer shall be easy for the lay person to understand and apply. 22.2.   Devices for use by lay persons shall be designed and manufactured in such a way as to: — ensure that the device can be used safely and accurately by the intended user at all stages of the procedure, if necessary after appropriate training and/or information, — reduce, as far as possible and appropriate, the risk from unintended cuts and pricks such as needle stick injuries, and — reduce as far as possible the risk of error by the intended user in the handling of the device and, if applicable, in the interpretation of the results. 22.3.   Devices for use by lay persons shall, where appropriate, include a procedure by which the lay person: — can verify that, at the time of use, the device will perform as intended by the manufacturer, and — if applicable, is warned if the device has failed to provide a valid result. CHAPTER III REQUIREMENTS REGARDING THE INFORMATION SUPPLIED WITH THE DEVICE 23.   Label and instructions for use 23.1.   General requirements regarding the information supplied by the manufacturer Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate. Such information may appear on the device itself, on the packaging or in the instructions for use, and shall, if the manufacturer has a website, be made available and kept up to date on the website, taking into account the following: (a) The medium, format, content, legibility, and location of the label and instructions for use shall be appropriate to the particular device, its intended purpose and the technical knowledge, experience, education or training of the intended user(s). In particular, instructions for use shall be written in terms readily understood by the intended user and, where appropriate, supplemented with drawings and diagrams. (b) The information required on the label shall be provided on the device itself. If this is not practicable or appropriate, some or all of the information may appear on the packaging for each unit, and/or on the packaging of multiple devices. (c) Labels shall be provided in a human-readable format and may be supplemented by machine-readable information, such as radio-frequency identification (‘RFID’) or bar codes. (d) Instructions for use shall be provided together with devices. By way of exception, instructions for use shall not be required for class I and class IIa devices if such devices can be used safely without any such instructions and unless otherwise provided for elsewhere in this Section. (e) Where multiple devices are supplied to a single user and/or location, a single copy of the instructions for use may be provided if so agreed by the purchaser who in any case may request further copies to be provided free of charge. (f) Instructions for use may be provided to the user in non-paper format (e.g. electronic) to the extent, and only under the conditions, set out in Regulation (EU) No 207/2012 or in any subsequent implementing rules adopted pursuant to this Regulation. (g) Residual risks which are required to be communicated to the user and/or other person shall be included as limitations, contra-indications, precautions or warnings in the information supplied by the manufacturer. (h) Where appropriate, the information supplied by the manufacturer shall take the form of internationally recognised symbols. Any symbol or identification colour used shall conform to the harmonised standards or CS. In areas for which no harmonised standards or CS exist, the symbols and colours shall be described in the documentation supplied with the device. 23.2.   Information on the label The label shall bear all of the following particulars: (a) the name or trade name of the device; (b) the details strictly necessary for a user to identify the device, the contents of the packaging and, where it is not obvious for the user, the intended purpose of the device; (c) the name, registered trade name or registered trade mark of the manufacturer and the address of its registered place of business; (d) if the manufacturer has its registered place of business outside the Union, the name of the authorised representative and address of the registered place of business of the authorised representative; (e) where applicable, an indication that the device contains or incorporates: — a medicinal substance, including a human blood or plasma derivative, or — tissues or cells, or their derivatives, of human origin, or — tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012; (f) where applicable, information labelled in accordance with Section 10.4.5.; (g) the lot number or the serial number of the device preceded by the words LOT NUMBER or SERIAL NUMBER or an equivalent symbol, as appropriate; (h) the UDI carrier referred to in Article 27(4) and Part C of Annex VII; (i) an unambiguous indication of t the time limit for using or implanting the device safely, expressed at least in terms of year and month, where this is relevant; (j) where there is no indication of the date until when it may be used safely, the date of manufacture. This date of manufacture may be included as part of the lot number or serial number, provided the date is clearly identifiable; (k) an indication of any special storage and/or handling condition that applies; (l) if the device is supplied sterile, an indication of its sterile state and the sterilisation method; (m) warnings or precautions to be taken that need to be brought to the immediate attention of the user of the device, and to any other person. This information may be kept to a minimum in which case more detailed information shall appear in the instructions for use, taking into account the intended users; (n) if the device is intended for single use, an indication of that fact. A manufacturer's indication of single use shall be consistent across the Union; (o) if the device is a single-use device that has been reprocessed, an indication of that fact, the number of reprocessing cycles already performed, and any limitation as regards the number of reprocessing cycles; (p) if the device is custom-made, the words ‘custom-made device’; (q) an indication that the device is a medical device. If the device is intended for clinical investigation only, the words ‘exclusively for clinical investigation’; (r) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the overall qualitative composition of the device and quantitative information on the main constituent or constituents responsible for achieving the principal intended action; (s) for active implantable devices, the serial number, and for other implantable devices, the serial number or the lot number. 23.3.   Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’) The following particulars shall appear on the sterile packaging: (a) an indication permitting the sterile packaging to be recognised as such, (b) a declaration that the device is in a sterile condition, (c) the method of sterilisation, (d) the name and address of the manufacturer, (e) a description of the device, (f) if the device is intended for clinical investigations, the words ‘exclusively for clinical investigations’, (g) if the device is custom-made, the words ‘custom-made device’, (h) the month and year of manufacture, (i) an unambiguous indication of the time limit for using or implanting the device safely expressed at least in terms of year and month, and (j) an instruction to check the instructions for use for what to do if the sterile packaging is damaged or unintentionally opened before use. 23.4.   Information in the instructions for use The instructions for use shall contain all of the following particulars: (a) the particulars referred to in points (a), (c), (e), (f), (k), (l), (n) and (r) of Section 23.2; (b) the device's intended purpose with a clear specification of indications, contra-indications, the patient target group or groups, and of the intended users, as appropriate; (c) where applicable, a specification of the clinical benefits to be expected. (d) where applicable, links to the summary of safety and clinical performance referred to in Article 32; (e) the performance characteristics of the device; (f) where applicable, information allowing the healthcare professional to verify if the device is suitable and select the corresponding software and accessories; (g) any residual risks, contra-indications and any undesirable side-effects, including information to be conveyed to the patient in this regard; (h) specifications the user requires to use the device appropriately, e.g. if the device has a measuring function, the degree of accuracy claimed for it; (i) details of any preparatory treatment or handling of the device before it is ready for use or during its use, such as sterilisation, final assembly, calibration, etc., including the levels of disinfection required to ensure patient safety and all available methods for achieving those levels of disinfection; (j) any requirements for special facilities, or special training, or particular qualifications of the device user and/or other persons; (k) the information needed to verify whether the device is properly installed and is ready to perform safely and as intended by the manufacturer, together with, where relevant: — details of the nature, and frequency, of preventive and regular maintenance, and of any preparatory cleaning or disinfection, — identification of any consumable components and how to replace them, — information on any necessary calibration to ensure that the device operates properly and safely during its intended lifetime, and — methods for eliminating the risks encountered by persons involved in installing, calibrating or servicing devices; (l) if the device is supplied sterile, instructions in the event of the sterile packaging being damaged or unintentionally opened before use; (m) if the device is supplied non-sterile with the intention that it is sterilised before use, the appropriate instructions for sterilisation; (n) if the device is reusable, information on the appropriate processes for allowing reuse, including cleaning, disinfection, packaging and, where appropriate, the validated method of re-sterilisation appropriate to the Member State or Member States in which the device has been placed on the market. Information shall be provided to identify when the device should no longer be reused, e.g. signs of material degradation or the maximum number of allowable reuses; (o) an indication, if appropriate, that a device can be reused only if it is reconditioned under the responsibility of the manufacturer to comply with the general safety and performance requirements; (p) if the device bears an indication that it is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. This information shall be based on a specific section of the manufacturer's risk management documentation, where such characteristics and technical factors shall be addressed in detail. If in accordance with point (d) of Section 23.1. no instructions for use are required, this information shall be made available to the user upon request; (q) for devices intended for use together with other devices and/or general purpose equipment: — information to identify such devices or equipment, in order to obtain a safe combination, and/or — information on any known restrictions to combinations of devices and equipment; (r) if the device emits radiation for medical purposes: — detailed information as to the nature, type and where appropriate, the intensity and distribution of the emitted radiation, — the means of protecting the patient, user, or other person from unintended radiation during use of the device; (s) information that allows the user and/or patient to be informed of any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. That information shall, where relevant, allow the user to brief the patient about any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. The information shall cover, where appropriate: — warnings, precautions and/or measures to be taken in the event of malfunction of the device or changes in its performance that may affect safety, — warnings, precautions and/or measures to be taken as regards the exposure to reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, or temperature, — warnings, precautions and/or measures to be taken as regards the risks of interference posed by the reasonably foreseeable presence of the device during specific diagnostic investigations, evaluations, or therapeutic treatment or other procedures such as electromagnetic interference emitted by the device affecting other equipment, — if the device is intended to administer medicinal products, tissues or cells of human or animal origin, or their derivatives, or biological substances, any limitations or incompatibility in the choice of substances to be delivered, — warnings, precautions and/or limitations related to the medicinal substance or biological material that is incorporated into the device as an integral part of the device; and — precautions related to materials incorporated into the device that contain or consist of CMR substances or endocrine-disrupting substances, or that could result in sensitisation or an allergic reaction by the patient or user; (t) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, warnings and precautions, where appropriate, related to the general profile of interaction of the device and its products of metabolism with other devices, medicinal products and other substances as well as contra-indications, undesirable side-effects and risks relating to overdose; (u) in the case of implantable devices, the overall qualitative and quantitative information on the materials and substances to which patients can be exposed; (v) warnings or precautions to be taken in order to facilitate the safe disposal of the device, its accessories and the consumables used with it, if any. This information shall cover, where appropriate: — infection or microbial hazards such as explants, needles or surgical equipment contaminated with potentially infectious substances of human origin, and — physical hazards such as from sharps. If in accordance with the point (d) of Section 23.1 no instructions for use are required, this information shall be made available to the user upon request; (w) for devices intended for use by lay persons, the circumstances in which the user should consult a healthcare professional; (x) for the devices covered by this Regulation pursuant to Article 1(2), information regarding the absence of a clinical benefit and the risks related to use of the device; (y) date of issue of the instructions for use or, if they have been revised, date of issue and identifier of the latest revision of the instructions for use; (z) a notice to the user and/or patient that any serious incident that has occurred in relation to the device should be reported to the manufacturer and the competent authority of the Member State in which the user and/or patient is established; (aa) information to be supplied to the patient with an implanted device in accordance with Article 18; (ab) for devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. (1)  Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 ( OJ L 353, 31.12.2008, p. 1). (2)  Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (OJ L 396, 30.12.2006, p. 1). (3)  Regulation (EU) No 528/2012 of the European Parliament and the Council of 22 May 2012 concerning the making available on the market of and use of biocidal products (OJ L 167, 27.6.2012, p. 1). (4)  Council Directive 80/181/EEC of 20 December 1979 on the approximation of the laws of the Member States relating to units of measurement and on the repeal of Directive 71/354/EEC (OJ L 39, 15.2.1980, p. 40). ANNEX II TECHNICAL DOCUMENTATION The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex. 1.   DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 1.1.   Device description and specification (a) product or trade name and a general description of the device including its intended purpose and intended users; (b) the Basic UDI-DI as referred to in Part C of Annex VI assigned by the manufacturer to the device in question, as soon as identification of this device becomes based on a UDI system, or otherwise a clear identification by means of product code, catalogue number or other unambiguous reference allowing traceability; (c) the intended patient population and medical conditions to be diagnosed, treated and/or monitored and other considerations such as patient selection criteria, indications, contra-indications, warnings; (d) principles of operation of the device and its mode of action, scientifically demonstrated if necessary; (e) the rationale for the qualification of the product as a device; (f) the risk class of the device and the justification for the classification rule(s) applied in accordance with Annex VIII; (g) an explanation of any novel features; (h) a description of the accessories for a device, other devices and other products that are not devices, which are intended to be used in combination with it; (i) a description or complete list of the various configurations/variants of the device that are intended to be made available on the market; (j) a general description of the key functional elements, e.g. its parts/components (including software if appropriate), its formulation, its composition, its functionality and, where relevant, its qualitative and quantitative composition. Where appropriate, this shall include labelled pictorial representations (e.g. diagrams, photographs, and drawings), clearly indicating key parts/components, including sufficient explanation to understand the drawings and diagrams; (k) a description of the raw materials incorporated into key functional elements and those making either direct contact with the human body or indirect contact with the body, e.g., during extracorporeal circulation of body fluids; (l) technical specifications, such as features, dimensions and performance attributes, of the device and any variants/configurations and accessories that would typically appear in the product specification made available to the user, for example in brochures, catalogues and similar publications. 1.2.   Reference to previous and similar generations of the device (a) an overview of the previous generation or generations of the device produced by the manufacturer, where such devices exist; (b) an overview of identified similar devices available on the Union or international markets, where such devices exist. 2.   INFORMATION TO BE SUPPLIED BY THE MANUFACTURER A complete set of: — the label or labels on the device and on its packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions, in the languages accepted in the Member States where the device is envisaged to be sold; and — the instructions for use in the languages accepted in the Member States where the device is envisaged to be sold. 3.   DESIGN AND MANUFACTURING INFORMATION (a) information to allow the design stages applied to the device to be understood; (b) complete information and specifications, including the manufacturing processes and their validation, their adjuvants, the continuous monitoring and the final product testing. Data shall be fully included in the technical documentation; (c) identification of all sites, including suppliers and sub-contractors, where design and manufacturing activities are performed. 4.   GENERAL SAFETY AND PERFORMANCE REQUIREMENTS The documentation shall contain information for the demonstration of conformity with the general safety and performance requirements set out in Annex I that are applicable to the device taking into account its intended purpose, and shall include a justification, validation and verification of the solutions adopted to meet those requirements. The demonstration of conformity shall include: (a) the general safety and performance requirements that apply to the device and an explanation as to why others do not apply; (b) the method or methods used to demonstrate conformity with each applicable general safety and performance requirement; (c) the harmonised standards, CS or other solutions applied; and (d) the precise identity of the controlled documents offering evidence of conformity with each harmonised standard, CS or other method applied to demonstrate conformity with the general safety and performance requirements. The information referred to under this point shall incorporate a cross-reference to the location of such evidence within the full technical documentation and, if applicable, the summary technical documentation. 5.   BENEFIT-RISK ANALYSIS AND RISK MANAGEMENT The documentation shall contain information on: (a) the benefit-risk analysis referred to in Sections 1 and 8 of Annex I, and (b) the solutions adopted and the results of the risk management referred to in Section 3 of Annex I. 6.   PRODUCT VERIFICATION AND VALIDATION The documentation shall contain the results and critical analyses of all verifications and validation tests and/or studies undertaken to demonstrate conformity of the device with the requirements of this Regulation and in particular the applicable general safety and performance requirements. 6.1.   Pre-clinical and clinical data (a) results of tests, such as engineering, laboratory, simulated use and animal tests, and evaluation of published literature applicable to the device, taking into account its intended purpose, or to similar devices, regarding the pre-clinical safety of the device and its conformity with the specifications; (b) detailed information regarding test design, complete test or study protocols, methods of data analysis, in addition to data summaries and test conclusions regarding in particular: — the biocompatibility of the device including the identification of all materials in direct or indirect contact with the patient or user; — physical, chemical and microbiological characterisation; — electrical safety and electromagnetic compatibility; — software verification and validation (describing the software design and development process and evidence of the validation of the software, as used in the finished device. This information shall typically include the summary results of all verification, validation and testing performed both in-house and in a simulated or actual user environment prior to final release. It shall also address all of the different hardware configurations and, where applicable, operating systems identified in the information supplied by the manufacturer); — stability, including shelf life; and — performance and safety. Where applicable, conformity with the provisions of Directive 2004/10/EC of the European Parliament and of the Council (1) shall be demonstrated. Where no new testing has been undertaken, the documentation shall incorporate a rationale for that decision. An example of such a rationale would be that biocompatibility testing on identical materials was conducted when those materials were incorporated in a previous version of the device that has been legally placed on the market or put into service; (c) the clinical evaluation report and its updates and the clinical evaluation plan referred to in Article 61(12) and Part A of Annex XIV; (d) the PMCF plan and PMCF evaluation report referred to in Part B of Annex XIV or a justification why a PMCF is not applicable. 6.2.   Additional information required in specific cases (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as referred to in the first subparagraph of Article 1(8), a statement indicating this fact. In this case, the documentation shall identify the source of that substance and contain the data of the tests conducted to assess its safety, quality and usefulness, taking account of the intended purpose of the device. (b) Where a device is manufactured utilising tissues or cells of human or animal origin, or their derivatives, and is covered by this Regulation in accordance with points (f) and (g) of Article 1(6, and where a device incorporates, as an integral part, tissues or cells of human origin or their derivatives that have an action ancillary to that of the device and is covered by this Regulation in accordance with the first subparagraph of Article 1(10), a statement indicating this fact. In such a case, the documentation shall identify all materials of human or animal origin used and provide detailed information concerning the conformity with Sections 13.1. or 13.2., respectively, of Annex I. (c) In the case of devices that are composed of substances or combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, detailed information, including test design, complete test or study protocols, methods of data analysis, and data summaries and test conclusions, regarding studies in relation to: — absorption, distribution, metabolism and excretion; — possible interactions of those substances, or of their products of metabolism in the human body, with other devices, medicinal products or other substances, considering the target population, and its associated medical conditions; — local tolerance; and — toxicity, including single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, as applicable depending on the level and nature of exposure to the device. In the absence of such studies, a justification shall be provided. (d) In the case of devices containing CMR or endocrine-disrupting substances referred to in Section 10.4.1 of Annex I, the justification referred to in Section 10.4.2 of that Annex. (e) In the case of devices placed on the market in a sterile or defined microbiological condition, a description of the environmental conditions for the relevant manufacturing steps. In the case of devices placed on the market in a sterile condition, a description of the methods used, including the validation reports, with respect to packaging, sterilisation and maintenance of sterility. The validation report shall address bioburden testing, pyrogen testing and, if applicable, testing for sterilant residues. (f) In the case of devices placed on the market with a measuring function, a description of the methods used in order to ensure the accuracy as given in the specifications. (g) If the device is to be connected to other device(s) in order to operate as intended, a description of this combination/configuration including proof that it conforms to the general safety and performance requirements when connected to any such device(s) having regard to the characteristics specified by the manufacturer. (1)  Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances (OJ L 50, 20.2.2004, p. 44). ANNEX III TECHNICAL DOCUMENTATION ON POST-MARKET SURVEILLANCE The technical documentation on post-market surveillance to be drawn up by the manufacturer in accordance with Articles 83 to 86 shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements described in this Annex. 1.1.   The post-market surveillance plan drawn up in accordance with Article 84. The manufacturer shall prove in a post-market surveillance plan that it complies with the obligation referred to in Article 83. (a) The post-market surveillance plan shall address the collection and utilization of available information, in particular: — information concerning serious incidents, including information from PSURs, and field safety corrective actions; — records referring to non-serious incidents and data on any undesirable side-effects; — information from trend reporting; — relevant specialist or technical literature, databases and/or registers; — information, including feedbacks and complaints, provided by users, distributors and importers; and — publicly available information about similar medical devices. (b) The post-market surveillance plan shall cover at least: — a proactive and systematic process to collect any information referred to in point (a). The process shall allow a correct characterisation of the performance of the devices and shall also allow a comparison to be made between the device and similar products available on the market; — effective and appropriate methods and processes to assess the collected data; — suitable indicators and threshold values that shall be used in the continuous reassessment of the benefit-risk analysis and of the risk management as referred to in Section 3 of Annex I; — effective and appropriate methods and tools to investigate complaints and analyse market-related experience collected in the field; — methods and protocols to manage the events subject to the trend report as provided for in Article 88, including the methods and protocols to be used to establish any statistically significant increase in the frequency or severity of incidents as well as the observation period; — methods and protocols to communicate effectively with competent authorities, notified bodies, economic operators and users; — reference to procedures to fulfil the manufacturers obligations laid down in Articles 83, 84 and 86; — systematic procedures to identify and initiate appropriate measures including corrective actions; — effective tools to trace and identify devices for which corrective actions might be necessary; and — a PMCF plan as referred to in Part B of Annex XIV, or a justification as to why a PMCF is not applicable. 1.2.   The PSUR referred to in Article 86 and the post-market surveillance report referred to in Article 85. ANNEX IV EU DECLARATION OF CONFORMITY The EU declaration of conformity shall contain all of the following information: 1. Name, registered trade name or registered trade mark and, if already issued, SRN as referred to in Article 31 of the manufacturer, and, if applicable, its authorised representative, and the address of their registered place of business where they can be contacted and their location be established; 2. A statement that the EU declaration of conformity is issued under the sole responsibility of the manufacturer; 3. The Basic UDI-DI as referred to in Part C of Annex VI; 4. Product and trade name, product code, catalogue number or other unambiguous reference allowing identification and traceability of the device covered by the EU declaration of conformity, such as a photograph, where appropriate, as well as its intended purpose. Except for the product or trade name, the information allowing identification and traceability may be provided by the Basic UDI-DI referred to in point 3; 5. Risk class of the device in accordance with the rules set out in Annex VIII; 6. A statement that the device that is covered by the present declaration is in conformity with this Regulation and, if applicable, with any other relevant Union legislation that provides for the issuing of an EU declaration of conformity; 7. References to any CS used and in relation to which conformity is declared; 8. Where applicable, the name and identification number of the notified body, a description of the conformity assessment procedure performed and identification of the certificate or certificates issued; 9. Where applicable, additional information; 10. Place and date of issue of the declaration, name and function of the person who signed it as well as an indication for, and on behalf of whom, that person signed, signature. ANNEX V CE MARKING OF CONFORMITY 1. The CE marking shall consist of the initials ‘CE’ taking the following form: 2. If the CE marking is reduced or enlarged, the proportions given in the above graduated drawing shall be respected. 3. The various components of the CE marking shall have substantially the same vertical dimension, which may not be less than 5 mm. This minimum dimension may be waived for small-scale devices. ANNEX VI INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31, CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29, AND THE UDI SYSTEM PART A INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31 Manufacturers or, when applicable, authorised representatives, and, when applicable, importers shall submit the information referred to in Section 1 and shall ensure that the information on their devices referred to in Section 2 is complete, correct and updated by the relevant party. 1.   Information relating to the economic operator 1.1. type of economic operator(manufacturer, authorised representative, or importer), 1.2. name, address and contact details of the economic operator, 1.3. where submission of information is carried out by another person on behalf of any of the economic operators mentioned under Section 1.1, the name, address and contact details of that person, 1.4. name address and contact details of the person or persons responsible for regulatory compliance referred to in Article 15. 2.   Information relating to the device 2.1. Basic UDI-DI, 2.2. type, number and expiry date of the certificate issued by the notified body and the name or identification number of that notified body and the link to the information that appears on the certificate and was entered by the notified body in the electronic system on notified bodies and certificates, 2.3. Member State in which the device is to or has been placed on the market in the Union, 2.4. in the case of class IIa, class IIb or class III devices: Member States where the device is or is to be made available, 2.5. risk class of the device, 2.6. reprocessed single-use device (y/n), 2.7. presence of a substance which, if used separately, may be considered to be a medicinal product and name of that substance, 2.8. presence of a substance which, if used separately, may be considered to be a medicinal product derived from human blood or human plasma and name of this substance, 2.9. presence of tissues or cells of human origin, or their derivatives (y/n), 2.10. presence of tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 (y/n), 2.11. where applicable, the single identification number of the clinical investigation or investigations conducted in relation to the device or a link to the clinical investigation registration in the electronic system on clinical investigations, 2.12. in the case of devices listed in Annex XVI, specification as to whether the intended purpose of the device is other than a medical purpose, 2.13. in the case of devices designed and manufactured by another legal or natural person as referred in Article 10(15), the name, address and contact details of that legal or natural person, 2.14. in the case of class III or implantable devices, the summary of safety and clinical performance, 2.15. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART B CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29 The manufacturer shall provide to the UDI database the UDI-DI and all of the following information relating to the manufacturer and the device: 1. quantity per package configuration, 2. the Basic UDI-DI as referred to in Article 29 and any additional UDI-DIs, 3. the manner in which production of the device is controlled (expiry date or manufacturing date, lot number, serial number), 4. if applicable, the unit of use UDI-DI (where a UDI is not labelled on the device at the level of its unit of use, a ‘unit of use’ DI shall be assigned so as to associate the use of a device with a patient), 5. name and address of the manufacturer (as indicated on the label), 6. the SRN issued in accordance with Article 31(2), 7. if applicable, name and address of the authorised representative (as indicated on the label), 8. the medical device nomenclature code as provided for in Article 26, 9. risk class of the device, 10. if applicable, name or trade name, 11. if applicable, device model, reference, or catalogue number, 12. if applicable, clinical size (including volume, length, gauge, diameter), 13. additional product description (optional), 14. if applicable, storage and/or handling conditions (as indicated on the label or in the instructions for use), 15. if applicable, additional trade names of the device, 16. labelled as a single-use device (y/n), 17. if applicable, the maximum number of reuses, 18. device labelled sterile (y/n), 19. need for sterilisation before use (y/n), 20. containing latex (y/n), 21. where applicable, information labelled in accordance with Section 10.4.5 of Annex I, 22. URL for additional information, such as electronic instructions for use (optional), 23. if applicable, critical warnings or contra-indications, 24. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART C THE UDI SYSTEM 1.   Definitions Automatic identification and data capture (‘AIDC’) AIDC is a technology used to automatically capture data. AIDC technologies include bar codes, smart cards, biometrics and RFID. Basic UDI-DI The Basic UDI-DI is the primary identifier of a device model. It is the DI assigned at the level of the device unit of use. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity. Unit of Use DI The Unit of Use DI serves to associate the use of a device with a patient in instances in which a UDI is not labelled on the individual device at the level of its unit of use, for example in the event of several units of the same device being packaged together. Configurable device A configurable device is a device that consists of several components which can be assembled by the manufacturer in multiple configurations. Those individual components may be devices in themselves. Configurable devices include computed tomography (CT) systems, ultrasound systems, anaesthesia systems, physiological Monitoring systems, radiology information systems (RIS). Configuration Configuration is a combination of items of equipment, as specified by the manufacturer, that operate together as a device to achieve an intended purpose. The combination of items may be modified, adjusted or customized to meet specific needs. Configurations include inter alia: — gantries, tubes, tables, consoles and other items of equipment that can be configured/combined to deliver an intended function in computed tomography. — ventilators, breathing circuits, vaporizers combined to deliver an intended function in anaesthesia. UDI-DI The UDI-DI is a unique numeric or alphanumeric code specific to a model of device and that is also used as the ‘access key’ to information stored in a UDI database. Human Readable Interpretation (‘HRI’) HRI is a legible interpretation of the data characters encoded in the UDI carrier. Packaging levels Packaging levels means the various levels of device packaging that contain a defined quantity of devices, such as a carton or case. UDI-PI The UDI-PI is a numeric or alphanumeric code that identifies the unit of device production. The different types of UDI-PIs include serial number, lot number, software identification and manufacturing or expiry date or both types of date. Radio Frequency Identification RFID RFID is a technology that uses communication through the use of radio waves to exchange data between a reader and an electronic tag attached to an object, for the purpose of identification. Shipping containers A shipping container is a container in relation to which traceability is controlled by a process specific to logistics systems. Unique Device Identifier (‘UDI’) The UDI is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific device on the market. The UDI is comprised of the UDI-DI and the UDI-PI. The word ‘Unique’ does not imply serialisation of individual production units. UDI carrier The UDI carrier is the means of conveying the UDI by using AIDC and, if applicable, its HRI. UDI carriers include, inter alia, ID/linear bar code, 2D/Matrix bar code, RFID. 2.   General requirements 2.1.   The affixing of the UDI is an additional requirement — it does not replace any other marking or labelling requirements laid down in Annex I to this Regulation. 2.2.   The manufacturer shall assign and maintain unique UDIs for its devices. 2.3.   Only the manufacturer may place the UDI on the device or its packaging. 2.4.   Only coding standards provided by issuing entities designated by the Commission pursuant to Article 27(2) may be used. 3.   The UDI 3.1.   A UDI shall be assigned to the device itself or its packaging. Higher levels of packaging shall have their own UDI. 3.2.   Shipping containers shall be exempted from the requirement in Section 3.1. By way of example, a UDI shall not be required on a logistics unit; where a healthcare provider orders multiple devices using the UDI or model number of individual devices and the manufacturer places those devices in a container for shipping or to protect the individually packaged devices, the container (logistics unit) shall not be subject to UDI requirements. 3.3.   The UDI shall contain two parts: a UDI-DI and a UDI-PI. 3.4.   The UDI-DI shall be unique at each level of device packaging. 3.5.   If a lot number, serial number, software identification or expiry date appears on the label, it shall be part of the UDI-PI. If there is also a manufacturing date on the label, it does not need to be included in the UDI-PI. If there is only a manufacturing date on the label, this shall be used as the UDI-PI. 3.6.   Each component that is considered to be a device and is commercially available on its own shall be assigned a separate UDI unless the components are part of a configurable device that is marked with its own UDI. 3.7.   Systems and procedure packs as referred to in Article 22 shall be assigned and bear their own UDI. 3.8.   The manufacturer shall assign the UDI to a device following the relevant coding standard. 3.9.   A new UDI-DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability; in particular, any change of one of the following UDI database data elements shall require a new UDI-DI: (a) name or trade name, (b) device version or model, (c) labelled as single use, (d) packaged sterile, (e) need for sterilization before use, (f) quantity of devices provided in a package, (g) critical warnings or contra-indications: e.g. containing latex or DEHP. 3.10.   Manufacturers that repackage and/or relabel devices, with their own label shall retain a record of the original device manufacturer's UDI. 4.   UDI carrier 4.1.   The UDI carrier (AIDC and HRI representation of the UDI) shall be placed on the label or on the device itself and on all higher levels of device packaging. Higher levels do not include shipping containers. 4.2.   In the event of there being significant space constraints on the unit of use packaging, the UDI carrier may be placed on the next higher packaging level. 4.3.   For single-use devices of classes I and IIa packaged and labelled individually, the UDI carrier shall not be required to appear on the packaging but it shall appear on a higher level of packaging, e.g. a carton containing several individually packaged devices. However, when the healthcare provider is not expected to have access, in cases such as in home healthcare settings, to the higher level of device packaging, the UDI shall be placed on the packaging of the individual device. 4.4.   For devices exclusively intended for retail point of sale the UDI-PIs in AIDC shall not be required to appear on the point of sale packaging. 4.5.   When AIDC carriers other than the UDI carrier are part of the product labelling, the UDI carrier shall be readily identifiable. 4.6.   If linear bar codes are used, the UDI-DI and UDI-PI may be concatenated or non-concatenated in two or more bar codes. All parts and elements of the linear bar code shall be distinguishable and identifiable. 4.7.   If there are significant constraints limiting the use of both AIDC and HRI on the label, only the AIDC format shall be required to appear on the label. For devices intended to be used outside healthcare facilities, such as devices for home care, the HRI shall however appear on the label even if this results in there being no space for the AIDC. 4.8.   The HRI format shall follow the rules of the UDI code-issuing entity. 4.9.   If the manufacturer is using RFID technology, a linear or 2D bar code in line with the standard provided by the issuing entities shall also be provided on the label. 4.10.   Devices that are reusable shall bear a UDI carrier on the device itself. The UDI carrier for reusable devices that require cleaning, disinfection, sterilisation or refurbishing between patient uses shall be permanent and readable after each process performed to make the device ready for the subsequent use throughout the intended lifetime of the device. The requirement of this Section shall not apply to devices in the following circumstances: (a) any type of direct marking would interfere with the safety or performance of the device; (b) the device cannot be directly marked because it is not technologically feasible. 4.11.   The UDI carrier shall be readable during normal use and throughout the intended lifetime of the device. 4.12.   If the UDI carrier is readily readable or, in the case of AIDC, scannable, through the device's packaging, the placing of the UDI carrier on the packaging shall not be required. 4.13.   In the case of single finished devices made up of multiple parts that must be assembled before their first use, it shall be sufficient to place the UDI carrier on only one part of each device. 4.14.   The UDI carrier shall be placed in a manner such that the AIDC can be accessed during normal operation or storage. 4.15.   Bar code carriers that include both a UDI-DI and a UDI-PI may also include essential data for the device to operate or other data. 5.   General principles of the UDI database 5.1.   The UDI database shall support the use of all core UDI database data elements referred to in Part B of this Annex. 5.2.   Manufacturers shall be responsible for the initial submission and updates of the identifying information and other device data elements in the UDI database. 5.3.   Appropriate methods/procedures for validation of the data provided shall be implemented. 5.4.   Manufacturers shall periodically verify the correctness of all of the data relevant to devices they have placed on the market, except for devices that are no longer available on the market. 5.5.   The presence of the device UDI-DI in the UDI database shall not be assumed to mean that the device is in conformity with this Regulation. 5.6.   The database shall allow for the linking of all the packaging levels of the device. 5.7.   The data for new UDI-DIs shall be available at the time the device is placed on the market. 5.8.   Manufacturers shall update the relevant UDI database record within 30 days of a change being made to an element, which does not require a new UDI-DI. 5.9.   Internationally-accepted standards for data submission and updates shall, wherever possible, be used by the UDI database. 5.10.   The user interface of the UDI database shall be available in all official languages of the Union. The use of free-text fields shall, however, be minimized in order to reduce translations. 5.11.   Data relating to devices that are no longer available on the market shall be retained in the UDI database. 6.   Rules for specific device types 6.1.   Implantable devices: 6.1.1. Implantable devices shall, at their lowest level of packaging (‘unit packs’), be identified, or marked using AIDC, with a UDI (UDI-DI + UDI-PI); 6.1.2. The UDI-PI shall have at least the following characteristics: (a) the serial number for active implantable devices, (b) the serial number or lot number for other implantable devices. 6.1.3. The UDI of the implantable device shall be identifiable prior to implantation. 6.2.   Reusable devices requiring cleaning, disinfection, sterilisation or refurbishing between uses 6.2.1.   The UDI of such devices shall be placed on the device and be readable after each procedure to make the device ready for the next use. 6.2.2.   The UDI-PI characteristics such as the lot or serial number shall be defined by the manufacturer. 6.3.   Systems and procedure packs as referred to in Article 22 6.3.1.   The natural or legal person referred to in Article 22 shall be responsible for identifying the system or procedure pack with a UDI including both UDI-DI and UDI-PI. 6.3.2.   Device contents of system or procedure packs shall bear a UDI carrier on their packaging or on the device itself. Exemptions: (a) individual single-use disposable devices, the uses of which are generally known to the persons by whom they are intended to be used, which are contained within a system or procedure pack, and which are not intended for individual use outside the context of the system or procedure pack, shall not be required to bear their own UDI carrier; (b) devices that are exempted from bearing a UDI carrier on the relevant level of packaging shall not be required to bear a UDI carrier when included within a system or procedure pack. 6.3.3.   Placement of the UDI carrier on systems or procedure packs (a) The system or procedure pack UDI carrier shall as a general rule be affixed to the outside of the packaging. (b) The UDI carrier shall be readable, or, in the case of AIDC, scannable, whether placed on the outside of the packaging of the system or procedure pack or inside transparent packaging. 6.4.   Configurable devices: 6.4.1.   A UDI shall be assigned to the configurable device in its entirety and shall be called the configurable device UDI. 6.4.2.   The configurable device UDI-DI shall be assigned to groups of configurations, not per configuration within the group. A group of configurations is defined as the collection of possible configurations for a given device as described in the technical documentation. 6.4.3.   A configurable device UDI-PI shall be assigned to each individual configurable device. 6.4.4.   The carrier of the configurable device UDI shall be placed on the assembly that is most unlikely to be exchanged during the lifetime of the system and shall be identified as the configurable device UDI. 6.4.5.   Each component that is considered a device and is commercially available on its own shall be assigned a separate UDI. 6.5.   Device Software 6.5.1.   UDI assignment Criteria The UDI shall be assigned at the system level of the software. Only software which is commercially available on its own and software which constitutes a device in itself shall be subject to that requirement. The software identification shall be considered to be the manufacturing control mechanism and shall be displayed in the UDI-PI. 6.5.2.   A new UDI-DI shall be required whenever there is a modification that changes: (a) the original performance; (b) the safety or the intended use of the software; (c) interpretation of data. Such modifications include new or modified algorithms, database structures, operating platform, architecture or new user interfaces or new channels for interoperability. 6.5.3.   Minor software revisions shall require a new UDI-PI and not a new UDI-DI. Minor software revisions are generally associated with bug fixes, usability enhancements that are not for safety purposes, security patches or operating efficiency. Minor software revisions shall be identified by a manufacturer-specific form of identification. 6.5.4.   UDI placement criteria for software (a) where the software is delivered on a physical medium, e.g. CD or DVD, each packaging level shall bear the human readable and AIDC representation of the complete UDI. The UDI that is applied to the physical medium containing the software and its packaging shall be identical to the UDI assigned to the system level software; (b) the UDI shall be provided on a readily accessible screen for the user in an easily-readable plain-text format, such as an ‘about’ file, or included on the start-up screen; (c) software lacking a user interface such as middleware for image conversion, shall be capable of transmitting the UDI through an application programming interface (API); (d) only the human readable portion of the UDI shall be required in electronic displays of the software. The marking of UDI using AIDC shall not be required in the electronic displays, such as ‘about’ menu, splash screen etc.; (e) the human readable format of the UDI for the software shall include the Application Identifiers (AI) for the standard used by the issuing entities, so as to assist the user in identifying the UDI and determining which standard is being used to create the UDI. ANNEX VII REQUIREMENTS TO BE MET BY NOTIFIED BODIES 1.   ORGANISATIONAL AND GENERAL REQUIREMENTS 1.1.   Legal status and organisational structure 1.1.1.   Each notified body shall be established under the national law of a Member State, or under the law of a third country with which the Union has concluded an agreement in this respect. Its legal personality and status shall be fully documented. Such documentation shall include information about ownership and the legal or natural persons exercising control over the notified body. 1.1.2.   If the notified body is a legal entity that is part of a larger organisation, the activities of that organisation as well as its organisational structure and governance, and the relationship with the notified body shall be clearly documented. In such cases, the requirements of Section 1.2 are applicable to both the notified body and the organisation to which it belongs. 1.1.3.   If a notified body wholly or partly owns legal entities established in a Member State or in a third country or is owned by another legal entity, the activities and responsibilities of those entities, as well as their legal and operational relationships with the notified body, shall be clearly defined and documented. Personnel of those entities performing conformity assessment activities under this Regulation shall be subject to the applicable requirements of this Regulation. 1.1.4.   The organisational structure, allocation of responsibilities, reporting lines and operation of the notified body shall be such that they ensure that there is confidence in the performance by the notified body and in the results of the conformity assessment activities it conducts. 1.1.5.   The notified body shall clearly document its organisational structure and the functions, responsibilities and authority of its top-level management and of other personnel who may have an influence upon the performance by the notified body and upon the results of its conformity assessment activities. 1.1.6.   The notified body shall identify the persons in top-level management that have overall authority and responsibility for each of the following: — the provision of adequate resources for conformity assessment activities; — the development of procedures and policies for the operation of the notified body; — the supervision of implementation of the procedures, policies and quality management systems of the notified body; — the supervision of the notified body's finances; — the activities and decisions taken by the notified body, including contractual agreements; — the delegation of authority to personnel and/or committees, where necessary, for the performance of defined activities; — the interaction with the authority responsible for notified bodies and the obligations regarding communications with other competent authorities, the Commission and other notified bodies. 1.2.   Independence and impartiality 1.2.1.   The notified body shall be a third-party body that is independent of the manufacturer of the device in relation to which it performs conformity assessment activities. The notified body shall also be independent of any other economic operator having an interest in the device as well as of any competitors of the manufacturer. This does not preclude the notified body from carrying out conformity assessment activities for competing manufacturers. 1.2.2.   The notified body shall be organised and operated so as to safeguard the independence, objectivity and impartiality of its activities. The notified body shall document and implement a structure and procedures for safeguarding impartiality and for promoting and applying the principles of impartiality throughout its organisation, personnel and assessment activities. Such procedures shall provide for the identification, investigation and resolution of any case in which a conflict of interest may arise, including involvement in consultancy services in the field of devices prior to taking up employment with the notified body. The investigation, outcome and its resolution shall be documented. 1.2.3.   The notified body, its top-level management and the personnel responsible for carrying out the conformity assessment tasks shall not: (a) be the designer, manufacturer, supplier, installer, purchaser, owner or maintainer of devices which they assess, nor the authorised representative of any of those parties. Such restriction shall not preclude the purchase and use of assessed devices that are necessary for the operations of the notified body and the conduct of the conformity assessment, or the use of such devices for personal purposes; (b) be involved in the design, manufacture or construction, marketing, installation and use, or maintenance of the devices for which they are designated, nor represent the parties engaged in those activities; (c) engage in any activity that may conflict with their independence of judgement or integrity in relation to conformity assessment activities for which they are designated; (d) offer or provide any service which may jeopardise the confidence in their independence, impartiality or objectivity. In particular, they shall not offer or provide consultancy services to the manufacturer, its authorised representative, a supplier or a commercial competitor as regards the design, construction, marketing or maintenance of devices or processes under assessment, and (e) be linked to any organisation which itself provides consultancy services as referred to in point (d). Such restriction does not preclude general training activities that are not client specific and that relate to regulation of devices or to related standards. 1.2.4.   Involvement in consultancy services in the field of devices prior to taking up employment with a notified body shall be fully documented at the time of employment and potential conflicts of interest shall be monitored and resolved in accordance with this Annex. Personnel who were formerly employed by a specific client, or provided consultancy services in the field of devices to that specific client prior to taking up employment with a notified body, shall not be assigned for conformity assessment activities for that specific client or companies belonging to the same group for a period of three years. 1.2.5.   The impartiality of notified bodies, of their top-level management and of the assessment personnel shall be guaranteed. The level of the remuneration of the top-level management and assessment personnel of a notified body and subcontractors, involved in assessment activities shall not depend on the results of the assessments. Notified bodies shall make publicly available the declarations of interest of their top-level management. 1.2.6.   If a notified body is owned by a public entity or institution, independence and absence of any conflict of interest shall be ensured and documented between, on the one hand, the authority responsible for notified bodies and/or the competent authority and, on the other hand, the notified body. 1.2.7.   The notified body shall ensure and document that the activities of its subsidiaries or subcontractors, or of any associated body, including the activities of its owners do not affect its independence, impartiality or the objectivity of its conformity assessment activities. 1.2.8.   The notified body shall operate in accordance with a set of consistent, fair and reasonable terms and conditions, taking into account the interests of small and medium-sized enterprises as defined in Recommendation 2003/361/EC in relation to fees. 1.2.9.   The requirements laid down in this Section in no way preclude exchanges of technical information and regulatory guidance between a notified body and a manufacturer applying for conformity assessment. 1.3.   Confidentiality 1.3.1.   The notified body shall have documented procedures in place ensuring that its personnel, committees, subsidiaries, subcontractors, and any associated body or personnel of external bodies respect the confidentiality of the information which comes into its possession during the performance of conformity assessment activities, except when disclosure is required by law. 1.3.2.   The personnel of a notified body shall observe professional secrecy in carrying out their tasks under this Regulation or any provision of national law giving effect to it, except in relation to the authorities responsible for notified bodies, competent authorities for medical devices in the Member States or the Commission. Proprietary rights shall be protected. The notified body shall have documented procedures in place in respect of the requirements of this Section. 1.4.   Liability 1.4.1.   The notified body shall take out appropriate liability insurance for its conformity assessment activities, unless liability is assumed by the Member State in question in accordance with national law or that Member State is directly responsible for the conformity assessment. 1.4.2.   The scope and overall financial value of the liability insurance shall correspond to the level and geographic scope of activities of the notified body and be commensurate with the risk profile of the devices certified by the notified body. The liability insurance shall cover cases where the notified body may be obliged to withdraw, restrict or suspend certificates. 1.5.   Financial requirements The notified body shall have at its disposal the financial resources required to conduct its conformity assessment activities within its scope of designation and related business operations. It shall document and provide evidence of its financial capacity and its long-term economic viability, taking into account, where relevant, any specific circumstances during an initial start-up phase. 1.6.   Participation in coordination activities 1.6.1.   The notified body shall participate in, or ensure that its assessment personnel is informed of, any relevant standardisation activities and in the activities of the notified body coordination group referred to in Article 49 and that its assessment and decision-making personnel are informed of all relevant legislation, guidance and best practice documents adopted in the framework of this Regulation. 1.6.2.   The notified body shall take into consideration guidance and best practice documents. 2.   QUALITY MANAGEMENT REQUIREMENTS 2.1.   The notified body shall establish, document, implement, maintain and operate a quality management system that is appropriate to the nature, area and scale of its conformity assessment activities and is capable of supporting and demonstrating the consistent fulfilment of the requirements of this Regulation. 2.2.   The quality management system of the notified body shall address at least the following: — management system structure and documentation, including policies and objectives for its activities; — policies for assignment of activities and responsibilities to personnel; — assessment and decision-making processes in accordance with the tasks, responsibilities and role of the notified body's personnel and top-level management; — the planning, conduct, evaluation and, if necessary, adaptation of its conformity assessment procedures; — control of documents; — control of records; — management reviews; — internal audits; — corrective and preventive actions; — complaints and appeals; and — continuous training. Where documents are used in various languages, the notified body shall ensure and control that they have the same content. 2.3.   The top-level management of the notified body shall ensure that the quality management system is fully understood, implemented and maintained throughout the notified body organisation including subsidiaries and subcontractors involved in conformity assessment activities pursuant to this Regulation. 2.4.   The notified body shall require all personnel to formally commit themselves by a signature or equivalent to comply with the procedures defined by the notified body. That commitment shall cover aspects relating to confidentiality and to independence from commercial and other interests, and any existing or prior association with clients. The personnel shall be required to complete written statements indicating their compliance with confidentiality, independence and impartiality principles. 3.   RESOURCE REQUIREMENTS 3.1.   General 3.1.1.   Notified bodies shall be capable of carrying out all the tasks falling to them under this Regulation with the highest degree of professional integrity and the requisite competence in the specific field, whether those tasks are carried out by notified bodies themselves or on their behalf and under their responsibility. In particular, notified bodies shall have the necessary personnel and possess or have access to all equipment, facilities and competence needed to perform properly the technical, scientific and administrative tasks entailed in the conformity assessment activities in relation to which they have been designated. Such requirement presupposes at all times and for each conformity assessment procedure and each type of devices in relation to which they have been designated, that the notified body has permanent availability of sufficient administrative, technical and scientific personnel who possess experience and knowledge relating to the relevant devices and the corresponding technologies. Such personnel shall be in sufficient numbers to ensure that the notified body in question can perform the conformity assessment tasks, including the assessment of the medical functionality, clinical evaluations and the performance and safety of devices, for which it has been designated, having regard to the requirements of this Regulation, in particular, those set out in Annex I. A notified body's cumulative competences shall be such as to enable it to assess the types of devices for which it is designated. The notified body shall have sufficient internal competence to critically evaluate assessments conducted by external expertise. Tasks which a notified body is precluded from subcontracting are set out in Section 4.1. Personnel involved in the management of the operation of a notified body's conformity assessment activities for devices shall have appropriate knowledge to set up and operate a system for the selection of assessment and verification staff, for verification of their competence, for authorisation and allocation of their tasks, for organisation of their initial and ongoing training and for the assignment of their duties and the monitoring of those staff, in order to ensure that personnel who carry out and perform assessment and verification operations are competent to fulfil the tasks required of them. The notified body shall identify at least one individual within its top-level management as having overall responsibility for all conformity assessment activities in relation to devices. 3.1.2.   The notified body shall ensure that personnel involved in conformity assessment activities maintain their qualification and expertise by implementing a system for exchange of experience and a continuous training and education programme. 3.1.3.   The notified body shall clearly document the extent and limits of duties and responsibilities and the level of authorisation of the personnel, including any subcontractors and external experts, involved in conformity assessment activities and inform those personnel accordingly. 3.2.   Qualification criteria in relation to personnel 3.2.1.   The Notified Body shall establish and document qualification criteria and procedures for selection and authorisation of persons involved in conformity assessment activities, including as regards knowledge, experience and other competence required, and the required initial and ongoing training. The qualification criteria shall address the various functions within the conformity assessment process, such as auditing, product evaluation or testing, technical documentation review and decision-making, as well as the devices, technologies and areas, such as biocompatibility, sterilisation, tissues and cells of human and animal origin and clinical evaluation, covered by the scope of designation. 3.2.2.   The qualification criteria referred to in Section 3.2.1 shall refer to the scope of a notified body's designation in accordance with the scope description used by the Member State for the notification referred to in Article 42(3), providing a sufficient level of detail for the required qualification within the subdivisions of the scope description. Specific qualification criteria shall be defined at least for the assessment of: — the pre-clinical evaluation, — clinical evaluation, — tissues and cells of human and animal origin, — functional safety, — software, — packaging, — devices that incorporate as an integral part a medicinal product, — devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body and — the different types of sterilisation processes. 3.2.3.   The personnel responsible for establishing qualification criteria and for authorising other personnel to perform specific conformity assessment activities shall be employed by the notified body itself and shall not be external experts or subcontracted. They shall have proven knowledge and experience in all of the following: — Union devices legislation and relevant guidance documents; — the conformity assessment procedures provided for in this Regulation; — a broad base of knowledge of device technologies and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualification criteria; — training relevant to personnel involved in conformity assessment activities in relation to devices; — adequate experience in conformity assessments under this Regulation or previously applicable law within a notified body. 3.2.4.   The notified body shall have permanent availability of personnel with relevant clinical expertise and where possible such personnel shall be employed by the notified body itself. Such personnel shall be integrated throughout the notified body's assessment and decision-making process in order to: — identify when specialist input is required for the assessment of the clinical evaluation conducted by the manufacturer and identify appropriately qualified experts; — appropriately train external clinical experts in the relevant requirements of this Regulation, CS, guidance and harmonised standards and ensure that the external clinical experts are fully aware of the context and implications of their assessment and the advice they provide; — be able to review and scientifically challenge the clinical data contained within the clinical evaluation, and any associated clinical investigations, and appropriately guide external clinical experts in the assessment of the clinical evaluation presented by the manufacturer; — be able to scientifically evaluate and, if necessary, challenge the clinical evaluation presented, and the results of the external clinical experts' assessment of the manufacturer's clinical evaluation; — be able to ascertain the comparability and consistency of the assessments of clinical evaluations conducted by clinical experts; — be able to make an assessment of the manufacturer's clinical evaluation and a clinical judgement of the opinion provided by any external expert and make a recommendation to the notified body's decision maker; and — be able to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.5.   The personnel responsible for carrying out product-related reviews (product reviewers), such as technical documentation reviews or type examination, including aspects such as clinical evaluation, biological safety, sterilisation and software validation, shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, e.g. medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the design, manufacture, testing or use of the device or technology to be assessed or related to the scientific aspects to be assessed; — knowledge of device legislation, including the general safety and performance requirements set out in Annex I; — appropriate knowledge and experience of relevant harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge and experience of clinical evaluation; — appropriate knowledge of the devices which they are assessing; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those assessments; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.6.   The personnel responsible for carrying out audits of the manufacturer's quality management system (site auditors) shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, such as medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the area of quality management; — appropriate knowledge of devices legislation as well as related harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge of quality management systems and related standards and guidance documents; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those audits; — training in auditing techniques enabling them to challenge quality management systems; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.7.   The personnel with overall responsibility for final reviews and decision-making on certification shall be employed by the notified body itself and shall not be external experts or be subcontracted. Those personnel shall, as a group, have proven knowledge and comprehensive experience of all of the following: — devices legislation and relevant guidance documents; — the device conformity assessments relevant to this Regulation; — the types of qualifications, experience and expertise relevant to device conformity assessment; — a broad base of knowledge of device technologies, including sufficient experience of conformity assessment of devices being reviewed for certification, the device industry and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualifications for personnel involved; — the ability to draw up records and reports demonstrating that the conformity assessment activities have been appropriately carried out. 3.3.   Documentation of qualification, training and authorisation of personnel 3.3.1.   The notified body shall have a procedure in place to fully document the qualification of each member of personnel involved in conformity assessment activities and the satisfaction of the qualification criteria referred to in Section 3.2. Where in exceptional circumstances the fulfilment of the qualification criteria set out in Section 3.2. cannot be fully demonstrated, the notified body shall justify to the authority responsible for notified bodies the authorisation of those members of personnel to carry out specific conformity assessment activities. 3.3.2.   For all of its personnel referred to in Sections 3.2.3 to 3.2.7, the notified body shall establish and maintain up to date: — a matrix detailing the authorisations and responsibilities of the personnel in respect of conformity assessment activities; and — records attesting to the required knowledge and experience for the conformity assessment activity for which they are authorised. The records shall contain a rationale for defining the scope of the responsibilities for each of the assessment personnel and records of the conformity assessment activities carried out by each of them. 3.4.   Subcontractors and external experts 3.4.1.   Notified bodies may, without prejudice to Section 3.2, subcontract certain clearly defined component parts of a conformity assessment activity. The subcontracting of the auditing of quality management systems or of product related reviews as a whole shall not be permitted; nevertheless parts of those activities may be conducted by subcontractors and external auditors and experts working on behalf of the notified body. The notified body in question shall retain full responsibility for being able to produce appropriate evidence of the competence of subcontractors and experts to fulfil their specific tasks, for making a decision based on a subcontractor's assessment and for the work conducted by subcontractors and experts on its behalf. The following activities may not be subcontracted by notified bodies: — review of the qualifications and monitoring of the performance of external experts; — auditing and certification activities where the subcontracting in question is to auditing or certification organisations; — allocation of work to external experts for specific conformity assessment activities; and — final review and decision making functions. 3.4.2.   Where a notified body subcontracts certain conformity assessment activities either to an organisation or an individual, it shall have a policy describing the conditions under which subcontracting may take place, and shall ensure that: — the subcontractor meets the relevant requirements of this Annex; — subcontractors and external experts do not further subcontract work to organisations or personnel; and — the natural or legal person that applied for conformity assessment has been informed of the requirements referred to in the first and second indent. Any subcontracting or consultation of external personnel shall be properly documented, shall not involve any intermediaries and shall be subject to a written agreement covering, among other things, confidentiality and conflicts of interest. The notified body in question shall take full responsibility for the tasks performed by subcontractors. 3.4.3.   Where subcontractors or external experts are used in the context of a conformity assessment, in particular regarding novel, invasive and implantable devices or technologies, the notified body in question shall have internal competence in each product area for which it is designated that is adequate for the purpose of leading the overall conformity assessment, verifying the appropriateness and validity of expert opinions and making decisions on certification. 3.5.   Monitoring of competences, training and exchange of experience 3.5.1.   The notified body shall establish procedures for the initial evaluation and on-going monitoring of the competence, conformity assessment activities and performance of all internal and external personnel, and subcontractors, involved in conformity assessment activities. 3.5.2.   Notified bodies shall review at regular intervals, the competence of their personnel, identify training needs and draw up a training plan to maintain the required level of qualification and knowledge of individual personnel. That review shall at a minimum, verify that personnel: — are aware of Union and national law in force on devices, relevant harmonised standards, CS, guidance documents and the results of the coordination activities referred to in Section 1.6; and — take part in the internal exchange of experience and the continuous training and education programme referred to in Section 3.1.2. 4.   PROCESS REQUIREMENTS 4.1.   General The notified body shall have in place documented processes and sufficiently detailed procedures for the conduct of each conformity assessment activity for which it is designated, comprising the individual steps from pre-application activities up to decision making and surveillance and taking into account, when necessary, the respective specificities of the devices. The requirements laid down in Sections 4.3, 4.4, 4.7 and 4.8 shall be fulfilled as part of the internal activities of notified bodies and shall not be subcontracted. 4.2.   Notified body quotations and pre-application activities The notified body shall: (a) publish a publicly available description of the application procedure by which manufacturers can obtain certification from it. That description shall include which languages are acceptable for submission of documentation and for any related correspondence; (b) have documented procedures relating to, and documented details about, fees charged for specific conformity assessment activities and any other financial conditions relating to notified bodies' assessment activities for devices; (c) have documented procedures in relation to advertising of their conformity assessment services. Those procedures shall ensure that advertising or promotional activities in no way imply or are capable of leading to an inference that their conformity assessment will offer manufacturers earlier market access or be quicker, easier or less stringent than that of other notified bodies; (d) have documented procedures requiring the review of pre-application information, including the preliminary verification that the product is covered by this Regulation and its classification, prior to issuing any quotation to the manufacturer relating to a specific conformity assessment; and (e) ensure that all contracts relating to the conformity assessment activities covered by this Regulation are concluded directly between the manufacturer and the notified body and not with any other organisation. 4.3.   Application review and contract The notified body shall require a formal application signed by a manufacturer or an authorised representative containing all of the information and the manufacturer's declarations required by the relevant conformity assessment as referred to in Annexes IX to XI. The contract between a notified body and a manufacturer shall take the form of a written agreement signed by both parties. It shall be kept by the notified body. This contract shall have clear terms and conditions and contain obligations that enable the notified body to act as required under this Regulation, including an obligation on the manufacturer to inform the notified body of vigilance reports, the right of the notified body to suspend, restrict or withdraw certificates issued and the duty of the notified body to fulfil its information obligations. The notified body shall have documented procedures to review applications, addressing: (a) the completeness of those applications with respect to the requirements of the relevant conformity assessment procedure, as referred to in the corresponding Annex, under which approval has been sought, (b) the verification of the qualification of products covered by those applications as devices and their respective classifications, (c) whether the conformity assessment procedures chosen by the applicant are applicable to the device in question under this Regulation, (d) the ability of the notified body to assess the application based on its designation, and (e) the availability of sufficient and appropriate resources. The outcome of each review of an application shall be documented. Refusals or withdrawals of applications shall be notified to the electronic system referred to in Article 57 and shall be accessible to other notified bodies. 4.4.   Allocation of resources The notified body shall have documented procedures to ensure that all conformity assessment activities are conducted by appropriately authorised and qualified personnel who are sufficiently experienced in the evaluation of the devices, systems and processes and related documentation that are subject to conformity assessment. For each application, the notified body shall determine the resources needed and identify one individual responsible for ensuring that the assessment of that application is conducted in accordance with the relevant procedures and for ensuring that the appropriate resources including personnel are utilised for each of the tasks of the assessment. The allocation of tasks required to be carried out as part of the conformity assessment and any changes subsequently made to this allocation shall be documented. 4.5.   Conformity assessment activities 4.5.1.   General The notified body and its personnel shall carry out the conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific fields. The notified body shall have expertise, facilities and documented procedures that are sufficient to effectively conduct the conformity assessment activities for which the notified body in question is designated, taking account of the relevant requirements set out in Annexes IX to XI, and in particular all of the following requirements: — appropriately plan the conduct of each individual project, — ensure that the composition of the assessment teams is such that there is sufficient experience in relation to the technology concerned, and that there is continuous objectivity and independence, and to provide for rotation of the members of the assessment team at appropriate intervals, — specify the rationale for fixing time limits for completion of conformity assessment activities, — assess the manufacturer's technical documentation and the solutions adopted to meet the requirements laid down in Annex I, — review the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects, — review the manufacturer's procedures and documentation relating to clinical evaluation, — address the interface between the manufacturer's risk management process and its appraisal and analysis of the pre-clinical and clinical evaluation and to evaluate their relevance for the demonstration of conformity with the relevant requirements in Annex I, — carry out the specific procedures referred to in Sections 5.2 to 5.4 of Annex IX, — in the case of class IIa or class IIb devices, assess the technical documentation of devices selected on a representative basis, — plan and periodically carry out appropriate surveillance audits and assessments, carry out or request certain tests to verify the proper functioning of the quality management system and to perform unannounced on site audits, — relating to the sampling of devices, verify that the manufactured device is in conformity with the technical documentation; such requirements shall define the relevant sampling criteria and testing procedure prior to sampling, — evaluate and verify a manufacturer's compliance with relevant Annexes. The notified body shall, where relevant, take into consideration available CS, guidance and best practice documents and harmonised standards, even if the manufacturer does not claim to be in compliance. 4.5.2.   Quality management system auditing (a) As part of the assessment of the quality management system, a notified body shall prior to an audit and in accordance with its documented procedures: — assess the documentation submitted in accordance with the relevant conformity assessment Annex, and draw up an audit programme which clearly identifies the number and sequence of activities required to demonstrate complete coverage of a manufacturer's quality management system and to determine whether it meets the requirements of this Regulation, — identify links between, and allocation of responsibilities among, the various manufacturing sites, and identify relevant suppliers and/or subcontractors of the manufacturer, and consider the need to specifically audit any of those suppliers or subcontractors or both, — clearly define, for each audit identified in the audit programme, the objectives, criteria and scope of the audit, and draw up an audit plan that adequately addresses and takes account of the specific requirements for the devices, technologies and processes involved, — draw up and keep up to date, for class IIa and class IIb devices, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III covering the range of such devices covered by the manufacturer's application. That plan shall ensure that all devices covered by the certificate are sampled over the period of validity of the certificate, and — select and assign appropriately qualified and authorised personnel for conducting the individual audits. The respective roles, responsibilities and authorities of the team members shall be clearly defined and documented. (b) Based on the audit programme it has drawn up, the notified body shall, in accordance with its documented procedures: — audit the manufacturer's quality management system, in order to verify that the quality management system ensures that the devices covered conform to the relevant provisions of this Regulation which apply to devices at every stage, from design through final quality control to ongoing surveillance, and shall determine whether the requirements of this Regulation are met, — based on relevant technical documentation and in order to determine whether the manufacturer meets the requirements referred to in the relevant conformity assessment Annex, review and audit the manufacturer's processes and subsystems, in particular for: — design and development, — production and process controls, — product documentation, — purchasing controls including verification of purchased devices, — corrective and preventive actions, including for post-market surveillance, and — PMCF, and review and audit requirements and provisions adopted by the manufacturer, including those in relation to fulfilling the general safety and performance requirements set out in Annex I. The documentation shall be sampled in such a manner as to reflect the risks associated with the intended use of the device, the complexity of the manufacturing technologies, the range and classes of devices produced and any available post-market surveillance information, — if not already covered by the audit programme, audit the control of processes on the premises of the manufacturer's suppliers, when the conformity of finished devices is significantly influenced by the activity of suppliers and, in particular when the manufacturer cannot demonstrate sufficient control over its suppliers, — conduct assessments of the technical documentation based on its sampling plan and taking account of Sections 4.5.4. and 4.5.5. for pre-clinical and clinical evaluations, and — the notified body shall ensure that audit findings are appropriately and consistently classified in accordance with the requirements of this Regulation and with relevant standards, or with best practice documents developed or adopted by the MDCG. 4.5.3.   Product verification Assessment of the technical documentation For assessment of the technical documentation conducted in accordance with Chapter II of Annex IX, notified bodies shall have sufficient expertise, facilities and documented procedures for: — the allocation of appropriately qualified and authorised personnel for the examination of individual aspects such as use of the device, biocompatibility, clinical evaluation, risk management, and sterilisation, and — the assessment of conformity of the design with this Regulation, and for taking account of Sections 4.5.4. to 4.5.6. That assessment shall include examination of the implementation by manufacturers of incoming, in-process and final checks and the results thereof. If further tests or other evidence is required for the assessment of conformity with the requirements of this Regulation, the notified body in question shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. Type-examinations The notified body shall have documented procedures, sufficient expertise and facilities for the type-examination of devices in accordance with Annex X including the capacity to: — examine and assess the technical documentation taking account of Sections 4.5.4. to 4.5.6., and verify that the type has been manufactured in conformity with that documentation; — establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility; — document its rationale for the selection of those parameters; — carry out the appropriate examinations and tests in order to verify that the solutions adopted by the manufacturer meet the general safety and performance requirements set out in Annex I. Such examinations and tests shall include all tests necessary to verify that the manufacturer has in fact applied the relevant standards it has opted to use; — agree with the applicant as to where the necessary tests will be performed if they are not to be carried out directly by the notified body; and — assume full responsibility for test results. Test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. Verification by examination and testing of every product The notified body shall: (a) have documented procedures, sufficient expertise and facilities for the verification by examination and testing of every product in accordance with Part B of Annex XI; (b) establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility in order to: — verify, for class IIb devices, the conformity of the device with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to those devices, — confirm, for class IIa devices, the conformity with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to those devices; (c) document its rationale for the selection of the parameters referred to in point (b); (d) have documented procedures to carry out the appropriate assessments and tests in order to verify the conformity of the device with the requirements of this Regulation by examining and testing every product as specified in Section 15 of Annex XI; (e) have documented procedures providing for the reaching of an agreement with the applicant concerning when and where necessary tests that are not to be carried out by the notified body itself are to be performed; and (f) assume full responsibility for test results in accordance with documented procedures; test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. 4.5.4.   Pre-clinical evaluation assessment The notified body shall have documented procedures in place for the review of the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects. The notified body shall examine, validate and verify that the manufacturer's procedures and documentation adequately address: (a) the planning, conduct, assessment, reporting and, where appropriate, updating of the pre-clinical evaluation, in particular of — the scientific pre-clinical literature search, and — the pre-clinical testing, for example laboratory testing, simulated use testing, computer modelling, the use of animal models, (b) the nature and duration of body contact and the specific associated biological risks, (c) the interface with the risk management process, and (d) the appraisal and analysis of the available pre-clinical data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I. The notified body's assessment of pre-clinical evaluation procedures and documentation shall address the results of literature searches and all validation, verification and testing performed and conclusions drawn, and shall typically include considering the use of alternative materials and substances and take account of the packaging, stability, including shelf life, of the finished device. Where no new testing has been undertaken by a manufacturer or where there are deviations from procedures, the notified body in question shall critically examine the justification presented by the manufacturer. 4.5.5.   Clinical evaluation assessment The notified body shall have documented procedures in place relating to the assessment of a manufacturer's procedures and documentation relating to clinical evaluation both for initial conformity assessment and on an ongoing basis. The notified body shall examine, validate and verify that manufacturers' procedures and documentation adequately address: — the planning, conduct, assessment, reporting and updating of the clinical evaluation as referred to in Annex XIV, — post-market surveillance and PMCF, — the interface with the risk management process, — the appraisal and analysis of the available data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I, and — the conclusions drawn with regard to the clinical evidence and drawing up of the clinical evaluation report. These procedures referred to in the first paragraph shall take into consideration available CS, guidance and best practice documents. The notified body's assessment of clinical evaluations as referred to in Annex XIV shall cover: — the intended use specified by the manufacturer and claims for the device defined by it, — the planning of the clinical evaluation, — the methodology for the literature search, — relevant documentation from the literature search, — the clinical investigation, — validity of equivalence claimed in relation to other devices, the demonstration of equivalence, the suitability and conclusions data from equivalent and similar devices, — post-market surveillance and PMCF, — the clinical evaluation report, and — justifications in relation to non-performance of clinical investigations or PMCF. In relation to clinical data from clinical investigations included within the clinical evaluation, the notified body in question shall ensure that the conclusions drawn by the manufacturer are valid in the light of the approved clinical investigation plan. The notified body shall ensure that the clinical evaluation adequately addresses the relevant safety and performance requirements provided for in Annex I, that it is appropriately aligned with the risk management requirements, that it is conducted in accordance with Annex XIV and that it is appropriately reflected in the information provided relating to the device. 4.5.6.   Specific Procedures The notified body shall have documented procedures, sufficient expertise and facilities for the procedures referred to in Sections 5 and 6 of Annex IX, Section 6 of Annex X and Section 16 of Annex XI, for which they are designated. In the case of devices manufactured utilising tissues or cells of animal origin or their derivatives, such as from TSE susceptible species, as referred to in Regulation (EU) No 722/2012, the notified body shall have documented procedures in place that fulfil the requirements laid down in that Regulation, including for the preparation of a summary evaluation report for the relevant competent authority. 4.6.   Reporting The notified body shall: — ensure that all steps of the conformity assessment are documented so that the conclusions of the assessment are clear and demonstrate compliance with the requirements of this Regulation and can represent objective evidence of such compliance to persons that are not themselves involved in the assessment, for example personnel in designating authorities, — ensure that records that are sufficient to provide a discernible audit trail are available for quality management system audits, — clearly document the conclusions of its assessment of clinical evaluation in a clinical evaluation assessment report, and — for each specific project, provide a detailed report which shall be based on a standard format containing a minimum set of elements determined by the MDCG. The report of the notified body shall: — clearly document the outcome of its assessment and draw clear conclusions from the verification of the manufacturer's conformity with the requirements of this Regulation, — make a recommendation for a final review and for a final decision to be taken by the notified body; this recommendation shall be signed off by the member of personnel responsible in the notified body, and — be provided to the manufacturer in question. 4.7.   Final review The notified body shall prior to making a final decision: — ensure that the personnel assigned for the final review and decision-making on specific projects are appropriately authorised and are different from the personnel who have conducted the assessments, — verify that the report or reports and supporting documentation needed for decision making, including concerning resolution of non-conformities noted during assessment, are complete and sufficient with respect to the scope of the application, and — verify whether there are any unresolved non-conformities preventing issuance of a certificate. 4.8.   Decisions and Certifications The notified body shall have documented procedures for decision-making including as regards the allocation of responsibilities for the issuance, suspension, restriction and withdrawal of certificates. Those procedures shall include the notification requirements laid down in Chapter V of this Regulation. The procedures shall allow the notified body in question to: — decide, based on the assessment documentation and additional information available, whether the requirements of this Regulation are fulfilled, — decide, based on the results of its assessment of the clinical evaluation and risk management, whether the post-market surveillance plan, including the PMCF plan, is adequate, — decide on specific milestones for further review by the notified body of the up to date clinical evaluation, — decide whether specific conditions or provisions need to be defined for the certification, — decide, based on the novelty, risk classification, clinical evaluation and conclusions from the risk analysis of the device, on a period of certification not exceeding five years, — clearly document decision making and approval steps including approval by signature of the members of personnel responsible, — clearly document responsibilities and mechanisms for communication of decisions, in particular, where the final signatory of a certificate differs from the decision maker or decision makers or does not fulfil the requirements laid down in Section 3.2.7, — issue a certificate or certificates in accordance with the minimum requirements laid down in Annex XII for a period of validity not exceeding five years and shall indicate whether there are specific conditions or limitations associated with the certification, — issue a certificate or certificates for the applicant alone and shall not issue certificates covering multiple entities, and — ensure that the manufacturer is notified of the outcome of the assessment and the resultant decision and that they are entered into the electronic system referred to in Article 57. 4.9.   Changes and modifications The notified body shall have documented procedures and contractual arrangements with manufacturers in place relating to the manufacturers' information obligations and the assessment of changes to: — the approved quality management system or systems or to the product-range covered, — the approved design of a device, — the intended use of or claims made for the device, — the approved type of a device, and — any substance incorporated in or utilised for the manufacturing of a device and being subject to the specific procedures in accordance with Section 4.5.6. The procedures and contractual arrangements referred to in the first paragraph shall include measures for checking the significance of the changes referred to in the first paragraph. In accordance with its documented procedures, the notified body in question shall: — ensure that manufacturers submit for prior approval plans for changes as referred to in the first paragraph and relevant information relating to such changes, — assess the changes proposed and verify whether, after these changes, the quality management system, or the design of a device or type of a device, still meets the requirements of this Regulation, and — notify the manufacturer of its decision and provide a report or as applicable a supplementary report, which shall contain the justified conclusions of its assessment. 4.10.   Surveillance activities and post-certification monitoring The notified body shall have documented procedures: — defining how and when surveillance activities of manufacturers are to be conducted. Those procedures shall include arrangements for unannounced on-site audits of manufacturers and, where applicable, subcontractors and suppliers carrying out product tests and the monitoring of compliance with any conditions binding manufacturers and associated with certification decisions, such as updates to clinical data at defined intervals, — for screening relevant sources of scientific and clinical data and post-market information relating to the scope of their designation. Such information shall be taken into account in the planning and conduct of surveillance activities, and — to review vigilance data to which they have access under Article 92(2) in order to estimate its impact, if any, on the validity of existing certificates. The results of the evaluation and any decisions taken shall be thoroughly documented. The notified body in question shall, upon receipt of information about vigilance cases from a manufacturer or competent authorities, decide which of the following options to apply: — not to take action on the basis that the vigilance case is clearly not related to the certification granted, — observe the manufacturer's and competent authority's activities and the results of the manufacturer's investigation so as to determine whether the certification granted is at risk or whether adequate corrective action has been taken, — perform extraordinary surveillance measures, such as document reviews, short-notice or unannounced audits and product testing, where it is likely that the certification granted is at risk, — increase the frequency of surveillance audits, — review specific products or processes on the occasion of the next audit of the manufacturer, or — take any other relevant measure. In relation to surveillance audits of manufacturers, the notified body shall have documented procedures to: — conduct surveillance audits of the manufacturer on at least an annual basis which shall be planned and conducted in line with the relevant requirements in Section 4.5, — ensure adequate assessment of the manufacturer's documentation on, and application of the provisions on, vigilance, the post-market surveillance, and PMCF, — sample and test devices and technical documentation, during audits, according to pre-defined sampling criteria and testing procedures to ensure that the manufacturer continuously applies the approved quality management system, — ensure that the manufacturer complies with the documentation and information obligations laid down in the relevant Annexes and that its procedures take into account best practices in the implementation of quality management systems, — ensure that the manufacturer does not use quality management system or device approvals in a misleading manner, — gather sufficient information to determine if the quality management system continues to comply with the requirements of this Regulation, — ask the manufacturer, if non-conformities are detected, for corrections, corrective actions and, where applicable, preventive actions, and — where necessary, impose specific restrictions on the relevant certificate, or suspend or withdraw it. The notified body shall, if listed as part of the conditions for certification: — conduct an in-depth review of the clinical evaluation as most recently updated by the manufacturer based on the manufacturer's post-market surveillance, on its PMCF and on clinical literature relevant to the condition being treated with the device or on clinical literature relevant to similar devices, — clearly document the outcome of the in-depth review and address any specific concerns to the manufacturer or impose any specific conditions on it, and — ensure that the clinical evaluation as most recently updated, is appropriately reflected in the instructions for use and, where applicable, the summary of safety and performance. 4.11.   Re-certification The notified body shall have documented procedures in place relating to the re-certification reviews and the renewal of certificates. Re-certification of approved quality management systems or EU technical documentation assessment certificates or EU type-examination certificates shall occur at least every five years. The notified body shall have documented procedures relating to renewals of EU technical documentation assessment certificates and EU type-examination certificates and those procedures shall require the manufacturer in question to submit a summary of changes and scientific findings for the device, including: (a) all changes to the originally approved device, including changes not yet notified, (b) experience gained from post-market surveillance, (c) experience from risk management, (d) experience from updating the proof of compliance with the general safety and performance requirements set out in Annex I, (e) experience from reviews of the clinical evaluation, including the results of any clinical investigations and PMCF, (f) changes to the requirements, to components of the device or to the scientific or regulatory environment, (g) changes to applied or new harmonised standards, CS or equivalent documents, and (h) changes in medical, scientific and technical knowledge, such as: — new treatments, — changes in test methods, — new scientific findings on materials and components, including findings on their biocompatibility, — experience from studies on comparable devices, — data from registers and registries, — experience from clinical investigations with comparable devices. The notified body shall have documented procedures to assess the information referred to in the second paragraph and shall pay particular attention to clinical data from post-market surveillance and PMCF activities undertaken since the previous certification or re-certification, including appropriate updates to manufacturers' clinical evaluation reports. For the decision on re-certification, the notified body in question shall use the same methods and principles as for the initial certification decision. If necessary, separate forms shall be established for re-certification taking into account the steps taken for certification such as application and application review. ANNEX VIII CLASSIFICATION RULES CHAPTER I DEFINITIONS SPECIFIC TO CLASSIFICATION RULES 1.   DURATION OF USE 1.1.    ‘Transient’ means normally intended for continuous use for less than 60 minutes. 1.2.    ‘Short term’ means normally intended for continuous use for between 60 minutes and 30 days. 1.3.    ‘Long term’ means normally intended for continuous use for more than 30 days. 2.   INVASIVE AND ACTIVE DEVICES 2.1.    ‘Body orifice’ means any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma. 2.2.    ‘Surgically invasive device’ means: (a) an invasive device which penetrates inside the body through the surface of the body, including through mucous membranes of body orifices with the aid or in the context of a surgical operation; and (b) a device which produces penetration other than through a body orifice. 2.3.    ‘Reusable surgical instrument’ means an instrument intended for surgical use in cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without a connection to an active device and which is intended by the manufacturer to be reused after appropriate procedures such as cleaning, disinfection and sterilisation have been carried out. 2.4.    ‘Active therapeutic device’ means any active device used, whether alone or in combination with other devices, to support, modify, replace or restore biological functions or structures with a view to treatment or alleviation of an illness, injury or disability. 2.5.    ‘Active device intended for diagnosis and monitoring’ means any active device used, whether alone or in combination with other devices, to supply information for detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities. 2.6.    ‘Central circulatory system’ means the following blood vessels: arteriae pulmonales, aorta ascendens, arcus aortae, aorta descendens to the bifurcatio aortae, arteriae coronariae, arteria carotis communis, arteria carotis externa, arteria carotis interna, arteriae cerebrales, truncus brachiocephalicus, venae cordis, venae pulmonales, vena cava superior and vena cava inferior. 2.7.    ‘Central nervous system’ means the brain, meninges and spinal cord. 2.8.    ‘Injured skin or mucous membrane’ means an area of skin or a mucous membrane presenting a pathological change or change following disease or a wound. CHAPTER II IMPLEMENTING RULES 3.1.   Application of the classification rules shall be governed by the intended purpose of the devices. 3.2.   If the device in question is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. Accessories for a medical device and for a product listed in Annex XVI shall be classified in their own right separately from the device with which they are used. 3.3.   Software, which drives a device or influences the use of a device, shall fall within the same class as the device. If the software is independent of any other device, it shall be classified in its own right. 3.4.   If the device is not intended to be used solely or principally in a specific part of the body, it shall be considered and classified on the basis of the most critical specified use. 3.5.   If several rules, or if, within the same rule, several sub-rules, apply to the same device based on the device's intended purpose, the strictest rule and sub-rule resulting in the higher classification shall apply. 3.6.   In calculating the duration referred to in Section 1, continuous use shall mean: (a) the entire duration of use of the same device without regard to temporary interruption of use during a procedure or temporary removal for purposes such as cleaning or disinfection of the device. Whether the interruption of use or the removal is temporary shall be established in relation to the duration of the use prior to and after the period when the use is interrupted or the device removed; and (b) the accumulated use of a device that is intended by the manufacturer to be replaced immediately with another of the same type. 3.7.   A device is considered to allow direct diagnosis when it provides the diagnosis of the disease or condition in question by itself or when it provides decisive information for the diagnosis. CHAPTER III CLASSIFICATION RULES 4.   NON-INVASIVE DEVICES 4.1.   Rule 1 All non-invasive devices are classified as class I, unless one of the rules set out hereinafter applies. 4.2.   Rule 2 All non-invasive devices intended for channelling or storing blood, body liquids, cells or tissues, liquids or gases for the purpose of eventual infusion, administration or introduction into the body are classified as class IIa: — if they may be connected to a class IIa, class IIb or class III active device; or — if they are intended for use for channelling or storing blood or other body liquids or for storing organs, parts of organs or body cells and tissues, except for blood bags; blood bags are classified as class IIb. In all other cases, such devices are classified as class I. 4.3.   Rule 3 All non-invasive devices intended for modifying the biological or chemical composition of human tissues or cells, blood, other body liquids or other liquids intended for implantation or administration into the body are classified as class IIb, unless the treatment for which the device is used consists of filtration, centrifugation or exchanges of gas, heat, in which case they are classified as class IIa. All non-invasive devices consisting of a substance or a mixture of substances intended to be used in vitro in direct contact with human cells, tissues or organs taken from the human body or used in vitro with human embryos before their implantation or administration into the body are classified as class III. 4.4.   Rule 4 All non-invasive devices which come into contact with injured skin or mucous membrane are classified as: — class I if they are intended to be used as a mechanical barrier, for compression or for absorption of exudates; — class IIb if they are intended to be used principally for injuries to skin which have breached the dermis or mucous membrane and can only heal by secondary intent; — class IIa if they are principally intended to manage the micro-environment of injured skin or mucous membrane; and — class IIa in all other cases. This rule applies also to the invasive devices that come into contact with injured mucous membrane. 5.   INVASIVE DEVICES 5.1.   Rule 5 All invasive devices with respect to body orifices, other than surgically invasive devices, which are not intended for connection to an active device or which are intended for connection to a class I active device are classified as: — class I if they are intended for transient use; — class IIa if they are intended for short-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity, in which case they are classified as class I; and — class IIb if they are intended for long-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity and are not liable to be absorbed by the mucous membrane, in which case they are classified as class IIa. All invasive devices with respect to body orifices, other than surgically invasive devices, intended for connection to a class IIa, class IIb or class III active device, are classified as class IIa. 5.2.   Rule 6 All surgically invasive devices intended for transient use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are reusable surgical instruments, in which case they are classified as class I; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionising radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class IIb; or — are intended to administer medicinal products by means of a delivery system, if such administration of a medicinal product is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are classified as class IIb. 5.3.   Rule 7 All surgically invasive devices intended for short-term use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionizing radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class IIb, except if the devices are placed in the teeth; or — are intended to administer medicines, in which case they are classified as class IIb. 5.4.   Rule 8 All implantable devices and long-term surgically invasive devices are classified as class IIb unless they: — are intended to be placed in the teeth, in which case they are classified as class IIa; — are intended to be used in direct contact with the heart, the central circulatory system or the central nervous system, in which case they are classified as class III; — have a biological effect or are wholly or mainly absorbed, in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class III, except if the devices are placed in the teeth; — are intended to administer medicinal products, in which case they are classified as class III; — are active implantable devices or their accessories, in which cases they are classified as class III; — are breast implants or surgical meshes, in which cases they are classified as class III; — are total or partial joint replacements, in which case they are classified as class III, with the exception of ancillary components such as screws, wedges, plates and instruments; or — are spinal disc replacement implants or are implantable devices that come into contact with the spinal column, in which case they are classified as class III with the exception of components such as screws, wedges, plates and instruments. 6.   ACTIVE DEVICES 6.1.   Rule 9 All active therapeutic devices intended to administer or exchange energy are classified as class IIa unless their characteristics are such that they may administer energy to or exchange energy with the human body in a potentially hazardous way, taking account of the nature, the density and site of application of the energy, in which case they are classified as class IIb. All active devices intended to control or monitor the performance of active therapeutic class IIb devices, or intended directly to influence the performance of such devices are classified as class IIb. All active devices intended to emit ionizing radiation for therapeutic purposes, including devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. All active devices that are intended for controlling, monitoring or directly influencing the performance of active implantable devices are classified as class III. 6.2.   Rule 10 Active devices intended for diagnosis and monitoring are classified as class IIa: — if they are intended to supply energy which will be absorbed by the human body, except for devices intended to illuminate the patient's body, in the visible spectrum, in which case they are classified as class I; — if they are intended to image in vivo distribution of radiopharmaceuticals; or — if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for monitoring of vital physiological parameters and the nature of variations of those parameters is such that it could result in immediate danger to the patient, for instance variations in cardiac performance, respiration, activity of the central nervous system, or they are intended for diagnosis in clinical situations where the patient is in immediate danger, in which cases they are classified as class IIb. Active devices intended to emit ionizing radiation and intended for diagnostic or therapeutic radiology, including interventional radiology devices and devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. 6.3.   Rule 11 Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: — death or an irreversible deterioration of a person's state of health, in which case it is in class III; or — a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. 6.4.   Rule 12 All active devices intended to administer and/or remove medicinal products, body liquids or other substances to or from the body are classified as class IIa, unless this is done in a manner that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the mode of application in which case they are classified as class IIb. 6.5.   Rule 13 All other active devices are classified as class I. 7.   SPECIAL RULES 7.1.   Rule 14 All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the devices, are classified as class III. 7.2.   Rule 15 All devices used for contraception or prevention of the transmission of sexually transmitted diseases are classified as class IIb, unless they are implantable or long term invasive devices, in which case they are classified as class III. 7.3.   Rule 16 All devices intended specifically to be used for disinfecting, cleaning, rinsing or, where appropriate, hydrating contact lenses are classified as class IIb. All devices intended specifically to be used for disinfecting or sterilising medical devices are classified as class IIa, unless they are disinfecting solutions or washer-disinfectors intended specifically to be used for disinfecting invasive devices, as the end point of processing, in which case they are classified as class IIb. This rule does not apply to devices that are intended to clean devices other than contact lenses by means of physical action only. 7.4.   Rule 17 Devices specifically intended for recording of diagnostic images generated by X-ray radiation are classified as class IIa. 7.5.   Rule 18 All devices manufactured utilising tissues or cells of human or animal origin, or their derivatives, which are non-viable or rendered non-viable, are classified as class III, unless such devices are manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable and are devices intended to come into contact with intact skin only. 7.6.   Rule 19 All devices incorporating or consisting of nanomaterial are classified as: — class III if they present a high or medium potential for internal exposure; — class IIb if they present a low potential for internal exposure; and — class IIa if they present a negligible potential for internal exposure. 7.7.   Rule 20 All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are classified as class IIa, unless their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or they are intended to treat life-threatening conditions, in which case they are classified as class IIb. 7.8.   Rule 21 Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as: — class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose; — class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body; — class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities; and — class IIb in all other cases. 7.9.   Rule 22 Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. ANNEX IX CONFORMITY ASSESSMENT BASED ON A QUALITY MANAGEMENT SYSTEM AND ON ASSESSMENT OF TECHNICAL DOCUMENTATION CHAPTER I QUALITY MANAGEMENT SYSTEM 1.   The manufacturer shall establish, document and implement a quality management system as described in Article 10(9) and maintain its effectiveness throughout the life cycle of the devices concerned. The manufacturer shall ensure the application of the quality management system as specified in Section 2 and shall be subject to audit, as laid down in Sections 2.3 and 2.4, and to surveillance as specified in Section 3. 2.   Quality management system assessment 2.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — the name of the manufacturer and address of its registered place of business and any additional manufacturing site covered by the quality management system, and, if the manufacturer's application is lodged by its authorised representative, the name of the authorised representative and the address of the authorised representative's registered place of business, — all relevant information on the device or group of devices covered by the quality management system, — a written declaration that no application has been lodged with any other notified body for the same device-related quality management system, or information about any previous application for the same device-related quality management system, — a draft of an EU declaration of conformity in accordance with Article 19 and Annex IV for the device model covered by the conformity assessment procedure, — the documentation on the manufacturer's quality management system, — a documented description of the procedures in place to fulfil the obligations arising from the quality management system and required under this Regulation and the undertaking by the manufacturer in question to apply those procedures, — a description of the procedures in place to ensure that the quality management system remains adequate and effective, and the undertaking by the manufacturer to apply those procedures, — the documentation on the manufacturer's post-market surveillance system and, where applicable, on the PMCF plan, and the procedures put in place to ensure compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, — a description of the procedures in place to keep up to date the post-market surveillance system, and, where applicable, the PMCF plan, and the procedures ensuring compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, as well as the undertaking by the manufacturer to apply those procedures, — documentation on the clinical evaluation plan, and — a description of the procedures in place to keep up to date the clinical evaluation plan, taking into account the state of the art. 2.2.   Implementation of the quality management system shall ensure compliance with this Regulation. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures such as quality programmes, quality plans and quality records. Moreover, the documentation to be submitted for the assessment of the quality management system shall include an adequate description of, in particular: (a) the manufacturer's quality objectives; (b) the organisation of the business and in particular: — the organisational structures with the assignment of staff responsibilities in relation to critical procedures, the responsibilities of the managerial staff and their organisational authority, — the methods of monitoring whether the operation of the quality management system is efficient and in particular the ability of that system to achieve the desired design and device quality, including control of devices which fail to conform, — where the design, manufacture and/or final verification and testing of the devices, or parts of any of those processes, is carried out by another party, the methods of monitoring the efficient operation of the quality management system and in particular the type and extent of control applied to the other party, and — where the manufacturer does not have a registered place of business in a Member State, the draft mandate for the designation of an authorised representative and a letter of intention from the authorised representative to accept the mandate; (c) the procedures and techniques for monitoring, verifying, validating and controlling the design of the devices and the corresponding documentation as well as the data and records arising from those procedures and techniques. Those procedures and techniques shall specifically cover: — the strategy for regulatory compliance, including processes for identification of relevant legal requirements, qualification, classification, handling of equivalence, choice of and compliance with conformity assessment procedures, — identification of applicable general safety and performance requirements and solutions to fulfil those requirements, taking applicable CS and, where opted for, harmonised standards or other adequate solutions into account, — risk management as referred to in Section 3 of Annex I, — the clinical evaluation, pursuant to Article 61 and Annex XIV, including post-market clinical follow-up, — solutions for fulfilling the applicable specific requirements regarding design and construction, including appropriate pre-clinical evaluation, in particular the requirements of Chapter II of Annex I, — solutions for fulfilling the applicable specific requirements regarding the information to be supplied with the device, in particular the requirements of Chapter III of Annex I, — the device identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture, and — management of design or quality management system changes; and (d) the verification and quality assurance techniques at the manufacturing stage and in particular the processes and procedures which are to be used, particularly as regards sterilisation and the relevant documents; and (e) the appropriate tests and trials which are to be carried out before, during and after manufacture, the frequency with which they are to take place, and the test equipment to be used; it shall be possible to trace back adequately the calibration of that test equipment. In addition, the manufacturer shall grant the notified body access to the technical documentation referred to in Annexes II and III. 2.3.   Audit The notified body shall audit the quality management system to determine whether it meets the requirements referred to in Section 2.2. Where the manufacturer uses a harmonised standard or CS related to a quality management system, the notified body shall assess conformity with those standards or CS. The notified body shall assume that a quality management system which satisfies the relevant harmonised standards or CS conforms to the requirements covered by those standards or CS, unless it duly substantiates not doing so. The audit team of the notified body shall include at least one member with past experience of assessments of the technology concerned in accordance with Sections 4.3. to 4.5. of Annex VII. In circumstances where such experience is not immediately obvious or applicable, the notified body shall provide a documented rationale for the composition of that team. The assessment procedure shall include an audit on the manufacturer's premises and, if appropriate, on the premises of the manufacturer's suppliers and/or subcontractors to verify the manufacturing and other relevant processes. Moreover, in the case of class IIa and class IIb devices, the quality management system assessment shall be accompanied by the assessment of technical documentation for devices selected on a representative basis in accordance with Sections 4.4 to 4.8. In choosing representative samples, the notified body shall take into account the published guidance developed by the MDCG pursuant to Article 105 and in particular the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended purpose and the results of any previous relevant assessments such as with regard to physical, chemical, biological or clinical properties, that have been carried out in accordance with this Regulation. The notified body in question shall document its rationale for the samples taken. If the quality management system conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality management system certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. The decision shall contain the conclusions of the audit and a reasoned report. 2.4.   The manufacturer in question shall inform the notified body which approved the quality management system of any plan for substantial changes to the quality management system, or the device-range covered. The notified body shall assess the changes proposed, determine the need for additional audits and verify whether after those changes the quality management system still meets the requirements referred to in Section 2.2. It shall notify the manufacturer of its decision which shall contain the conclusions of the assessment, and where applicable, conclusions of additional audits. The approval of any substantial change to the quality management system or the device-range covered shall take the form of a supplement to the EU quality management system certificate. 3.   Surveillance assessment applicable to class IIa, class IIb and class III devices 3.1.   The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations arising from the approved quality management system. 3.2.   The manufacturer shall give authorisation to the notified body to carry out all the necessary audits, including on-site audits, and supply it with all relevant information, in particular: — the documentation on its quality management system, — documentation on any findings and conclusions resulting from the application of the post-market surveillance plan, including the PMCF plan, for a representative sample of devices, and of the provisions on vigilance set out in Articles 87 to 92, — the data stipulated in the part of the quality management system relating to design, such as the results of analyses, calculations, tests and the solutions adopted regarding the risk-management as referred to in Section 4 of Annex I, and — the data stipulated in the part of the quality management system relating to manufacture, such as quality control reports and test data, calibration data, and records on the qualifications of the personnel concerned. 3.3.   Notified bodies shall periodically, at least once every 12 months, carry out appropriate audits and assessments to make sure that the manufacturer in question applies the approved quality management system and the post-market surveillance plan. Those audits and assessments shall include audits on the premises of the manufacturer and, if appropriate, of the manufacturer's suppliers and/or subcontractors. At the time of such on-site audits, the notified body shall, where necessary, carry out or ask for tests in order to check that the quality management system is working properly. It shall provide the manufacturer with a surveillance audit report and, if a test has been carried out, with a test report. 3.4.   The notified body shall randomly perform at least once every five years unannounced audits on the site of the manufacturer and, where appropriate, of the manufacturer's suppliers and/or subcontractors, which may be combined with the periodic surveillance assessment referred to in Section 3.3. or be performed in addition to that surveillance assessment. The notified body shall establish a plan for such unannounced on-site audits but shall not disclose it to the manufacturer. Within the context of such unannounced on-site audits, the notified body shall test an adequate sample of the devices produced or an adequate sample from the manufacturing process to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to unannounced on-site audits, the notified body shall specify the relevant sampling criteria and testing procedure. Instead of, or in addition to, sampling referred to in the second paragraph, the notified body shall take samples of devices from the market to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to the sampling, the notified body in question shall specify the relevant sampling criteria and testing procedure. The notified body shall provide the manufacturer in question with an on-site audit report which shall include, if applicable, the result of the sample test. 3.5.   In the case of class IIa and class IIb devices, the surveillance assessment shall also include an assessment of the technical documentation as referred to in Sections 4.4 to 4.8 for the device or devices concerned on the basis of further representative samples chosen in accordance with the rationale documented by the notified body in accordance with the second paragraph of Section 2.3. In the case of class III devices, the surveillance assessment shall also include a test of the approved parts and/or materials that are essential for the integrity of the device, including, where appropriate, a check that the quantities of produced or purchased parts and/or materials correspond to the quantities of finished devices. 3.6.   The notified body shall ensure that the composition of the assessment team is such that there is sufficient experience with the evaluation of the devices, systems and processes concerned, continuous objectivity and neutrality; this shall include a rotation of the members of the assessment team at appropriate intervals. As a general rule, a lead auditor shall neither lead nor attend audits for more than three consecutive years in respect of the same manufacturer. 3.7.   If the notified body finds a divergence between the sample taken from the devices produced or from the market and the specifications laid down in the technical documentation or the approved design, it shall suspend or withdraw the relevant certificate or impose restrictions on it. CHAPTER II ASSESSMENT OF THE TECHNICAL DOCUMENTATION 4.   Assessment of the technical documentation applicable to class III devices and to the class IIb devices referred to in the second subparagraph of Article 52(4) 4.1.   In addition to the obligations laid down in Section 2, the manufacturer shall lodge with the notified body an application for assessment of the technical documentation relating to the device which it plans to place on the market or put into service and which is covered by the quality management system referred to in Section 2. 4.2.   The application shall describe the design, manufacture and performance of the device in question. It shall include the technical documentation as referred to in Annexes II and III. 4.3.   The notified body shall examine the application by using staff, employed by it, with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of the Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. 4.4.   The notified body shall review the clinical evidence presented by the manufacturer in the clinical evaluation report and the related clinical evaluation that was conducted. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or the clinical condition in which it is utilised, for the purposes of that review. 4.5.   The notified body shall, in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity. For any characteristic of the device claimed as innovative by the manufacturer or for new indications, the notified body shall assess to what extent specific claims are supported by specific pre-clinical and clinical data and risk analysis. 4.6.   The notified body shall verify that the clinical evidence and the clinical evaluation are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. That verification shall include consideration of the adequacy of the benefit-risk determination, the risk management, the instructions for use, the user training and the manufacturer's post-market surveillance plan, and include a review of the need for, and the adequacy of, the PMCF plan proposed, where applicable. 4.7.   Based on its assessment of the clinical evidence, the notified body shall consider the clinical evaluation and the benefit-risk determination, and whether specific milestones need to be defined to allow the notified body to review updates to the clinical evidence that result from post-market surveillance and PMCF data. 4.8.   The notified body shall clearly document the outcome of its assessment in the clinical evaluation assessment report. 4.9.   The notified body shall provide the manufacturer with a report on the technical documentation assessment, including a clinical evaluation assessment report. If the device conforms to the relevant provisions of this Regulation, the notified body shall issue an EU technical documentation assessment certificate. The certificate shall contain the conclusions of the technical documentation assessment, the conditions of the certificate's validity, the data needed for identification of the approved design, and, where appropriate, a description of the intended purpose of the device. 4.10.   Changes to the approved device shall require approval from the notified body which issued the EU technical documentation assessment certificate where such changes could affect the safety and performance of the device or the conditions prescribed for use of the device. Where the manufacturer plans to introduce any of the above-mentioned changes it shall inform the notified body which issued the EU technical documentation assessment certificate thereof. The notified body shall assess the planned changes and decide whether the planned changes require a new conformity assessment in accordance with Article 52 or whether they could be addressed by means of a supplement to the EU technical documentation assessment certificate. In the latter case, the notified body shall assess the changes, notify the manufacturer of its decision and, where the changes are approved, provide it with a supplement to the EU technical documentation assessment certificate. 5.   Specific additional procedures 5.1.   Assessment procedure for certain class III and class IIb devices (a) For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product as referred to in Section 6.4. of Annex VIII (Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer referred to in Article 61(12), prepare a clinical evaluation assessment report which sets out its conclusions concerning the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication or indications and the PMCF plan referred to in Article 10(3) and Part B of Annex XIV. The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer's clinical evaluation documentation, referred to in points (c) and (d) of Section 6.1 of Annex II, to the Commission. The Commission shall immediately transmit those documents to the relevant expert panel referred to in Article 106. (b) The notified body may be requested to present its conclusions as referred to in point (a) to the expert panel concerned. (c) The expert panel shall decide, under the supervision of the Commission, on the basis of all of the following criteria: (i) the novelty of the device or of the related clinical procedure involved, and the possible major clinical or health impact thereof; (ii) a significantly adverse change in the benefit-risk profile of a specific category or group of devices due to scientifically valid health concerns in respect of components or source material or in respect of the impact on health in the case of failure of the device; (iii) a significantly increased rate of serious incidents reported in accordance with Article 87 in respect of a specific category or group of devices, whether to provide a scientific opinion on the clinical evaluation assessment report of the notified body based on the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the medical indication or indications and the PMCF plan. That scientific opinion shall be provided within a period of 60 days, starting on the day of receipt of the documents from the Commission as referred to in point (a). The reasons for the decision to provide a scientific opinion on the basis of the criteria in points (i), (ii) and (iii) shall be included in the scientific opinion. Where the information submitted is not sufficient for the expert panel to reach a conclusion, this shall be stated in the scientific opinion. (d) The expert panel may decide, under the supervision of the Commission, on the basis of the criteria laid down in point (c) not to provide a scientific opinion, in which case it shall inform the notified body as soon as possible and in any event within 21 days of receipt of the documents as referred to in point (a) from the Commission. The expert panel shall within that time limit provide the notified body and the Commission with the reasons for its decision, whereupon the notified body may proceed with the certification procedure of that device. (e) The expert panel shall within 21 days of receipt of the documents from the Commission notify the Commission, through Eudamed whether it intends to provide a scientific opinion, pursuant to point (c), or whether it intends not to provide a scientific opinion, pursuant to point (d). (f) Where no opinion has been delivered within a period of 60 days, the notified body may proceed with the certification procedure of the device in question. (g) The notified body shall give due consideration to the views expressed in the scientific opinion of the expert panel. Where the expert panel finds that the level of clinical evidence is not sufficient or otherwise gives rise to serious concerns about the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication(s), and with the PMCF plan, the notified body shall, if necessary, advise the manufacturer to restrict the intended purpose of the device to certain groups of patients or certain medical indications and/or to impose a limit on the duration of validity of the certificate, to undertake specific PMCF studies, to adapt the instructions for use or the summary of safety and performance, or to impose other restrictions in its conformity assessment report, as appropriate. The notified body shall provide a full justification where it has not followed the advice of the expert panel in its conformity assessment report and the Commission shall without prejudice to Article 109 make both the scientific opinion of the expert panel and the written justification provided by the notified body publicly available via Eudamed. (h) The Commission, after consultation with the Member States and relevant scientific experts shall provide guidance for expert panels for consistent interpretation of the criteria in point (c) before 26 May 2020. 5.2.   Procedure in the case of devices incorporating a medicinal substance (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (b) Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device. Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA. (c) When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body. (d) The medicinal products authority consulted shall provide its opinion to the notified body within 210 days of receipt of all the necessary documentation. (e) The scientific opinion of the medicinal products authority consulted, and any possible update of that opinion, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision. The notified body shall not deliver the certificate if the scientific opinion is unfavourable and shall convey its final decision to the medicinal products authority consulted. (f) Before any change is made with respect to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the manufacturer shall inform the notified body of the changes. That notified body shall seek the opinion of the medicinal products authority consulted, in order to confirm that the quality and safety of the ancillary substance remain unchanged. The medicinal products authority consulted shall take into account the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The medicinal products authority consulted shall provide its opinion within 60 days after receipt of all the necessary documentation regarding the changes. The notified body shall not deliver the supplement to the EU technical documentation assessment certificate if the scientific opinion provided by the medicinal products authority consulted is unfavourable. The notified body shall convey its final decision to the medicinal products authority consulted. (g) Where the medicinal products authority consulted obtains information on the ancillary substance, which could have an impact on the risk or benefit previously established concerning the incorporation of the substance into the device, it shall advise the notified body as to whether this information has an impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The notified body shall take that advice into account in reconsidering its assessment of the conformity assessment procedure. 5.3.   Procedure in the case of devices manufactured utilising, or incorporating, tissues or cells of human or animal origin, or their derivatives, that are non-viable or rendered non-viable 5.3.1.   Tissues or cells of human origin or their derivatives (a) For devices manufactured utilising derivatives of tissues or cells of human origin that are covered by this Regulation in accordance with point (g) of Article 1(6) and for devices that incorporate, as an integral part, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, that have an action ancillary to that of the device, the notified body shall, prior to issuing an EU technical documentation assessment certificate, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2004/23/EC (‘human tissues and cells competent authority’) on the aspects relating to the donation, procurement and testing of tissues or cells of human origin or their derivatives. The notified body shall submit a summary of the preliminary conformity assessment which provides, among other things, information about the non-viability of the human tissues or cells in question, their donation, procurement and testing and the risk or benefit of the incorporation of the tissues or cells of human origin or their derivatives into the device. (b) Within 120 days of receipt of all the necessary documentation, the human tissues and cells competent authority shall provide to the notified body its opinion. (c) The scientific opinion of the human tissues and cells competent authority, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion of the human tissues and cells competent authority when making its decision. The notified body shall not deliver the certificate if that scientific opinion is unfavourable. It shall convey its final decision to the human tissues and cells competent authority concerned. (d) Before any change is made with respect to non-viable tissues or cells of human origin or their derivatives incorporated in a device, in particular relating to their donation, testing or procurement, the manufacturer shall inform the notified body of the intended changes. The notified body shall consult the authority that was involved in the initial consultation, in order to confirm that the quality and safety of the tissues or cells of human origin or their derivatives incorporated in the device are maintained. The human tissues and cells competent authority concerned shall take into account the data relating to the usefulness of incorporation of the tissues or cells of human origin or their derivatives into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit-risk ratio of the addition of the tissues or cells of human origin or their derivatives in the device. It shall provide its opinion within 60 days of receipt of all the necessary documentation regarding the intended changes. The notified body shall not deliver a supplement to the EU technical documentation assessment certificate if the scientific opinion is unfavourable and shall convey its final decision to the human tissues and cells competent authority concerned. 5.3.2.   Tissues or cells of animal origin or their derivatives In the case of devices manufactured utilising animal tissue which is rendered non-viable or utilising non-viable products derived from animal tissue, as referred to in Regulation (EU) No 722/2012, the notified body shall apply the relevant requirements laid down in that Regulation. 5.4.   Procedure in the case of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body (a) The quality and safety of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by, or locally dispersed in, the human body, shall be verified where applicable and only in respect of the requirements not covered by this Regulation, in accordance with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. (b) In addition, for devices, or their products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, the notified body shall seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the compliance of the device with the relevant requirements laid down in Annex I to Directive 2001/83/EC. (c) The opinion of the medicinal products authority consulted shall be drawn up within 150 days of receipt of all the necessary documentation. (d) The scientific opinion of the medicinal products authority consulted, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision and shall convey its final decision to the medicinal products authority consulted. 6.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in Article 1(8) Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. CHAPTER III ADMINISTRATIVE PROVISIONS 7.   The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 and in particular the data and records arising from the procedures referred to in point (c) of the second paragraph of Section 2.2, — information on the changes referred to in Section 2.4, — the documentation referred to in Section 4.2, and — the decisions and reports from the notified body as referred to in this Annex. 8.   Each Member State shall require that the documentation referred to in Section 7 is kept at the disposal of competent authorities for the period indicated in that Section in case a manufacturer, or its authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of that period. ANNEX X CONFORMITY ASSESSMENT BASED ON TYPE-EXAMINATION 1.   EU type-examination is the procedure whereby a notified body ascertains and certifies that a device, including its technical documentation and relevant life cycle processes and a corresponding representative sample of the device production envisaged, fulfils the relevant provisions of this Regulation. 2.   Application The manufacturer shall lodge an application for assessment with a notified body. The application shall include: — the name of the manufacturer and address of the registered place of business of the manufacturer and, if the application is lodged by the authorised representative, the name of the authorised representative and the address of its registered place of business, — the technical documentation referred to in Annexes II and III. The applicant shall make a representative sample of the device production envisaged (‘type’) available to the notified body. The notified body may request other samples as necessary, and — a written declaration that no application has been lodged with any other notified body for the same type, or information about any previous application for the same type that was refused by another notified body or was withdrawn by the manufacturer or its authorised representative before that other notified body made its final assessment. 3.   Assessment The notified body shall: (a) examine the application by using staff with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of this Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests; (b) examine and assess the technical documentation for conformity with the requirements of this Regulation that are applicable to the device and verify that the type has been manufactured in conformity with that documentation; it shall also record the items designed in conformity with the applicable standards referred to in Article 8 or with applicable CS, and record the items not designed on the basis of the relevant standards referred to in Article 8 or of the relevant CS; (c) review the clinical evidence presented by the manufacturer in the clinical evaluation report in accordance with Section 4 of Annex XIV. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or to the clinical condition in which it is utilised, for the purposes of that review; (d) in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be similar or equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity; (e) clearly document the outcome of its assessment in a pre-clinical and clinical evaluation assessment report as part of the EU type examination report referred to in point (i); (f) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether the solutions adopted by the manufacturer meet the general safety and performance requirements laid down in this Regulation, in the event that the standards referred to in Article 8 or the CS have not been applied. Where the device has to be connected to another device or devices in order to operate as intended, proof shall be provided that it conforms to the general safety and performance requirements when connected to any such device or devices having the characteristics specified by the manufacturer; (g) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether, in the event that the manufacturer has chosen to apply the relevant harmonised standards, those standards have actually been applied; (h) agree with the applicant on the place where the necessary assessments and tests are to be carried out; and (i) draw up an EU type-examination report on the results of the assessments and tests carried out under points (a) to (g). 4.   Certificate If the type conforms to this Regulation, the notified body shall issue an EU type-examination certificate. The certificate shall contain the name and address of the manufacturer, the conclusions of the type examination assessment, the conditions of the certificate's validity and the data needed for identification of the type approved. The certificate shall be drawn up in accordance with Annex XII. The relevant parts of the documentation shall be annexed to the certificate and a copy kept by the notified body. 5.   Changes to the type 5.1.   The applicant shall inform the notified body which issued the EU type-examination certificate of any planned change to the approved type or of its intended purpose and conditions of use. 5.2.   Changes to the approved device including limitations of its intended purpose and conditions of use shall require approval from the notified body which issued the EU type-examination certificate where such changes may affect conformity with the general safety and performance requirements or with the conditions prescribed for use of the product. The notified body shall examine the planned changes, notify the manufacturer of its decision and provide him with a supplement to the EU type-examination report. The approval of any change to the approved type shall take the form of a supplement to the EU type-examination certificate. 5.3.   Changes to the intended purpose and conditions of use of the approved device, with the exception of limitations of the intended purpose and conditions of use, shall necessitate a new application for a conformity assessment. 6.   Specific additional procedures Section 5 of Annex IX shall apply with the proviso that any reference to an EU technical documentation assessment certificate shall be understood as a reference to an EU type-examination certificate. 7.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the documentation referred to in the second indent of Section 2, — information on the changes referred to in Section 5, and — copies of EU type-examination certificates, scientific opinions and reports and their additions/supplements. Section 8 of Annex IX shall apply. ANNEX XI CONFORMITY ASSESSMENT BASED ON PRODUCT CONFORMITY VERIFICATION 1.   The objective of the conformity assessment based on product conformity verification is to ensure that devices conform to the type for which an EU type-examination certificate has been issued, and that they meet the provisions of this Regulation which apply to them. 2.   Where an EU type-examination certificate has been issued in accordance with Annex X, the manufacturer may either apply the procedure set out in Part A (production quality assurance) or the procedure set out in Part B (product verification) of this Annex. 3.   By way of derogation from Sections 1 and 2 above, the procedures in this Annex coupled with the drawing up of technical documentation as set out in Annexes II and III may also be applied by manufacturers of class IIa devices. PART A PRODUCTION QUALITY ASSURANCE 4.   The manufacturer shall ensure that the quality management system approved for the manufacture of the devices concerned is implemented, shall carry out a final verification, as specified in Section 6, and shall be subject to the surveillance referred to in Section 7. 5.   When the manufacturer fulfils the obligations laid down in Section 4, it shall draw up and keep an EU declaration of conformity in accordance with Article 19 and Annex IV for the device covered by the conformity assessment procedure. By issuing an EU declaration of conformity, the manufacturer shall be deemed to ensure and to declare that the device concerned conforms to the type described in the EU type-examination certificate and meets the requirements of this Regulation which apply to the device. 6.   Quality management system 6.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — all elements listed in Section 2.1 of Annex IX, — the technical documentation referred to in Annexes II and III for the types approved, and — a copy of the EU type-examination certificates referred to in Section 4 of Annex X; if the EU type-examination certificates have been issued by the same notified body with which the application is lodged, a reference to the technical documentation and its updates and the certificates issued shall also be included in the application. 6.2.   Implementation of the quality management system shall be such as to ensure that there is compliance with the type described in the EU type-examination certificate and with the provisions of this Regulation which apply to the devices at each stage. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures, such as quality programmes, quality plans and quality records. That documentation shall, in particular, include an adequate description of all elements listed in points (a), (b), (d) and (e) of Section 2.2 of Annex IX. 6.3.   The first and second paragraph of Section 2.3 of Annex IX shall apply. If the quality management system is such that it ensures that the devices conform to the type described in the EU type-examination certificate and that it conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality assurance certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. That decision shall contain the conclusions of the notified body's audit and a reasoned assessment. 6.4.   Section 2.4 of Annex IX shall apply. 7.   Surveillance Section 3.1, the first, second and fourth indents of Section 3.2, Sections 3.3, 3.4, 3.6 and 3.7 of Annex IX shall apply. In the case of class III devices, surveillance shall also include a check that the quantities of produced or purchased raw material or crucial components approved for the type and correspond to the quantities of finished devices. 8.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 9.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 of Annex IX, — the documentation referred to in the eighth indent of Section 2.1 of Annex IX, including the EU type-examination certificate referred to in Annex X, — information on the changes referred to in Section 2.4 of Annex IX, and — the decisions and reports from the notified body as referred to in Sections 2.3, 3.3 and 3.4 of Annex IX. Section 8 of Annex IX shall apply. 10.   Application to class IIa devices 10.1.   By way of derogation from Section 5, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 10.2.   For class IIa devices the notified body shall assess, as part of the assessment referred to in Section 6.3, whether the technical documentation as referred to in Annexes II and III for the devices selected on a representative basis is compliant with this Regulation. In choosing a representative sample or samples of devices, the notified body shall take into account the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended use and the results of any previous relevant assessments (e.g. with regard to physical, chemical, biological or clinical properties) that have been carried out in accordance with this Regulation. The notified body shall document its rationale for the sample or samples of devices taken. 10.3.   Where the assessment under Section 10.2. confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 10.4.   Samples additional to those taken for the initial conformity assessment of devices shall be assessed by the notified body as part of the surveillance assessment referred to in Section 7. 10.5.   By way of derogation from Section 6, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 10.3. Section 8 of Annex IX shall apply. PART B PRODUCT VERIFICATION 11.   Product verification shall be understood to be the procedure whereby after examination of every manufactured device, the manufacturer, by issuing an EU declaration of conformity in accordance with Article 19 and Annex IV, shall be deemed to ensure and to declare that the devices which have been subject to the procedure set out in Sections 14 and 15 conform to the type described in the EU type-examination certificate and meet the requirements of this Regulation which apply to them. 12.   The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which conform to the type described in the EU type-examination certificate and to the requirements of the Regulation which apply to them. Prior to the start of manufacture, the manufacturer shall prepare documents defining the manufacturing process, in particular as regards sterilisation where necessary, together with all routine, pre-established procedures to be implemented to ensure homogeneous production and, where appropriate, conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. In addition, for devices placed on the market in a sterile condition, and only for those aspects of the manufacturing process designed to secure and maintain sterility, the manufacturer shall apply the provisions of Sections 6 and 7. 13.   The manufacturer shall undertake to institute and keep up to date a post-market surveillance plan, including a PMCF plan, and the procedures ensuring compliance with the obligations of the manufacturer resulting from the provisions on vigilance and post-market surveillance system set out in Chapter VII. 14.   The notified body shall carry out the appropriate examinations and tests in order to verify the conformity of the device with the requirements of the Regulation by examining and testing every product as specified in Section 15. The examinations and tests referred to in the first paragraph of this Section shall not apply to aspects of the manufacturing process designed to secure sterility. 15.   Verification by examination and testing of every product 15.1.   Every device shall be examined individually and the appropriate physical or laboratory tests as defined in the relevant standard or standards referred to in Article 8, or equivalent tests and assessments, shall be carried out in order to verify, where appropriate, the conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. 15.2.   The notified body shall affix, or have affixed, its identification number to each approved device and shall draw up an EU product verification certificate relating to the tests and assessments carried out. 16.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 17.   Administrative provisions The manufacturer or its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in Section 12, — the certificate referred to in Section 15.2, and — the EU type-examination certificate referred to in Annex X. Section 8 of Annex IX shall apply. 18.   Application to class IIa devices 18.1.   By way of derogation from Section 11, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 18.2.   The verification conducted by the notified body in accordance with Section 14 is intended to confirm the conformity of the class IIa devices in question with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to them. 18.3.   If the verification referred to in Section 18.2 confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 18.4.   By way of derogation from Section 17, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 18.3. Section 8 of Annex IX shall apply. ANNEX XII CERTIFICATES ISSUED BY A NOTIFIED BODY CHAPTER I GENERAL REQUIREMENTS 1. Certificates shall be drawn up in one of the official languages of the Union. 2. Each certificate shall refer to only one conformity assessment procedure. 3. Certificates shall only be issued to one manufacturer. The name and address of the manufacturer included in the certificate shall be the same as that registered in the electronic system referred to in Article 30. 4. The scope of the certificates shall unambiguously identify the device or devices covered: (a) EU technical documentation assessment certificates, EU type-examination certificates and EU product verification certificates shall include a clear identification, including the name, model and type, of the device or devices, the intended purpose, as included by the manufacturer in the instructions for use and in relation to which the device has been assessed in the conformity assessment procedure, risk classification and the Basic UDI-DI as referred to in Article 27(6); (b) EU quality management system certificates and EU quality assurance certificates shall include the identification of the devices or groups of devices, the risk classification, and, for class IIb devices, the intended purpose. 5. The notified body shall be able to demonstrate on request, which (individual) devices are covered by the certificate. The notified body shall set up a system that enables the determination of the devices, including their classification, covered by the certificate. 6. Certificates shall contain, if applicable, a note that, for the placing on the market of the device or devices it covers, another certificate issued in accordance with this Regulation is required. 7. EU quality management system certificates and EU quality assurance certificates for class I devices for which the involvement of a notified body is required pursuant to Article 52(7) shall include a statement that the audit by the notified body of the quality management system was limited to the aspects required under that paragraph. 8. Where a certificate is supplemented, modified or re-issued, the new certificate shall contain a reference to the preceding certificate and its date of issue with identification of the changes. CHAPTER II MINIMUM CONTENT OF THE CERTIFICATES 1. name, address and identification number of the notified body; 2. name and address of the manufacturer and, if applicable, of the authorised representative; 3. unique number identifying the certificate; 4. if already issued, the SRN of the manufacturer referred to in to Article 31(2); 5. date of issue; 6. date of expiry; 7. data needed for the unambiguous identification of the device or devices where applicable as specified in Section 4 of Part I; 8. if applicable, reference to any previous certificate as specified in Section 8 of Chapter I; 9. reference to this Regulation and the relevant Annex in accordance with which the conformity assessment has been carried out; 10. examinations and tests performed, e.g. reference to relevant CS, harmonised standards, test reports and audit report(s); 11. if applicable, reference to the relevant parts of the technical documentation or other certificates required for the placing on the market of the device or devices covered; 12. if applicable, information about the surveillance by the notified body; 13. conclusions of the notified body's conformity assessment with regard to the relevant Annex; 14. conditions for or limitations to the validity of the certificate; 15. legally binding signature of the notified body in accordance with the applicable national law. ANNEX XIII PROCEDURE FOR CUSTOM-MADE DEVICES 1. For custom-made devices, the manufacturer or its authorised representative shall draw up a statement containing all of the following information: — the name and address of the manufacturer, and of all manufacturing sites, — if applicable, the name and address of the authorised representative, — data allowing identification of the device in question, — a statement that the device is intended for exclusive use by a particular patient or user, identified by name, an acronym or a numerical code, — the name of the person who made out the prescription and who is authorised by national law by virtue of their professional qualifications to do so, and, where applicable, the name of the health institution concerned, — the specific characteristics of the product as indicated by the prescription, — a statement that the device in question conforms to the general safety and performance requirements set out in Annex I and, where applicable, indicating which general safety and performance requirements have not been fully met, together with the grounds, — where applicable, an indication that the device contains or incorporates a medicinal substance, including a human blood or plasma derivative, or tissues or cells of human origin, or of animal origin as referred to in Regulation (EU) No 722/2012. 2. The manufacturer shall undertake to keep available for the competent national authorities documentation that indicates its manufacturing site or sites and allows an understanding to be formed of the design, manufacture and performance of the device, including the expected performance, so as to allow assessment of conformity with the requirements of this Regulation. 3. The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which are manufactured in accordance with the documentation referred to in Section 2. 4. The statement referred to in the introductory part of Section 1 shall be kept for a period of at least 10 years after the device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Section 8 of Annex IX shall apply. 5. The manufacturer shall review and document experience gained in the post-production phase, including from PMCF as referred to in Part B of Annex XIV, and implement appropriate means to apply any necessary corrective action, In that context, it shall report in accordance with Article 87(1) to the competent authorities any serious incidents or field safety corrective actions or both as soon as it learns of them. ANNEX XIV CLINICAL EVALUATION AND POST-MARKET CLINICAL FOLLOW-UP PART A CLINICAL EVALUATION 1.   To plan, continuously conduct and document a clinical evaluation, manufacturers shall: (a) establish and update a clinical evaluation plan, which shall include at least: — an identification of the general safety and performance requirements that require support from relevant clinical data; — a specification of the intended purpose of the device; — a clear specification of intended target groups with clear indications and contra-indications; — a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters; — a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects; — an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device; — an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non-viable animal or human tissues, are to be addressed; and — a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF as referred to in Part B of this Annex with an indication of milestones and a description of potential acceptance criteria; (b) identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review; (c) appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device; (d) generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues; and (e) analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits. 2.   The clinical evaluation shall be thorough and objective, and take into account both favourable and unfavourable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer's claims in respect of the device. 3.   A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: — Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements; — Biological: the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables; — Clinical: the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence. 4.   The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device. The clinical evidence together with non-clinical data generated from non-clinical testing methods and other relevant documentation shall allow the manufacturer to demonstrate conformity with the general safety and performance requirements and shall be part of the technical documentation for the device in question. Both favourable and unfavourable data considered in the clinical evaluation shall be included in the technical documentation. PART B POST-MARKET CLINICAL FOLLOW-UP 5.   PMCF shall be understood to be a continuous process that updates the clinical evaluation referred to in Article 61 and Part A of this Annex and shall be addressed in the manufacturer's post-market surveillance plan. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data from the use in or on humans of a device which bears the CE marking and is placed on the market or put into service within its intended purpose as referred to in the relevant conformity assessment procedure, with the aim of confirming the safety and performance throughout the expected lifetime of the device, of ensuring the continued acceptability of identified risks and of detecting emerging risks on the basis of factual evidence. 6.   PMCF shall be performed pursuant to a documented method laid down in a PMCF plan. 6.1.   The PMCF plan shall specify the methods and procedures for proactively collecting and evaluating clinical data with the aim of: (a) confirming the safety and performance of the device throughout its expected lifetime, (b) identifying previously unknown side-effects and monitoring the identified side-effects and contraindications, (c) identifying and analysing emergent risks on the basis of factual evidence, (d) ensuring the continued acceptability of the benefit-risk ratio referred to in Sections 1 and 9 of Annex I, and (e) identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct. 6.2.   The PMCF plan shall include at least: (a) the general methods and procedures of the PMCF to be applied, such as gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of clinical data; (b) the specific methods and procedures of PMCF to be applied, such as evaluation of suitable registers or PMCF studies; (c) a rationale for the appropriateness of the methods and procedures referred to in points (a) and (b); (d) a reference to the relevant parts of the clinical evaluation report referred to in Section 4 and to the risk management referred to in Section 3 of Annex I; (e) the specific objectives to be addressed by the PMCF; (f) an evaluation of the clinical data relating to equivalent or similar devices; (g) reference to any relevant CS, harmonised standards when used by the manufacturer, and relevant guidance on PMCF; and (h) a detailed and adequately justified time schedule for PMCF activities (e.g. analysis of PMCF data and reporting) to be undertaken by the manufacturer. 7.   The manufacturer shall analyse the findings of the PMCF and document the results in a PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation. 8.   The conclusions of the PMCF evaluation report shall be taken into account for the clinical evaluation referred to in Article 61 and Part A of this Annex and in the risk management referred to in Section 3 of Annex I. If, through the PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer shall implement them. ANNEX XV CLINICAL INVESTIGATIONS CHAPTER I GENERAL REQUIREMENTS 1.   Ethical principles Each step in the clinical investigation, from the initial consideration of the need for and justification of the study to the publication of the results, shall be carried out in accordance with recognised ethical principles. 2.   Methods 2.1.   Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the manufacturer's claims regarding the safety, performance and aspects relating to benefit-risk of devices as referred to in Article 62(1); the clinical investigations shall include an adequate number of observations to guarantee the scientific validity of the conclusions. The rationale for the design and chosen statistical methodology shall be presented as further described in Section 3.6 of Chapter II of this Annex. 2.2.   The procedures used to perform the clinical investigation shall be appropriate to the device under investigation. 2.3.   The research methodologies used to perform the clinical investigation shall be appropriate to the device under investigation. 2.4.   Clinical investigations shall be performed in accordance with the clinical investigation plan by a sufficient number of intended users and in a clinical environment that is representative of the intended normal conditions of use of the device in the target patient population. Clinical investigations shall be in line with the clinical evaluation plan as referred to in Part A of Annex XIV. 2.5.   All the appropriate technical and functional features of the device, in particular those involving safety and performance, and their expected clinical outcomes shall be appropriately addressed in the investigational design. A list of the technical and functional features of the device and the related expected clinical outcomes shall be provided. 2.6.   The endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant. 2.7.   Investigators shall have access to the technical and clinical data regarding the device. Personnel involved in the conduct of an investigation shall be adequately instructed and trained in the proper use of the investigational device, and as regards the clinical investigation plan and good clinical practice. This training shall be verified and where necessary arranged by the sponsor and documented appropriately. 2.8.   The clinical investigation report, signed by the investigator, shall contain a critical evaluation of all the data collected during the clinical investigation, and shall include any negative findings. CHAPTER II DOCUMENTATION REGARDING THE APPLICATION FOR CLINICAL INVESTIGATION For investigational devices covered by Article 62, the sponsor shall draw up and submit the application in accordance with Article 70 accompanied by the following documents: 1.   Application form The application form shall be duly filled in, containing information regarding: 1.1. name, address and contact details of the sponsor and, if applicable, name, address and contact details of its contact person or legal representative in accordance with Article 62(2) established in the Union; 1.2. if different from those in Section 1.1, name, address and contact details of the manufacturer of the device intended for clinical investigation and, if applicable, of its authorised representative; 1.3. title of the clinical investigation; 1.4. status of the clinical investigation application (i.e. first submission, resubmission, significant amendment); 1.5. details and/or reference to the clinical evaluation plan; 1.6. If the application is a resubmission with regard to a device for which an application has been already submitted, the date or dates and reference number or numbers of the earlier application or in the case of significant amendment, reference to the original application. The sponsor shall identify all of the changes from the previous application together with a rationale for those changes, in particular, whether any changes have been made to address conclusions of previous competent authority or ethics committee reviews; 1.7. if the application is submitted in parallel with an application for a clinical trial in accordance with Regulation (EU) No 536/2014, reference to the official registration number of the clinical trial; 1.8. identification of the Member States and third countries in which the clinical investigation is to be conducted as part of a multicentre or multinational study at the time of application; 1.9. a brief description of the investigational device, its classification and other information necessary for the identification of the device and device type; 1.10. information as to whether the device incorporates a medicinal substance, including a human blood or plasma derivative or whether it is manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives; 1.11. summary of the clinical investigation plan including the objective or objectives of the clinical investigation, the number and gender of subjects, criteria for subject selection, whether there are subjects under 18 years of age, design of the investigation such as controlled and/or randomised studies, planned dates of commencement and of completion of the clinical investigation; 1.12. if applicable, information regarding a comparator device, its classification and other information necessary for the identification of the comparator device; 1.13. evidence from the sponsor that the clinical investigator and the investigational site are capable of conducting the clinical investigation in accordance with the clinical investigation plan; 1.14. details of the anticipated start date and duration of the investigation; 1.15. details to identify the notified body, if already involved at the stage of application for a clinical investigation; 1.16. confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application; and 1.17. the statement referred to in Section 4.1. 2.   Investigator's Brochure The investigator's brochure (IB) shall contain the clinical and non-clinical information on the investigational device that is relevant for the investigation and available at the time of application. Any updates to the IB or other relevant information that is newly available shall be brought to the attention of the investigators in a timely manner. The IB shall be clearly identified and contain in particular the following information: 2.1. Identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule pursuant to Annex VIII, design and manufacturing of the device and reference to previous and similar generations of the device. 2.2. Manufacturer's instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements, as well as, to the extent that such information is available, information to be placed on the label, and instructions for use to be provided with the device when placed on the market. In addition, information relating to any relevant training required. 2.3. Pre-clinical evaluation based on relevant pre-clinical testing and experimental data, in particular regarding in-design calculations, in vitro tests, ex vivo tests, animal tests, mechanical or electrical tests, reliability tests, sterilisation validation, software verification and validation, performance tests, evaluation of biocompatibility and biological safety, as applicable. 2.4. Existing clinical data, in particular: — from relevant scientific literature available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of the device and/or of equivalent or similar devices; — other relevant clinical data available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of equivalent or similar devices of the same manufacturer, including length of time on the market and a review of performance, clinical benefit and safety-related issues and any corrective actions taken. 2.5. Summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks, any undesirable effects, contraindications and warnings. 2.6. In the case of devices that incorporate a medicinal substance, including a human blood or plasma derivative or devices manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives, detailed information on the medicinal substance or on the tissues, cells or their derivatives, and on the compliance with the relevant general safety and performance requirements and the specific risk management in relation to the substance or tissues, cells or their derivatives, as well as evidence for the added value of incorporation of such constituents in relation to the clinical benefit and/or safety of the device. 2.7. A list detailing the fulfilment of the relevant general safety and performance requirements set out in Annex I, including the standards and CS applied, in full or in part, as well as a description of the solutions for fulfilling the relevant general safety and performance requirements, in so far as those standards and CS have not or have only been partly fulfilled or are lacking. 2.8. A detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation and in particular information on any deviation from normal clinical practice. 3.   Clinical Investigation Plan The clinical investigation plan (CIP) shall set out the rationale, objectives, design methodology, monitoring, conduct, record-keeping and the method of analysis for the clinical investigation. It shall contain in particular the information as laid down in this Annex. If part of this information is submitted in a separate document, it shall be referenced in the CIP. 3.1.   General 3.1.1.   Single identification number of the clinical investigation, as referred to in Article 70(1). 3.1.2.   Identification of the sponsor — name, address and contact details of the sponsor and, where applicable, the name, address and contact details of the sponsor's contact person or legal representative in accordance with Article 62(2) established in the Union. 3.1.3.   Information on the principal investigator at each investigational site, the coordinating investigator for the investigation, the address details for each investigational site and the emergency contact details for the principal investigator at each site. The roles, responsibilities and qualifications of the various kinds of investigators shall be specified in the CIP. 3.1.4.   A brief description of how the clinical investigation is financed and a brief description of the agreement between the sponsor and the site. 3.1.5.   Overall synopsis of the clinical investigation, in an official Union language determined by the Member State concerned. 3.2.   Identification and description of the device, including its intended purpose, its manufacturer, its traceability, the target population, materials coming into contact with the human body, the medical or surgical procedures involved in its use and the necessary training and experience for its use, background literature review, the current state of the art in clinical care in the relevant field of application and the proposed benefits of the new device. 3.3.   Risks and clinical benefits of the device to be examined, with justification of the corresponding expected clinical outcomes in the clinical investigation plan. 3.4.   Description of the relevance of the clinical investigation in the context of the state of the art of clinical practice. 3.5.   Objectives and hypotheses of the clinical investigation. 3.6.   Design of the clinical investigation with evidence of its scientific robustness and validity. 3.6.1.   General information such as type of investigation with rationale for choosing it, for its endpoints and for its variables as set out in the clinical evaluation plan. 3.6.2.   Information on the investigational device, on any comparator and on any other device or medication to be used in the clinical investigation. 3.6.3.   Information on subjects, selection criteria, size of investigation population, representativeness of investigation population in relation to target population and, if applicable, information on vulnerable subjects involved such as children, pregnant women, immuno-compromised or, elderly subjects. 3.6.4.   Details of measures to be taken to minimise bias, such as randomisation, and management of potential confounding factors. 3.6.5.   Description of the clinical procedures and diagnostic methods relating to the clinical investigation and in particular highlighting any deviation from normal clinical practice. 3.6.6.   Monitoring plan. 3.7.   Statistical considerations, with justification, including a power calculation for the sample size, if applicable. 3.8.   Data management. 3.9.   Information about any amendments to the CIP. 3.10.   Policy regarding follow-up and management of any deviations from the CIP at the investigational site and clear prohibition of use of waivers from the CIP. 3.11.   Accountability regarding the device, in particular control of access to the device, follow-up in relation to the device used in the clinical investigation and the return of unused, expired or malfunctioning devices. 3.12.   Statement of compliance with the recognised ethical principles for medical research involving humans, and the principles of good clinical practice in the field of clinical investigations of devices, as well as with the applicable regulatory requirements. 3.13.   Description of the Informed consent process. 3.14.   Safety reporting, including definitions of adverse events and serious adverse events, device deficiencies, procedures and timelines for reporting. 3.15.   Criteria and procedures for follow-up of subjects following the end, temporary halt or early termination of an investigation, for follow-up of subjects who have withdrawn their consent and procedures for subjects lost to follow-up. Such procedures shall for implantable devices, cover as a minimum traceability. 3.16.   A description of the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where such additional care is necessary because of the subjects' participation in the clinical investigation and where it differs from that normally expected for the medical condition in question. 3.17.   Policy as regards the establishment of the clinical investigation report and publication of results in accordance with the legal requirements and the ethical principles referred to in Section 1 of Chapter I. 3.18.   List of the technical and functional features of the device, with specific mention of those covered by the investigation. 3.19.   Bibliography. 4.   Other information 4.1.   A signed statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject. 4.2.   Where applicable according to national law, copy of the opinion or opinions of the ethics committee or committees concerned. Where according to national law the opinion or opinions of the ethics committee or committees is not required at the time of the submission of the application, a copy of the opinion or opinions shall be submitted as soon as available. 4.3.   Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 69 and the corresponding national law. 4.4.   Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document. 4.5.   Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data, in particular: — organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed; — a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects; and — a description of measures that will be implemented in case of a data security breach in order to mitigate the possible adverse effects. 4.6.   Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports, shall, upon request, be submitted to the competent authority reviewing an application. CHAPTER III OTHER OBLIGATIONS OF THE SPONSOR 1.   The sponsor shall undertake to keep available for the competent national authorities any documentation necessary to provide evidence for the documentation referred to in Chapter II of this Annex. If the sponsor is not the natural or legal person responsible for the manufacture of the investigational device, that obligation may be fulfilled by that person on behalf of the sponsor. 2.   The Sponsor shall have an agreement in place to ensure that any serious adverse events or any other event as referred to in Article 80(2) are reported by the investigator or investigators to the sponsor in a timely manner. 3.   The documentation mentioned in this Annex shall be kept for a period of at least 10 years after the clinical investigation with the device in question has ended, or, in the event that the device is subsequently placed on the market, at least 10 years after the last device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Each Member State shall require that this documentation is kept at the disposal of the competent authorities for the period referred to in the first subparagraph in case the sponsor, or its contact person or legal representative as referred to in Article 62(2) established within its territory, goes bankrupt or ceases its activity prior to the end of this period. 4.   The Sponsor shall appoint a monitor that is independent from the investigational site to ensure that the investigation is conducted in accordance with the CIP, the principles of good clinical practice and this Regulation. 5.   The Sponsor shall complete the follow-up of investigation subjects. 6.   The Sponsor shall provide evidence that the investigation is being conducted in line with good clinical practice, for instance through internal or external inspection. 7.   The Sponsor shall prepare a clinical investigation report which includes at least the following: — Cover/introductory page or pages indicating the title of the investigation, the investigational device, the single identification number, the CIP number and the details with signatures of the coordinating investigators and the principal investigators from each investigational site. — Details of the author and date of the report. — A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations. — Investigational device description, in particular clearly defined intended purpose. — A summary of the clinical investigation plan covering objectives, design, ethical aspects, monitoring and quality measures, selection criteria, target patient populations, sample size, treatment schedules, follow-up duration, concomitant treatments, statistical plan, including hypothesis, sample size calculation and analysis methods, as well as a justification. — Results of the clinical investigation covering, with rationale and justification, subject demographics, analysis of results related to chosen endpoints, details of subgroup analysis, as well as compliance with the CIP, and covering follow-up of missing data and of patients withdrawing from the clinical investigation, or lost to follow-up. — Summary of serious adverse events, adverse device effects, device deficiencies and any relevant corrective actions. — Discussion and overall conclusions covering safety and performance results, assessment of risks and clinical benefits, discussion of clinical relevance in accordance with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device, limitations of the investigation. ANNEX XVI LIST OF GROUPS OF PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE REFERRED TO IN ARTICLE 1(2) 1. Contact lenses or other items intended to be introduced into or onto the eye. 2. Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings. 3. Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing. 4. Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. 5. High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment. 6. Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.

Guidance-on-Article-15-MDR-IVDR-Person-responsible-for-Regulatory-Compliance.pdf.txt

This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 1 MDCG 2019- 7 Guidance on Article 15 of the Medical Device Regulation (MDR) and in vitro Diagnostic Device Regulation (IVDR) regarding a ‘person responsible for regulatory compliance’ (PRRC) Manufacturers1 (paragraph 1) “Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom -made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. ” Clarification on qualifications It shall be noted that : - For the purpose of fulfilling the requirement laid down in point “ a” of Article 15 (1), any qualification acquired outside the EU, including any university diplomas or certificates, should have been recognised by an EU Member State as equivalent to the EU corresponding qualification. 1 Enterprises which employ at least 50 persons and whose annual turnover and/or annual balance sheet total exceeds EUR 10 million (Commission Recommendation 2003/361/Ε C of 6 May 2003) . 2 - Professional experience in regulatory a ffairs or in quality management systems relating to medical devices should be related to the EU requirements in the field . Meaning of “within their organisation” The person responsible for regulatory compliance (PRRC) appointed would need to be an employee of the organisation. Organisations with more than one legal manufacturer Organisations with more than one legal manufacturer under the parent company would need to ensure that each legal manufacturer has its own PRRC.2 Can the PRRC be located out side the EU? As to the location of the PRRC, it is important that a close linkage, of a permanent and continuous nature, is established between the PRRC and the manufacturing activities. For this reason, for manufacturers located outside the EU, it must be assumed that the PRRC should also be located outside the EU. On the other hand, for manufacturers located in the EU, it must be assumed that the PRRC should also be located in the EU. Micro and small manufacturers3 (paragraph 2) “Micro and small enterpri ses within the meaning of Commission Recommendation 2003/361/EC shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal .” Meaning of “permanently and continuously at their disposal” The micro or small enterprise may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the manufacturer can de monstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation, with which the manufacturer has established a contract lay ing down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? For micro or small enterpr ises located in the EU, it must be assumed that any person to be permanent ly and continuously at their disposal should be also located in the EU . 2 In the context of Article 15, the obligation for having available within the organisation at least one PRRC refers to the individual legal manufacturer. 3 Enterprises which employ fewer than 50 persons and whose annual turnover and/or annual balance sheet total does not exceed EUR 10 million (Commission Recommendation 2003/361/ΕC of 6 May 2003) . 3 Authorised representatives (paragraph 6) “Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the followi ng qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. ” Meaning of “permanently and continuously at their disposal” The authorised representative may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the authorised representative can demonstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation with which the authorised representative has established e a contract laying down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? Taking into account that the Authorised Representative is located in the EU, it must be assumed that any person to be permanently and continuously at its disposal should be also located in the EU . Roles and responsibilities of the person r esponsible for regulatory compliance within a manufacturer (paragraph 3) For the purpose of this position paper, the roles and responsibilities of a PRRC have been cross -referred to the roles and responsibilities of a manufacturer, as stated in Article 10 of the MDR and IVDR. This paper does not interpret the roles and responsibilities of a PRRC. We recommend that any guidance on post -market surveillance, vigilance, clinical investigations and performance studies, created at a European level, should cross -refer to Article 15, paragraph 3 to provide guidance on what a PRRC of a manufacturer would be expected to do in these areas. 4 “The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the dev ices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; ” Manufacturers “of devices, other than investigational [performance study] devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device” (Article 10(9) of the MDR and Article 10(8) of the IVDR). “(b) the technical documentation and the EU declaration of conformity are drawn up and kept up- to-date; ” Manufacturers “[of devices other than custom -made devices] shall draw up and keep up to date technical documentation for those devices” (Article 10(4) of the MDR and IVDR) and “shall draw up an EU declaration of conformity” (Article 10(6) of the MDR and Article 10(5) of the IVDR). “(c) the post -market surveillance obligations are complied with in accordance with Article 10(10) [Article 10(9) of the IVDR]; ” Manufacturers “of devices shall implement and keep up to date the post -market surveillance system” (Article 10(10) of the MDR and Article 10(9) of the IVDR). “(d) the reporting obligations ref erred to in Articles 87 to 91 [Article 82 and 86 of the IVDR] are fulfilled; ” Manufacturers “shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88” (Article 10(13) of the MDR and Article 10(12) of the IVDR). “(e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV [Section 4.1 of Annex XIV of the IVDR] is issued. ” Manufacturers shall ensure that “a signed statement by the natural or legal person responsible for the manufacture of the investigational device [for performance study] that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigati on [performance study] and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.” 5 Roles and responsibilities of the person responsible for regulatory compliance within an authorised represent ative (paragraph 3) The PRRC of an AR should be responsible for ensuring that the tasks of an AR as specified in the given mandate, in accordance with Article 11(3), are fulfilled. . Can one individual be the PRRC for a manufacturer and its authorised representative? The person responsible for regulatory compliance for an authorised representative and for an 'outside EU' manufacturer cannot be the same person. There is a clear desire within the Regulations for the authorised representative to be adding an additional level of scrutiny and ensure that the supervision and control of the manufacture of devices, and the relevant post -market surveillance and vigilance activities are adequately effected. If the two roles were conducted by the same person, the additional level of scrutiny would be undermined. For the same reason, the PRRC of a micro or small enterprise and the PRRC of the authorised representative of that same enterprise shall not belong to the same external organisation.

md_mfr_stepbystep.pdf.txt

Implementation Model for Medical Devices Regulation Step by Step Guide MEDICAL DEVICES CHANGE OF LEGISLATION 1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the MDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (MDR Classes I, IIa, IIb and III) and confirm conformity assessment routes for existing and future products Check the new definition of MD, particularly with respect to its expanded scope. This also applies to products covered in Annex XVI Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 61) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market clinical follow-up plan (PMCF, Annex XIV Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for medical devices under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know! Internal market, Industry, Entrepreneurship and SMEs2Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs for the possible upgrade of risk class of MDs and for the new procedures for conformity assessment as well as the costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the MDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, resource requirements and a steering group, and ensure overall responsibility for MDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transitional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through MDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (clinical evaluation, technical documentation, relation with other economic operators, Unique Device Identification, labelling, registration, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for MDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the MDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the MDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ET-03-18-103-EN-N ISBN: 978-92-79-89702-3 DOI: 10.2873/66341

MDCG 2019-8 v2 Implant guidance Card.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-8 v2 MDCG 2019-8 v2 Guidance document Implant Card relating to the application of Article 18 Regulation (EU) 2017/745 of the European Pa rliament and of the Council of 5 April 2017 on medical devices March 2020 This document has been endorsed b y the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed o f representatives of all Member States and it is chaired by a representative of the European Co mmission. The document is not a European Commission document and it canno t be regarded as reflecting the official position of the European Commission. Any views express ed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices: Guidance document Implant Card relating to the app lication of Article 18 Regulati on (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medic al devices List of Content 1. Scope ............................................................................................................... 4 2. Purposes of the Implant Card ..................................................................... 4 3. Legal consideration on Implant Card design ........................................... 4 4. Information to be provided by the manufacturer on the Implant Card and information to be added by the health institution ........................... 5 5. Use of symbols .............................................................................................. 6 6. Language requirements on specific fields ................................................ 7 7. Benefits of an informativ e instruction leaflet ........................................... 7 8. Implant Card for implantable systems ...................................................... 7 Annex I examples of principle designs of Implant Cards and leaflets ....... 8 1. Scope This document provides guidance for Memb er States, concerned industry and other stakeholders on a blueprint of an implant card (IC) required by the MDR (Regulation (EU) 2017/745). It describes the intended use, cont ent and information to be provided by the manufacturer together on the IC and a definition of fields to be completed by the implanting healthcare institutions or healthcare provider s according to national law in Member States. Whereas the intended purpose and most of the da ta elements of the IC are already defined in Article 18 of the MDR, this document contains the description of other data elements which must be completed by the healthcare institution or healthcare provider and which must be considered by the individual Member State wh en implementing Article 18 MDR as required 1. 2. Purposes of the Implant Card The aim of introducing an IC has been to achieve three main objectives: 1. Enable the patient to identify the impl anted devices and to get access to other information related to the implanted device (e.g. via EUDAMED, and other websites). 2. Enable patients to identify themselves as persons requiring special care in relevant situations e.g. security checks. 3. Enabling e.g. emergency clinical staff or fi rst responder to be informed about special care/needs for relevant patients in case of emergency situations. 3. Legal consideration on Implant Card design Article 18 MDR describes the requirements rega rding the IC which shall be provided by the manufacturer together with the device. Wherea s Article 18 para 1a) describes the information which shall be provided by the manufacturer on the IC, Article 18 pa r a 2 l a y s d o w n t h e obligation of Member States to require health in stitutions to provide the IC to the concerned patient. In accordance with Article 18, 1a) the manufact urer should provide th e following information on the IC (preferably on the card itself or, alternatively, as stickers to be placed by the clinician):  Device name;  Serial number, lot number;  Unique device identification (UDI);  Name, address and the website of manufacturer;  Device type. 2 Article 18, 2 lays down that Member States shall require health institutions (or healthcare providers) inter alia to make available the IC to the relevant patient. The IC should bear their 1 This guidance doesn’t include the patient information described in Ar ticle 18 para 1 (b-d) which might be provided by the manufacturer by any means that allow rapid access to that information and that shall be stated in the language(s) determined by the concerned Member State. 2 In Article 18 1a) of the MDR, the term “device model” is used. However, this term which is not defined in the MDR, is part of the UDI-DI related info r m a t i o n t o b e p r o v i d e d t o E U D A M E D . T o a v o i d duplication and in the context of the intended purpos e of the IC (to be used in situations requiring special care or in emergency situations), it is cons idered that reference to device model in the MDR for the purpose of the IC shall be read as reference to device type, like “pacemaker”, “hip implant”, etc. When the European Medical device nomenclature is made available, a “standardised” set of terms of this nomenclature should be recommended for use in relation to the field “device type”. identity . For this purpose, the IC provided togeth er with the device should contain blank fields which shall be filled out by the health institution or healthcare provider, respectively. Since the establishment of (and the logistics behind) many different national IC designs is very expensive and of no additional benefit, Member States should ensure that, in the context of national implementation of Article 18 of the MD R, only the following information is required to be provided by the health institution or healthcare provider on the IC (together with the information provided by the manufacturer). Accordingly, a European or international blueprint for an IC which supports the purposes described in Article 18, 2 should contain the following blank fields: 1. Name of the patient or patient ID; 2. Name and address of the health institution or healthcare provider who performed the implantation; 3. Date of implantation. In order to be fit for the purposes described in Article 18, the outer dimensions of the IC should be the same as those of credit cards, ATM cards or ID cards (85.60 mm × 53.98 mm /3 3 ⁄8 × 2 1⁄8 inches) and with a radius of 2.88–3.48 mm 3. 4. Information to be provided by the manufacturer on the Implant Card and information to be adde d by the health institution The manufacturer shall provide the following necessary information: 1. Device name; 2. Device type; 3. Serial number or, where app licable, lot or batch number; 4. Unique device identification (UDI); the UDI as AIDC4 format and the UDI-DI as HRI5 5. Name and address of the manufacturer of the medical device; 6. Website of the manufacturer of the medical device. The text provided on the IC and on the instru ction for completing the IC by the healthcare institution or healthcare provider must be legible and at least 2 millimetres high. ‘Text’ includes any: number, letter, symbol, or letter or number in a symbol. In addition, the manufacturer shou ld design the IC in a way that the following blank fields to be filled out by the implanting healthcare institution or healthcare provider are available: 1. Name of the patient or patient ID; 2. Name and address of the healthcare inst itution which performed the implantation; 3. Date of implantation. 3 Dimensions to conform to the standard ISO/IEC 7810 ID-1. 4 AIDC - Automatic identification and data capture format (e.g. linear or 2D-Barcodes) 5 HRI - Human readable interpretation 5. Use of symbols To avoid national versions of the IC , the use of symbols is advisable. The following list contains symbols which have either been validated by users and have been submitted and accepted for inclusion in an upco ming international standard or already exist in the ISO database (Online Browsing Platform). The explanation of symbols on the IC should be provided in a leaflet (see section 7) or on the back of the IC, if space allows. Article 18(1) lays down that the information provided in the IC shall be stated in the language(s) determined by the concerned Member State. List of symbols recommended for use on the IC6: Patient Name or patient ID Date of implantation Name and Address of the implanting healthcare institution/provide r Name and Address of the manufacturer Information website for patients Device Name7 Serial Number Lot Number/Batch Code 6 The symbols for patient name or patient ID, name and ad dress of the implanting healthcare institution/provider, date of implantation, name and address of the manufacturer, serial number, lot number/batch code are already available and published in existing ISO standards. The symbols for device name, patient information website and UDI have been validated by users according to the ISO 15223-2 process. Note that the symbols listed here to indicate the following terms: ‘Device Name’, ‘Patient Name or Pati ent ID’, ‘Date of Implantation’, ‘Name and address of the implanting healthcare institution/provider’ on the implant card, are used in the ISO context to indicate ‘Medical Device’, ‘Patient Identification’, ‘Date’, ‘Health Care Center or Doctor’. 7 Please note that in the ISO context, the ‘MD’ symbol is used to identify that the product in question is a medical device. On the implant card, this symbol is used to indicate the device name. UDI as AIDC format UDI-DI information in a HRI format should be introduced by the wording “UDI-DI”. 6. Language requirements on specific fields Despite the nearly complete list of symbols for fields on the IC, there is currently no symbol available for the required field “Device Type”. The lack of a symbol and the purpose of this field makes it necessary that the information on the device type must be provided in the language accepted/required by the concerned Member State. There are several possibilities available to provid e this information in the necessary languages, e.g. the information is already printed on the IC in the different languages or stickers are provided with the IC and the healthcare professional selects the right one etc. 7. Benefits of an informati ve instruction leaflet8 As mentioned above (section 5), there is a need to provide, together with the IC, instructions on how to complete the IC and to explain the us ed symbols. This information shall be stated in the language(s) determined by the concerned Member State. For this reason, the use of a leaflet, containing the relevant information, to be provided together with the IC and the implantable device, is the recommended solution. As part of the risk management, the manufacturer has to investigate, by means of an ergonomic analysis or ergonomic usability test procedure, if the provided instructions are sufficient to enable the health professional to complete the IC correctly. The instructions must reflect the solution chosen by the manufacturer (e .g. pre-printed IC, blank IC with sticker(s) to be added, mixture of both). Special considerat ions might be needed when providing a system IC or an IC for a separate implantable compon ent, when there is not yet a common practice (standard) established. 8. Implant Card for implantable systems If an implantable device contains implantable components which might be replaced by other (or the same) components, for example in case of a later revision, the manufacturers should consider the use of a System IC. In Annex I to this guide an example is provided. W a y s c o u l d b e e x p l o r e d b y r e l e v a n t s t a k e h o l d e r s t o d e v e l o p c o m m o n r u l e s o n h o w t h e necessary information to be placed on the Sy stem IC is delivered with the replaceable component and how health professionals could en sure t hat the System I C is appropriately updated, when necessary. 8 This leaflet should not be confused with any possible vector of information referred to in points “b”, “c” and “d” of Article 18(1) of the MDR. UDI Annex I examples of principle designs of Implant Cards and leaf lets GENERAL NOTE: All examples contained in this Annex are to be intended as illustrative examples only.9 The basic shape of the IC shall be designed in compliance with ISO/IEC 7810 ID-1 (credit card form). The following pictures provide exam ples for individual device ICs. Example 1: Front – Not to scale (handwritten text on pre-printed content) Back – Not to scale (blank – serial printed content in production) 9 Please note that this includes translations (into languages other than English) shown in Examples throughout Annex 1, which are machine translated and not intended to be read as official translations into EU languages. International Implant Card https://www.genericmed.com/patientimplantinfo John Smith 27/05/2021 ABC Healthcare Center 123 Medical Parkway, Cork, Ireland Dr. H.C. Professional PM-5503 Pacer Advanced UDI-DI: (01)01865494261654 SN79856214 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Example 2: Back – Not to scale (blank – batch/lot printed content in production) PM-5503 Pacer Advanced UDI-DI: (01)03584124658462 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com AO.582122 Example 3 (suggested design of a foldable System IC): To be able to represent medical device syst ems in one IC, the IC shall be available in collapsible form. ABC Healthcare CenterInternational Implant Card www.genericmed.com/patientimplantinfo John Smith 27/05/2021 123 Medical Parkway Dr. H.C. Professional Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Cork, Ireland PM-5503 Pacer Advanced Pacemaker UDI-DI: (01)85412654285216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com PL-55-4 Pacer Lead Pro Pacemaker Lead UDI-DI: (01)89654213882154 SN86223214 Examples of IC Leaflet Front 1 (no stickers – preferred option) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. PM-5503 Pacer Advanced (01)8541265428 5216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 www.genericmed.com/patientimplantinfo Front 2 (sticker only for device type information) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare instit ution. To be filled by the healthcare institution/provider. 5. Add sticker with device type in required language. Stickers (to be detached and placed on the righ t place at the IC according to the numbers) PM-5503 Pacer Advanced (01)85412654285216 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 SN65695452 www.genericmed.com/patientimplantinfo 5 Front 3 (stickers) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. 4. Manufacturer’s information website. 5. Device type in required language. 6. Device name. 7. UDI-DI Code (HRI). 8. UDI code (AIDC format). 9. Serial number. 10. Name and address of the manufacturer of the implanted medical device. NOTE: Fields 4-10 might be filled with stickers (though this is not the preferred solution) Stickers (to be detached and plac ed on the right place at the IC according to the numbers) 5, 6 9 8 7 2 081019001 002 4 10 4 Back Explanation/ transl ation of symbols Patient Name or patient ID, Име на пациента , Jméno pacienta, Patientens navn, Patientenname, Όνομα ασθενούς , Nombre del paciente, Patsiendi nimi, Potilaan nimi, Nom du patient, Ime i prezime bolesnika, Imi ę i nazwisko pacjenta, A beteg neve, Nome del paziente, Paciento vardas ir pavard ė, Pacienta v ārds, uzvārds, Naam patiënt Pasientens navn, A beteg neve, Nome do doente, Nume pacient, Meno pacienta, Ime bolnika, Patientens namn Name and Address of the implanting healthcare institution/provide r , établissement sanitaire, centro de salud, struttura sanitaria, Gesundheitseinrichtung, gezondheidszorginstelling, placówka słu żby zdrowia, здравно заведение, veselības aprūpes iestāde, εγκατάσταση για την υγεία Date of Implantation , Дата на имплантиране, Datum implantace, Implanteringsdato, Implantationsdatum, Ημερομηνία εμφύτευσης, Fecha de implantación, Implanteerimiskuupäev, Implantointipäivämäärä, Date d’implantation, Datum implantacije, Beültetés dátuma, Data dell'impianto, Implantavimo data, Implant ēšanas datums, Implantatiedatum, Data wszczepienia , Data do implante, Data implant ării, Dátum implantácie, Datum vsaditve Device Name, Nazwa urz ądzenia medy cznego, Název zdravotnických prost ředků, Medicinsk enhed, Name des Medizinprodukts, Nombre del dispositivo médico, Nom du dispositif médical, Orvosi eszköz neve, Namn på medicinsk enhet, Ime medicinske naprave Nome do dispositivo médico κατασκευαστής, Producent, Fabrikant, Produttore, Fabricante, Fa bricant, manufacturer, Hersteller Information website for patients , Webová stránka s informacemi pro pacienta, Informationswebsite for patienten, Webseite mit Informationen für Patienten, Sitio web con información para el paciente, Site d'in formations pour le patient, Információs honlap betegek számára, Sito web con le informazioni per i pazienti, Website met informatie voor patiënten, Strona internetowa z informacjami dla pacjenta Translation of serial number in required languages. Translation of LOT number in required languages. Explanation of unique device identi fier (UDI) in required languages. Place to attach the Implant card

md_guidance-manufacturers_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019 -15 rev1 MDCG 2019 -15 rev.1 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES December 2019 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this doc ument are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 2 MDCG 2019 -15 revision 1 changes MDR postponement dates: from 2020 to 2021 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 3 Contents List of acronyms ................................ ................................ ................................ ................................ .... 4 Foreword ................................ ................................ ................................ ................................ ................ 5 Introduction ................................ ................................ ................................ ................................ ........... 5 Definitions ................................ ................................ ................................ ................................ .............. 8 Placing on the market of Class I medical devices: The necessary steps ................................ ......... 11 0) Integrate MDR in the Quality Management System (QMS). ................................ .................. 11 1) Confirm product as a medical device ................................ ................................ ........................ 11 2) Confirm product as a Class I medical device ................................ ................................ ............ 11 3) Procedures before placing on the market ................................ ................................ .................. 12 a) Meet the general safety and performance requirements ................................ ....................... 12 b) Conduct clinical evaluation ................................ ................................ ................................ ... 12 c) Prepare technical documentation ................................ ................................ .......................... 14 d) Request Notified Body involvement ................................ ................................ ..................... 16 e) Prepare Instructions for Use and Labelling ................................ ................................ ........... 16 4) Check compliance with general obligations for manufacturers ................................ ................ 17 5) Draw -up the EU Declaration of Conformity ................................ ................................ ............. 18 6) Affix the CE marking ................................ ................................ ................................ ................ 18 7) Registration of devices and manufacturers in Eudamed ................................ ........................... 19 8) Post Market Surveillance (PMS) ................................ ................................ ............................... 20 a) Review experience gained from Post -Market Surveillance ................................ .................. 20 b) Vigilance ................................ ................................ ................................ ............................... 20 c) Non conforming products ................................ ................................ ................................ ..... 22 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 4 List of acronyms MDD – Medical Devices Directive MDR – Medical Devices Regulation FSCA – Field Safety Corrective Action FSN - Field Safety Notice UDI - Unique Device Identifier SRN - Single Registration Number NB - Notified Body ISO - International Organization for Standardization IEC - International Electrotechnical Commission CA – Competent Authority PPE – Personal Protective Equipment QMS - Quality Management System Im – Class I devices with measuring function Is – Class I sterile devices Ir – Class I reusable surgical instruments DI – Device Identifier Eudamed - European database on medical devices MD - Medical Device CS - Common Specification PMS – Post Market Surveillance IFU – Instructions for use PMCF - Post Market Clinical Follow -up Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 5 Foreword These guidance notes do not aim to be a definitive interpretation of Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices (MDR) and are intended for guidance purposes only. Introduction The purpose of this document is to provide guidance to manufacturers of Class I medical devices (other than custom made devices) who place on the Union market medical devices (from now on referred to as devices) under their name or trade mark, to help them meet the provi sions of the MDR. This guidance should also be applicable for situations when an importer, distributor or any other legal person assumes the obligations incumbent on manufacturers, as per Article 16 (1), while not covering the exception indicated by Artic le 16 (2). The MDR has changed the scope of the medical device legislation and it now extends its application to all economic operators in the supply chain (manufacturer, authorised representative, importer and distributor) as well as a broadened range of products such as those specifically intended for the cleaning, disinfection or sterilization of devices (Article 2 (1)) and products without an intended medical purpose (such as certain aesthetic products, as indicated in Annex XVI of the MDR). In addition , more emphasis is placed on a life -cycle approach to safety, backed up by clinical data and new requirements such as transparency and traceability1. Before placing a device on the market, the manufacturer will affix the CE mark in accordance with Annex V and draw up the EU declaration of conformity, including all the information required by Annex IV. Prior to that, the manufacturer will demonstrate conformity with the MDR and compliance with the applicable general safety and performance requirements laid o ut in Annex I. In order to accomplish the abovementioned tasks, the manufacturer will carry out the following:  Put in place a quality management system and a system for risk management according to Article 10(2) and 10(9).  Conduct a clinical evaluation i n accordance with Article 61, as established in Article 10(3) and Annex XV.  Conduct a conformity assessment according to Article 52(7). In specific cases ( sterile devices, devices with measuring function, reusable surgical instruments ) defined in the referred Article, the manufacturer will request the involvement of a Notified Body (NB).  Draw up and keep up -to-date technical documentation related to devices as set out in Annexes II and III, in accordance with Article 10(4).  Draw up an EU declaration of conformity in accordance with Article 19.  Submit the required information to the electronic system for registration of economic operators (Eudamed) and comply with the registration obligation. The manufacturer will use the Single Regis tration Number (SRN) when applying to a NB for conformity assessment, if applicable and for further accessing Eudamed2 in order to fulfil its obligations related to registration of the devices.  Register the device in Eudamed assigning the Basic UDI -DI to t he device, as defined in Part C of Annex VI, and provide this to the UDI database together with the other core data elements referred in Part B of Annex VI related to that device.  Assign to the device and, if applicable, to all higher levels of packaging, a UDI which will allow identification and traceability. 1 More information can be found at https://ec.europa.eu/health/md_sector/overview 2 Regarding all references to Eudamed in this document, please be advised that for the purposes of this guidance, obligations s trictly related to Eudamed will only apply when it is fully functional and any u pdates will be published on the EU Commission webpage. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 6  Ensure that the device is accompanied by the information needed to identify it and its manufacturer, and any safety and performance information relevant to the user, or any other person, as appropria te (Article 10(11)). This information, set out according to Section 23 of Annex I, must be provided in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label w ill be indelible, easily legible and clearly comprehensible to the intended user or patient.  Implement a post -market surveillance system in accordance with Article 83 (Article 10(10)) proportional to the risk class and appropriate for the type of device, this includes additional aspects to be taken into account in case of devices placed on the market in sterile condition, with a measuring function or that are reusable surgical instruments. This system will be an integral part of the manufacturer's quality management system based on a post -market surveillance plan (Article 84) , which will be part of the technical documentation specified in Annex III.  Implement a system for recording and reporting incidents and field safety corrective actions as described in Articles 87 and 88 (Article 10(13)).  Put measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC3, without prejudice to more protective measures under national law. These measures will be proportional to the risk class, type of device and the size of the enterprise (Article 10(16)). Further detail on the aforementioned list of obligations is provided in the chapter “Placing Class I medical devices on the market ”. For devices placed on the market in a sterile condition, with a measuring function or which are reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI which require a NB assessment, limited t o critical aspects such as those concerning sterile condition, metrological requirements and the reuse of the device, as relevant, according with Article 52 (7 a, b and c). 3 Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of t he Member States concerning liability for defective products Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 7 Figure 1. Illustration of the conformity procedures for the assessment of Class I devices with and without NB involvement. For big and medium size enterprises, the manufacturer will have available within their organization at least one person responsible for regulatory compliance4, as established by Article 15. Micro and small enterprises5 are required to have such person permanently and continuously at their disposal. A manufacturer with a registered place of business outside the Union will designate a sole authorised representative, at least per each gener ic device group, according to a written mandate. Such a mandate will establish the tasks to be performed by the authorised representative. To enable the fulfilment of these tasks, the manufacturer ensures that the authorised representative has the necessar y documentation permanently available and up -to date. The mandate will require the authorised representative to perform at least the tasks described in Article 11(3), however the manufacturer cannot delegate its obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). In case of the change of authorised representative, Article 12 establishes the minimum content of agreement to be addressed between the manufacturer, where practicable the outgoing authorised representative, a nd the incoming authorised representative. Upon request, the manufacturer will provide all the information and documentation necessary to demonstrate conformity of the device to competent authorities and cooperate with them on any corrective action. If th e manufacturer does not cooperate or does not provide the requested information or documentation, the competent authority (CA) can adopt restrictive measures. The manufacturer should periodically verify whether implementing and delegated acts, common speci fications, technical standards and guidelines might be available on the European Commission website6. Such documents might for example cover specific parts of legislation (e.g. classification of 4 See the relevant MDCG guidance on Article 15 of MDR and IVDR regarding a "person responsible for regulatory compliance" (PRRC) 5 See Commission Recommendation 2003/361/EC 6 https://ec.europa.eu/health/md_sector/overview Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 8 medical devices, clinical evaluation) or specific requirement s regarding certain medical device technologies (e.g. software, 3D printing ) that can also be applicable for Class I devices. During the transitional period, manufacturers might be tempted to refer to guidance documents developed under the Directive 93/42/ EC. However, the old guidance documents, unless otherwise updated in line with the MDR, may have only some limited indicative value under the MDR. For the purpose of the MDR, only the text of the Regulation is valid in law and sets out requirements not reflected in the old guidance. Hence, the MDR alone can be relied upon as a legal basis . Definitions For the complete list of definitions refer to Article 2 of the MDR. This is an excerpt of some definitions. Accessory for a medical device - means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s) (Article 2(2)) . Authorised representative - means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under the MDR (Arti cle 2(32)). The designation of an authorised repre sentative will be in compliance with Article 11 and effective at least for all devices o f the same generic device group (Article 11(2)) . Adverse event - means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, inc luding an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device (Article 2(57)) . Benefit -risk determination - means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer (Article 2(24)) . Class I medical devices with measuring function - are considered Class I medical devices which measure physiological parameters or anatomical parameter or energy, respectively, or volume of medicinal products, body liquids or other substances administered to or removed from the body and display or indicate its value in a unit of measurement (example: urine bags, non -active thermometers, measuring spoons). Note: According to section 15.2 of Annex I, measurements made by devices with a measuring function will be expressed in legal un its7. CE marking of conformity or CE marking - means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in the MDR and other applicable Union harmonisation legislation providing for its affix ing (Article 2(43)) . Note: CE marking will be made in accordance with Annex V. Clinical evaluation - means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify th e safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. (Article 2(44)). Clinical data - means information concerning safety or performance that is generated from the use of a device and is sourced fr om the following:  clinical investigation(s) of the device concerned, 7 In conformance to the provisions of Council Directive 80/181/EEC Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 9  clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,  reports published in peer re viewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,  clinically relevant information coming from post -market surveillance, in particular the post - market clinical follow -up. (Article 2(48)) Conformity Assessment – The process demonstrating whether the requirements of the MDR relating to a device have been fulfilled. (Article 2(40)). This process depends on the medical device classification, according to the procedures described in the MDR, in particular Article 52 (7) applicable for class I devices. Distributor - means any natural or legal person in the supply chain, other than the manufacturer or the importer that makes a device available on the market, up until the point of putting into service (Article 2(34)) . Economic operator - means a manufacturer, an authorised representative, an importer, a distributor or the person referre d to in Article 22(1) and 22(3) (Article 2(35)) . Field safety corrective action - means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market (Article 2(68)) . Field safety notice - means a com munication sent by a manufacturer to users or customers in relation to a field safety corrective action (Article 2(69)) . Harmonised standard - means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) N° 1025/20128, (as referred on the Article 2(70)) – means a European standard adopted on the basis of a request made by the Commission for the application of Union harmonisation legislation. Importer - means any natural or legal person established within the Union that places a devic e from a third country on the Union market (Article 2(33)). Intended purpose/intended use - means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (Article 2(12)). Instructions for use - means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use, and of any precautions to be taken (Article 2(14)). Label - means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices (Article 2(13)). Medical device - means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: ‒ diagnosis, prevention, m onitoring, prediction, prognosis, treatment or alleviation of disease, ‒ diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, ‒ investigation, replacement or modification of the anatomy or of a physiological or path ological process or state, ‒ providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, 8 Regulation (EU) No 1025/2012 of the European Parliament and of the Council , of 25 October 2012 , on European standardization Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 10 and which does not achieve its principal intended action by pharmacological, immuno logical or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: ‒ devices for the control or support of conception; ‒ products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (Article 2(1)) Manufacturer - means a natural or legal person who manufactures or fully refur bishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark ; (Article 2(30)). Notified Body - means a conformity assessment body designated in accordance with the MDR (Article 2(42)). Placing on the market - means the first making available of a device, other than an investigational device, on the Union market (Article 2(28)). Post-market surveillance - means all activities carried out by manufacturers in cooperation with other economic op erators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediate ly apply any necessary corrective or preventive actions (Article 2(60)). Risk - means the combination of the probability of occurrence of harm and the severity of that harm (Article 2(23)). Serious incident - means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; ((Article 2( 65)) Serious public health threat - means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time (Article 2(66)) . Unique Device Identifier (UDI) - means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market (Article 2(15)). User - means any healthcare professional or lay person who uses a device (Article 2(37)). Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 11 Placing Class I medical devices on the market: The necessary steps Manufacturers that intend to place Class I medical devices on the market must guarantee compliance with all the requirements below. Please note that some of the described requirements are inter -dependent and can be performed in a differe nt order than the one presented. For Class I devices already placed on the market in accordance with the MDD, the manufacturer will conduct a gap analysis in order to guarantee that all the necessary requirements outlined below are fully completed at the d ate of the application of MDR. 0) Integrate MDR in the Quality Management System (QMS). The applicable provisions of the MDR will be integrated into the QMS of the manufacturer. This will allow the correct assessment/decision to be made and the proper documented evidence to be created, ensuring compliance with the following requirements. 1) Confirm product as a medical device Confirm that the product qualifies as a medical device as defined in Article 2(1) in accordance with its intended purpose and principal mode of action. If the manufacturer assigns several different intended purposes to their product, not all of which fall under the scope of the MDR, such a product qualifies as a medical device only with respect to those intended medical purposes which are covered by Article 2(1). This is applicable, for instance, for the case of examination gloves that are intended by the manufacturer to be used to protect the patient (medical purpose - MD) and also to protect the healthcare professional (protecti on purpose – PPE9). In that case the relevant requirements of both legislations will be applicable. In the case of accessories to medical devices, despite not being medical devices per se, they are covered by MDR provisions and fall under the term “device” in the meaning of the MDR. However, accessories to devices covered by the MDR by virtue of its Annex XVI are not covered by the MDR. For borderline products where such a determination could be difficult, please consult primarily the information10 available on the European Commission website. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 2) Confirm product as a Class I medical device Consult Annex VIII of the MDR to confirm that the product is correc tly classified as Class I. It should be noted that some Class I devices according to MDD will be reclassified under the MDR considering the new classification rules of that annex, this is the case for most software (rule 11) and devices that are composed o f substances or of combination of substances (rule 21) . For devices that were reclassified from Class I to higher risk classes by application of the MDR, the present guideline cannot be applied. The application of the classification rules will be governe d by the intended purpose of the device and 9 Directive 89/686/EEC is repealed with effect from 21 April 2018 by Regulation (EU) 2016/425 10 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 12 their inherent risks linked to the duration of use, part of the body, whether it is active or not, whether it is invasive or non -invasive. If more than one rule according to Annex VIII applies to the intended pur poses of the device, the highest classification applies to the device, i.e. it must be classified on the basis of the most critical specified use. For classification issues, please primarily consult the information11 available on the European Commission web site. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 3) Procedures before placing on the market a) Meet the general safety and performance requirements The devices will meet the general safety and per formance requirements set out in Annex I of the MDR which apply to them, taking into account the purposes intended by their manufacturers. Particular attention will be given to devices that are also machinery, within the meaning of Article 2(2), point (a) , Machinery Directive 2006/42/EC12, where the relevant requirements of that directive will also be covered given their specificity (according to Article 1(12)). The manufacturer will establish and implement a risk management system, which will allow for the identification and analysis of the hazards associated with each device, estimation and evaluation of the associated risks, elimination or control of residual risks and evaluation of the adopted measures based on the information collected from the post -market surveillance system. The risk management will be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. To carry out this process the manufacturer can find solutions in common sp ecifications, or in harmonised standards, published in the Official Journal of the European Union, or in other referential materials. Where a harmonised standard exists but the manufacturer is following other referential, the application of that referentia l should guarantee at least the same level of safety and performance. Conformity with the relevant harmonized standards will provide presumption of conformity with the requirements of the MDR covered by those standards or parts thereof. Where common speci fications are available the manufacturer is obliged to follow them unless they can duly justify that they have adopted a solution at least with the same level of safety and performance. The risk management, clinical evaluation processes and PMS will be inter-dependent and will be periodically updated. b) Conduct clinical evaluation All devices, regardless of risk classification, require a clinical evaluation as part of the technical documentation requirements of the MD R13. The manufacturer will specify and justify the level of clinical evidence necessary to demonstrate 11 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en%20 12 Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24) 13 For further, see Annex II of the MDR Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 13 conformity with the relevant general safety and performance requirements described in Annex I. That level of clinical evidence will be appropriate in view of the characteristics of the device and its intended purpose. In order to do that, manufacturers will plan, conduct and document a clinical evaluation in accordance with Article 61 and Part A of Annex XIV. Guidance on the process of conducting clinical eval uation is also available on the Commission website.14 Conformity to Annex I requirements can only be assumed when the following items are aligned with each other:  Risk management;  The information materials supplied by the manufacturer, including: o labelling , o instructions for use (where required), o available promotional materials, o any accompanying documents foreseen by the manufacturer;  The clinical evaluation (the device description used for the clinical evaluation, other contents of the clinical evaluati on report);  The available clinical data (such as results of clinical investigations, publications, Post Market Surveillance studies, clinical registries, etc.). The MDR reinforces the need to consider the following aspects when carrying out a clinical eval uation: • Consideration of available alternative treatment options is required as part of clinical evaluation for the MDR15. Whilst the existence of better alternative treatment options does not influence the compliance of the device with the MDR, the manufacturer needs to be able to justify the clinical benefit of using their device if alternatives are available. • The incorpo ration of clinical data obtained throughout the life cycle of the device from the manufacturers post -market clinical follow -up plan and post -market surveillance plan to update the clinic al evaluation and documentation16. • The acceptability of the benefit -risk ratio must be based upon sufficient clinical data and will be continuously monitored and reassessed from clinical data collected through the post - mark et surveillance phase. The post -market surveillance plan should incorporate suitable indicators and thr eshold values to be used in this reassessment 17. If available clinical data are not sufficient to demonstrate compliance with the MDR, further clinical data will be obtained or generated by clinical investigations. For devices which are currently certifie d with respect to the Directive 93/42/EC, and for which the available clinical data are not sufficient to demonstrate compliance with MDR, additional clinical data may be obtained by post -market clinical follow -up studies of the device. Sometimes, even dat a from the general post -market follow -up might suffice to close the gap18. Note : if a clinical investigation is required, then the Member State requires advance notification of the proposal and the provisions of Article 62 and Annex XV will be applicable. 14 https://ec.europa.eu/health/md_sector/new_regulations/guidance_en 15 MDR, Article 61(3)(c) 16 MDR, Article 61(11) 17 MDR, Article 61(1) and Annex III 1.1b 18 An MDCG guidance is intended to be published on this matter including ‘sufficient clinical da ta’ in 2020 and will be availabl e at the EU Commission webpage Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 14 In duly justified and substantiated cases, some Class I devices manufacturers may exceptionally demonstrate that the conformity with general safety and performance requirements based on clinical data is not deemed appropriate. Such a justification by the m anufacturer must be based upon an evaluation of evidence in accordance with Article 61(10). The clinical evaluation, risk management processes and PMS will be inter -dependent and will be periodically updated. c) Prepare technical documentation The manufactur er will draw up and keep up to date the technical documentation that demonstrates the conformity of their devices with the technical requirements of the MDR. This technical documentation must be prepared according to Annex II and III and prior to drawing u p the EU declaration of conformity. The technical documentation and, if applicable, its summary, will be drawn up and presented by the manufacturer in a clear, organised, readily searchable and unambiguous manner. The manufacturer must make the technical d ocumentation available to the CA, the authorised representative (when applicable) and NB (when applicable). The technical documentation will be prepared following review of the general safety and performance requirements and relevant technical provisions o f the MDR and, if applicable, of the Machinery Directive19 and will cover all the relevant aspects from Annex II and III, such as: - Rationale for the qualification as a medical device and the risk class attributed. - Description and specification - A general d escription of the device, including its intended purpose and intended users/patient population and, if applicable, accessories and variants of the product (for example trade names, model numbers, references, sizes). In addition , the Basic UDI-DI as per Par t C of Annex VI will be provided. - Technical Specifications of the device - Specifications including details of raw materials, drawings of components and/or master patterns and any quality control procedures. - Information to be supplied by the manufacturer - Labels on the device and packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions and instruction for use (if applicable), in the languages determined by the Member States where the device is envisaged to be sold. - Reference to previous generations of the device and to similar devices - Provide an overview of previous generation(s) of the device and similar devices available on the market as ap plicable - Design and manufacturing information – Information that allows the understanding of the design and manufacturing of a device, including the results of qualifications tests and design calculations relevant to the intended use of the product, includ ing connections to other devices in order for it to operate as intended. If the manufacturer can provide information showing that a safe design has been established for a number of years and that product has been performing as intended during that time suc h information is likely to be sufficient to cover this 19 According to Article 1 (12) Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 15 requirement. The identification of all sites, suppliers and sub -contractors, where design and manufacturing activities are performed will also be included. - General safety and performance requirements – information for the demonstration of conformity with the general safety and performance requirements, set out in Annex I. In order to do this, the manufacturer will refer to all the methods and solutions used for conformity demonstration with each safety and performance requirement, including harmonised standards and/or common specifications (CS). The same applies for the requirements contained in the Machinery Directive. - Demonstration of conformity with the requirements set out in Annex I should typically be presented in the form of a checklist. This should list all requirements referred to in Annex I and specify: (1) the applicability of each requirement to the device, (2) the solution adopted by the man ufacturer to comply with each applicable requirement, (3) the reference to any possible CS or harmonized standards applied in full or in part and (4) the reference to where to find evidence of the solution adopted in the technical documentation. Manufacturers wil l list the relevant harmonised standards (concerning for example sterilisation, labelling and information to be supplied with the device, biocompatibility, specific groups of products) which have been applied in full or in part. If harmonised standards hav e not been applied in full, additional data will be required and provided detailing remaining solutions adopted to meet the concerned requirements. Information on standards harmonised under the MDR will be made available in the Official Journal of the Euro pean Union. Changes on the harmonised standards used to demonstrate the conformity of device will be adequately taken into account in a timely manner. Please note that no standard harmonized under the Directive 93/42/EC, has ever covered all the requirements of the Annex I to that Directive. Hence, it is not likely that any one standard harmonized under the MDR will cover all the requirements of the Anne x I to the MDR. The scope of coverage is indicated in the so -called Annex Z to the European “EN” standard. The scope of coverage is never to be found in the ISO or IEC standard text. - Benefit -risk analysis (sections 1 and 8 of Annex I) and Risk management ( section 3 of Annex I). - Pre-clinical and Clinical evaluation data – Information to be provided on the results from pre - clinical and clinical evaluation. - The post -market surveillance system - The technical documentation on post -market surveillance to be dr awn up by the manufacturer in accordance with Articles 83 to 85 will be presented in a clear, organized, readily searchable and unambiguous manner. It shall address and cover the elements of point 1.1 of Annex III. The plan will cover the post -market clini cal follow up plan as referred to in part B of Annex XIV or a justification as to why it is not applicable. The PMS report of article 85 shall be part of the technical documentation on post -market surveillance. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 16 - Records - Manufacturers will keep the techn ical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market (Article 10(8)). Availability of documentation – In case of request by the CA, the manufacturer will provide the required technical documentation in an official Union language determined by the Member State concerned (Article 10(14)). d) Request Notified Body involvement In the case of devices placed on the market in sterile condition, having a measuring function or being reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI of MDR. This requires the involvement of a NB. In all other cases the intervention of a NB is not required for Class I devices. If involvement of the NB is needed it is limited: - In the case of devices placed on the market in sterile condition, to the aspects of manufacture concerned with securing and maintaining sterile conditions; - In the case of devices with a measuring function, to the aspects of man ufacture concerned with the conformity of the devices with the metrological requirements; - In the case of reusable surgical instruments20, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance a nd functional testing and the related instructions for use. Manufacturers can choose any NB designated according to the MDR for the relevant codes and corresponding types of devices as established by Regulation (EU) 2017/2185 (code MDS 1005 for “Devices in sterile condition”, code MDS 1006 for “Reusable surgical instruments” and code MDS 1010 for “Devices with a measuring function”) . The list of designated NBs is available in the NANDO database at the following link: http://ec.europa.eu/growth/tools -databases/nando/ Please note that notification under the Directive 93/42/EC, become s void after the application of the MDR on the 26 May 202 1. Hence, it is necessary to consult the NANDO database for the MDR. e) Prepare Instructions for Use and Labelling Each device must be accompanied by any safety and performance information needed to use it safely and to identify the device as well as the manufacturer and/or the authorised representative, taking account of the training and knowledge of the potential users. This information comprises the label, device packaging and the data in the instructions for use. By way of derogation to the general principles, no instructions for use are required for Class I de vices if they can be used properly and safely without such instruction. An exception is most likely posed for Class Ir devices as reprocessing (cleaning and sterilization) will require an instruction. The requirements regarding the information to be suppl ied with the device will be found in Annex I, Chapter III (23). In the labelling and instructions for use as well as in promotional materials of the device, the manufacturer may not (Article 7): 20 Please also note that involvement of a Notified Body in the case of reusable surgical instruments is a new requirement under the MDR, which did not exist under the MDD. Manufacturers of such products are advised to take this into consideration for their pl ans to meet the provisions of the MDR before its application on the 26 May 202 1. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 17 - Ascribe functions and properties to the device which the devi ce does not have; - Create a false impression regarding treatment or diagnosis, functions or properties which the device does not have; - Fail to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; - Suggest uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. National language requirements must be taken into account in relation to the labelling and instructions for use. Versions of labelling and IFU ( in each of the relevant national languages) will be included in the technical documentation. Note : According to Article 16(2), a distributor or importer may provide a translation of the information provided according to Section 23 of Annex I. The manufacturer will be informed about the intended translation and receive a copy 28 days prior to the date of making the device available in the respective country. It is advisable to perform a review of the translation, as a w rong or misleading translation can cause harm to patients or others, leading to possible liability of the manufacturer. Where appropriate, the information supplied by the manufacturer will take the form of internationally recognised symbols. Any symbol or identification colour used will conform to harmonised standards or common specifications (CS). In areas for which no harmonised standards or CS exist, the symbols and colours will be described in the documentation supplied with the device. The label should have the indication that the product is a “medical device”. 4) Check compliance with general obligations for manufacturers Before placing a device on the market, the manufacturer will make sure to comply with the general obligations for manufacturers as est ablished in Article 10. Special attention will be given to the establishment of an appropriate QMS that will ensure compliance with the MDR in the most effective manner, for example by means of an internal audit. The QMS will be documented, implemented, m aintained, kept up to date and continually improved and will cover at least the following aspects: a) a strategy for regulatory compliance; b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; c) responsibility of the management; d) resource management, including selection and control of suppliers and sub -contractors; e) risk management; f) clinical evaluation, including post market clinical follow -up (PMCF); g) product realisation, including planning, design, development, production and service provision; h) verification of the UDI assignments; i) setting -up, implementation and ma intenance of a post -market surveillance system; j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; k) processes for reporting of serious incidents and field safety corrective ac tions in the context of vigilance; l) management of corrective and preventive actions and verification of their effectiveness; m) processes for monitoring and measurement of output, data analysis and product improvement. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 18 The QMS will be established at least in parallel, if not prior to chapter 3 a) and 3 b) as described in this guidance note. Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Therefore, manufacturers sha ll, in a manner that is proportionate to the risk class, type of device and size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to mor e protective measures under national law. 5) Draw -up the EU Declaration of Conformity The EU declaration of conformity, referred to in Article 19, is the procedure whereby the manufacturer, who fulfils the obligations imposed by Article 52(7), declares that the devices concerned fulfil the requirements of the MDR which apply to them. The declaration of conformity will contain as a minimum all information referred to in Annex IV and will be available to the CA. The manufacturer will continuously update the EU declaration of conformity and will translate it into an official union language or languages required by Member States in which the device is made available. If, in addition to the MDR, a device is covered by other Union legislation which also requires an EU declaration of conformity, the manufacturers will elaborate a single EU declaration of conformity where all the Union legislation applied to the product are referred to. By drawing up the EU declaration of conformity the manufacturer assumes the respon sibility for the regulatory compliance of the device with all Union legislation applicable to it. Before affixing a CE mark, for class Ir, Im and Is devices, the manufacturer will have an EC certificate issued by NB according to the Annex IX, Chapter I and III, or to Annex XI, Part A. 6) Affix the CE marking All Class I medical devices placed on the mar ket will bear the CE marking of conformity, which will be affixed in a visible, legible and indelible form on the device or on its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE markin g shall be affixed to the packaging. The CE marking shall also appear on the instructions for use, as well as on any sales packaging. In the case of Class I medical devices placed on the market in a sterile condition and/or devices with measuring function and/or reusable surgical instruments, the CE marking will be accompanied by the identification number of the relevant NB. It is prohibited to affix marks which are likely to mislead third parties with regard to the meaning of the CE marking. Other additio nal marks may be affixed to the device, to the packaging or the instructions for use, but must not impair the visibility or legibility of the CE marking. The CE marking format will be in compliance with Annex V. Where the device is very small the minimum d imensions of the CE mark may be waived. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 19 7) Registration of devices and manufacturers in Eudamed Before placing a device on the market, the manufacturer of a Class I medical device will register the device in Eudamed. In order to register the device, the manufacturer will submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already been registered in accordance with Article 31. In cases where the conformity ass essment procedure requires the involvement of a NB pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI will be provided to that electronic system before applying to the NB. After having verified the data about the manufac turer, the CA will validate it in Eudamed and the manufacturer will obtain a SRN from said electronic system. The manufacturer will use the SRN when applying to a NB for conformity assessment and for accessing Eudamed in order to fulfil its obligations und er Article 29. Note: Authorised representatives and importers are also required to register to get an SRN in order to access Eudamed and provide data, as appropriate The registration of a device in Eudamed by the manufacturer includes:  Assignment of a UDI -DI (with a Basic UDI -DI) as defined in Part C of Annex VI to the device (in accordance with the rules of the issuing entity referred to in Article 27(2) and introduction of the UDI -DI (with a Basic UDI -DI) to the UDI database together with the other core d ata elements referred to in Part B of Annex VI related to that device.  Entering, or if already provided, verifying in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and thereafter keeping the information updated. If the manufacturer has its devices designed or manufactured by another legal or natural person, the information on the identity of that person will be part of the information (Section 2.13 of Part A of Annex VI) to be submitted to Eudamed before the registration of the device. Note 1 – The Unique Device Identification system will allow the identification and facilitate the traceability of devices (as referred on Article 27). [Special attention will be given to point 11 of Article 27]. Note 2 – The Basic UDI -DI as defined in Part C of Annex VI is the primary identifier of a device model. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity21. Note 3 – For Class I devices placed on the market according to MDD, afte r the date of application of MDR manufacturers will have in consideration the guidance documents applicable to legacy devices timelines22 and registration in Eudamed23. 21 For more information on the Basic UDI -DI, please refer to https://ec.europa.eu/docsroom/documents/28667 22 See at EU Commission webpage the relevant guidance on timelines for registration of device data elements in EUDAMED23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED 23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 20 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 21 All devices including legacy devices of the manufacturer portfolio which are placed on the market or put into service will have to be registered in Eudamed. However, until Eudamed is fully functional the manufacturer of a Class I medical device, or, where the manufacturer has no place of business in the EU, its authorised representative must inform the CA of the country in which they have their registered place of business and provide a description of the device that is sufficient to identify it. The manufacturer or its authorised representative will contact their relevant CA for the required procedures and forms required for such notifications. A fee might be applicable. 8) Post Market Surveillance (PMS) After placing the Class I device on the market, the manufacturer will follow the next PMS steps: a) Review experience gained from Post -Market Sur veillance The manufacturer will put in place the required post market surveillance (PMS) system and actively keep this PMS up to date in accordance with Article 83 of MDR. This includes actively and regularly collecting the user experience from devices on the market, reviewing these and ensuring timely implementation of any necessary corrective action, taking account of the nature and risks in relation to the product. In addition, there should be an evaluation of whether the intended benefits are achieved a nd whether the benefit -risk profile stays positive. The manufacturer will involve the distributors of the device and where applicable, the authorised representative and importers of the device in this system, in order to obtain the relevant information from the market. This system will be part of the QMS, and be supported by the manufacturer’s PMS plan, which must address a range of information (Annex III), such as information from the vigilance context, information from trending and trend reporting, inf ormation and data on any undesirable side -effects, information from reports, complaints and incidents, provided by users and economic operators, related to the device. Moreover, the manufacturer will gather and assess the relevant information such as techn ical literature, databases, registers review and public information for the device itself as well as for similar devices already present on the market. A PMS report will be prepared according to Article 85, summarizing the results and conclusions of the analysis of all of the data from the market. This report will be updated when necessary, for example the intended benefits are not achieved or there is a change in the benefit -risk balance. The report can be requested by the CA at any time. Data gathered from PMS system must be used to actively update the clinical evaluation, benefit -risk determination, improve risk management, as well as other technical documentation on a regular basis. b) Vigilance The manufacturer is responsible for reporting all serious incidents and field safety corrective actions (FSCA) to the relevant CAs, according to Article 87 (1) of the MDR. After serious incident notification, the manufacturer is obliged to make investigations, according to Article 89, which will include a risk assessment of the incident. If needed, a FSCA will be implemented in order to reduce the risk associated with the use of the device. The manufacturer will involve the distributors of the device and, where applicable, the authorised representative and import ers in the system, in order to obtain the information needed from the market, especially for FSCA and issued field safety notices (FSN) to ensure that required actions are followed and completed in a timely manner. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 22 When Eudamed is available, serious incide nts and FSCAs will be submitted via this electronic system only. Manufacturers will report any serious incident immediately after they have established the causal relationship between that incident and their device or that such a causal relationship is re asonably possible. The timeframe to report serious incidents must not exceed the following upper limits:  In the event of a serious public health threat, a report will be submitted not later than 2 days after becoming aware of the threat. (Article 87 (4))  In the event of death or an unanticipated deterioration in a person’s state of health a report will be submitted not later than 10 days after becoming aware of the serious incident. (Article 87 (5))  In all other cases not later than 15 days after becoming aware of the serious incident (Article 87 (3)) Where necessary to ensure timely reporting of serious incidents, the manufacturer may submit an initial report that is incomplete followed up by a complete report. If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report. Serious incidents will be reported only to the competent authority of the country in which the serious incident occurred via Eu damed. The manufacturer will provide a final report to that competent authority via Eudamed setting out its findings from the investigation. The report will set out conclusions and - where relevant - indicate corrective actions to be taken. When the compet ent authority notifies a manufacturer of a suspected serious incident, communicated to the competent authority by a healthcare professional, patient or user, the manufacturer is obliged to:  submit a report of this serious incident to the notifying competen t authority via Eudamed within the timeframes described above;  submit an explanatory statement, to the competent authority, if the manufacturer believes the suspected serious incident does not fulfil the reporting criteria. In case the competent authority disagrees with the explanatory statement provided by the manufacturer a report of the serious incident may be required to be provided to the competent authority that does not agree via Eudamed by the manufacturer. If a FSCA is undertaken, manufacturers wil l without unnecessary delay report the field safety corrective action via Eudamed in advance of the carrying out of the FSCA unless urgency demands the manufacturer to undertake the actions immediately. Manufacturers will ensure that the information relate d to the FSCA is brought without delay to the attention of users of the device in question by means of a FSN. Except in cases of urgency, the content of the draft FSN will be submitted to the evaluating competent authority or to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice will be consistent in all Member States. Manufacturers will also report the FSN(s) to Eudamed. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 23 The FSN w ill allow the correct identification of the manufacturer ( by including the, if issued, SRN), the device or devices affected (by including the relevant UDIs) and the FSN will explain, in a clear manner, without understating the level of risk, the reasons fo r the FSCA. This includes a clear reference to the device deficiency and the associated risks for patients, users or other persons and will clearly indicate all action to be taken by the users. Manufacturers will report by the means of a trend report to Eudamed any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side -effects, when it could have a significant impact on the benefit -risk analysis and which have led o r may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. Manufacturers will, if they exist, follow national provisions in the field of vigilance specifically in but not limited to the case of field safety corrective actions:  The allowed languages used to communicate with users by means of the Field Safety Notice. Manufacturers are asked to check if templates exist (on European Commission website) on any of the reporta ble forms and make sure that all the necessary information according to these templates is provided. This will be only applicable until Eudamed is available. Manufacturers should keep concerned economic operators informed of reported serious incidents and FSCA activities. c) Non-conforming products If a manufacturer has reasons to believe that a device which they have placed on the market or put into service is not in conformity with the MDR they will immediately take the necessary corrective action to bring t hat device into conformity, to withdraw it or to recall it, as appropriate. The manufacturer will inform the distributors of the device in question and, if applicable, the authorised representative and importers. If the device presents a serious risk, the manufacturer will immediately inform the competent authorities of the Member States in which the manufacturer made the device available and, where applicable, the notified body that issued a certificate for the device, in particular, of the non -compliance and of any corrective action taken.

mdcg_2019_3_rev1_cecp_en.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 1 of 4 MDCG 2019 -3 Rev. 1 Interpretation of Article 54(2)b April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 2 of 4 MDCG 2019 -3 Rev. 1 changes Addendum on procedural aspects New Interpretation of Article 54(2)b Article 54(2) of the MDR lays down three criteria that exempt devices from the pre - market clinical evaluation consultation procedure with the involvement of expert panels. In particular that article states that: “The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not ad versely affect the benefit -risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device”. Interpretation of point (b) of Article 54(2) is unclear, notably in relation to the application of the word “marketed”. In fact, while in point “a” the co -legislator explicitly indicates that the certificates referred to are those issued under the new Regulation, in point “b” there is no indication of whether a “device already marketed” refers to devices already marketed under the Directi ves or the Regulations. This has raised questions from the public and from Member States. As we are about to launch the procedures for the establishment of expert panels, clarification of this issue is extremely urgent, notably due to its impact on the fu ture workload of panels and hence on relevant budget and workload estimations. The following considerations seem to indicate that the expression “device already marketed” cannot be intended to refer to a device already marketed uniquely under the new Regu lation :  If the co -legislators had decided to restrict the application of point “b” to devices marketed uniquely under the MDR, they would have explicitly stated so, as they did for point “a”;  Article 54, together with other Articles (such as Article 61(6) and Article 120(3)), was written at the end of the negotiation process with a view to smoothen the Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 3 of 4 implementation of the new Regulation. Therefore the interpretation of the exemption should be understood in line with the spirit and intention of the co - legislators. It has to be noted that, in respect to devices that have been marketed already under the relevant Directives, the word “modification” shall be meant as limited only to those modifications needed in order to comply with the new legal requiremen ts introduced by the MDR1 2. Addendum - Procedural aspects Together with the application to be lodged under the applicable conformity assessment procedure, the manufacturer will provide the notified body with:  a statement that it has marketed the device in question for the same intended purpose under the relevant Directive,  copy of the last issued certificate(s) together with the certificate history, and  a description of the modifications introduced to comply with the MDR As part of its technical documen tation assessment according to the MDR, the notified body will verify that the “modifications”, as referred to in the main document, do not adversely affect the benefit -risk ratio. In particular, the notified body will verify:  that the device in question h ad a valid certificate under the Directives,  in case the certificate has been withdrawn, suspended3 or expired, if there is an impact on compliance with the general safety and performance requirements, and  that there is no pending assessment of changes fo r the device or outstanding non-compliance. In addition, the notified body will verify the description of modifications provided and assess if these modifications are limited only to those needed in order to comply with the new legal requirements introdu ced by the MDR. Limitations of the intended purpose of the device should not trigger the consultation procedure in accordance to Art. 54. 1 These devices will anyhow be subject to all applicable new MDR requirements, including those ones related to the clinical evaluation, and will need to be assessed by notified bodies against these new (and higher) requirements. This aspect together with the increased notified bodies’ oversight foreseen under MDR should guarantee a high standard of safety for these products. 2 From a practical perspective, u nder the scenario where those products had to be subject to clinical evaluation consultation procedure with the involvement of expert panels, as a result of the application of criteria set in Annex IX 5c, in most if not all of the cases, the panel would de cide not to give an opinion. Therefore , a very significant additional workload and financial burden would be created for an extremely limited added value. 3 Certificates for which the rationale for withdrawal or suspension is linked to lack of complian ce with essential requirements may adversely affect the benefit -risk ratio of the device and will require a clinical evaluation consultation procedure. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 4 of 4 In case that any of the abovementioned conditions are not fulfilled the notified body will follow the consultation procedure in accordance to Art. 54. The assessment of the above conditions will be documented by the notified body in accordance with Section 4.6 of Annex VII in the clinical evaluation assessment report that will be made available to competent authorities in accordance with Art. 54 (1) and (3). Clarifications in respect to the applicability of Art. 54(2)b with regard to devices already marketed under the MDR are to be provided in a separate guidance.

mdcg_2019_11_guidance_qualification_classification_software.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-11 MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR October 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 1 of 28 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR Guidance on Qualification and Classification of Software October 201 9 Page 2 of 28 Table of Contents 1. Scope and purpose of this document 3 2. Definitions and abbreviations 3 3. Qualification 6 3.1. Introduction to qualification criteria 6 3.2. Medical Device Software (MDSW) 7 3.3. ‘Software driving or influencing the use of a medical device’ 8 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device 10 4. Classification of MDSW per MDR 2017/745 12 4.1. Implementing Rules 12 4.2. Classification Rules 12 5. Classification and implemen ting rules per IVDR 2017/746 15 5.1. Implementing Rules: 15 5.2. Classification Rules: 15 6. Considerations on placing on the market and conformity asse ssment of MDSW 16 6.1. Option 1: as a medical device in its own right 16 6.2. Option 2: as an integral component/part of a device 17 7. Modules 17 8. Consideration of changes to an MDSW 18 9. Annex I: Illustrative examples of qualifica tion of software used in the healthcare environment 18 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 24 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 26 12. Annex IV – Classification examples 27 Page 3 of 28 1. Scope and purpose of this document This document, which primarily targets medical software manufacturers, defines the criteria for the qualification of software falling within the scope of the new medical devices regulations1 and provides guidance on the application of classification criteria for software under Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR.2 The guidance also provides information related to placing on the market. The classification criteria (classification rules) are set out in Annex VIII of the Medical Devices Regulation (EU) 2017/745 (MDR) and Annex VIII of the In vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR). The criteria specified in this document shall also apply to applications (commonly referred to as apps), may they be operating on a mobile phone, in the cloud or on other platforms. 2. Definitions and abbreviations Intended purpose : According to Regulation (EU) 2017/745 – MDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation;3 According to Regulation (EU) 2017/746 – IVDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements or as specified by the manufacturer in the performance evaluation; 4 Accessory: According to Regulation (EU) 2017/745 – MDR, “Acc essory for a medical device” means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); 5 According to Regulation (EU) 2017/746 – IVDR, “Accessory for an in vitro diagnostic medical device” means an article which, whilst not being itself an in vitro diagnostic medical device, is intended by its manufacturer to be used together with one or several particular in vitro diagnostic medical device(s) to specifically enable the in vitro diagnostic medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the in vitro diagnostic medical device(s) in terms of its/their intended purpose(s);6 Note: Software accessory may be driving or influencing the use of a medical device. Note: Manufacturers must describe in the technical documentation accessories of a medical device or an in vitro diagnostic medical device which are intended to be used in combination with it; and in case 1 The use of “The Medical Devices Regulations” from here on out refers to both Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR. 2 It shall be noted that the term “standalone software” which was used in the text of the medical device directives, is no longer used in the context of the Medical Device Regulation. The rationale of the change is that software should be qualified and classified depending on its intended purpose uniquely, regardless of its location. 3 Article 2(12) of Regulation (EU) 2017/745 – MDR 4 Article 2(12) of Regulation (EU) 2017/746 – IVDR 5 Article 2(2) of Regulation (EU) 2017/745 – MDR 6 Article 2(4) of Regulation (EU) 2017/746 – IVDR Page 4 of 28 of medical devices they must include in the instructions for use information allowing the selection of the corresponding software and accessories.7 Placing on the market: According to Regulation (EU) 2017/745 – MDR, “Placing on the market” means the first making available of a device, other than an investigational device, on the Union market; 8 According to Regulation (EU) 2017/746 – IVDR, “Placing on the market” means the first making available of a device, other than a device for performance study, on the Union market;9 Putting into service: According to Regulation (EU) 2017/745 – MDR, “Put ting into service” means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose;10 According to Regulation (EU) 2017/746 – IVDR, “Putti ng into service” means the stage at which a device, other than a device for performance study, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; 11 Medical device : “medical device” means any instrument, apparatus, appliance, software , implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, - investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, - providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: - devices for the control or support of conception; - products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point.12 Active medical device: “active device” means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; 13 7 Article 32.2(c), Annex I, Chapter III Section 23.4(f), Annex II Section 1.1(h) of Regulation (EU) 2017/745 – MDRArticle 29.2(c) and Annex II Section 1.1(m) of Regulation (EU) 2017/746 – IVDR 8 Article 2(28) of Regulation (EU) 2017/745 – MDR 9 Article 2(21) of Regulation (EU) 2017/746 – IVDR 10 Article 2(29) of Regulation (EU) 2017/745 – MDR 11 Article 2(22) of Regulation (EU) 2017/746 – IVDR 12 Article 2(1) of Regulation (EU) 2017/745 – MDR 13 Article 2(4) of Regulation (EU) 2017/745 – MDR Page 5 of 28 In vitro diagnostic medical device: “In vitro diagnostic medical device” means any medical device which is a reagent, reagent product, calibrator, control material, kit, instru ment, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following: - concerning a physiological or pathological process or state; - concerning congenital physical or mental impairments; - concerning the predisposition to a medical condition or a disease; - to determine the safety and compatibility with potential recipients; - to predict treatment response or reactions; - to define or monitoring therapeutic measures. Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;14 Software: For the purpose of this guidance, “software” is defined as a set of instructions that processes input data and creates output data. Input data : Any data provided to software in order to obtain ou tput data after computation of this data can be considered as input data. Input data examples (non-exhaustive): - Data given through the use of a human data-input device such as a keyboard, mouse, stylus, or touch screen; - Data given through speech recognition; - Digital document: formatted for general purpose such as Word file or pdf file or jpeg image, formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document. Note that digital documents have to be differentiated from software able to read such documents; - Data received from/transmitted by devices. Output data : Any data produced by a software can be considered as an output data. Output data examples (non- exhaustive): - Screen display data (such as layout with number, characters, picture, graphics, etc.); - Print data (such as layout with number, characters, picture, graphics, etc.); - Audio data; - Digital document (formatted for a general purpose such as Word file or pdf file or jpeg image, or formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document). - Haptic buzzing as an alternative to audio sound Software driving or influencing the use of a device Software which is intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: (a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device (b) or supply output related to the (hardware) functioning of that device Note: Software driving or influencing the use of a (hardware) medical device may be qualified as an accessory for a (hardware) medical device. 14 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 6 of 28 Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination, for a purpose as specified in the definition of a “medical device” in the medical devices regulation15 or in vitro diagnostic medical devices regulation.16 3. Qualification 3.1. Introduction to qualification criteria The purpose of this section is to clarify what software is in itself subject to the medical devices regulations. Software must have a medical purpose on its own to be qualified as a medical device software (MDSW). It should be noted that the intended purpose as described by the manufacturer of the software is relevant for the qualification and classification of any device. In order to be qualified as medical device software, the product must first fulfil the definition of software according to this guidance and the definiti on of a medical device according to Article 2(1) of Regulation (EU) 2017/745 – MDR. To be qualified as an in vitro diagnostic medical device software, the product must additionally fulfil the definition of an in vitro diagnostic medical device according to Article 2(2) of Regulati on (EU) 2017/746 – IVDR. Where a given product does not fall under the definition of a medical device, or is excluded by the scope of the Medical Devices Regulations, other Community and/or national legislation may be applicable. Software that does not meet th e definition of a medical device or an in vitro diagnostic medical device (i.e. software that is not MDSW) but is intended by the manufacturer to be an accessory for a medical device, or an in vitro diagnostic medical device, falls respectively under the scope of the Regulation (EU) 2017/745 – MDR or Regulation (EU) 2017/746 – IVDR. Software can directly control a (hardware) medical device (e.g. radiotherapy treatment software), can provide immediate decision-triggering information (e .g. blood glucose meter software), or can provide support for healthcare professionals (e.g. ECG interpretation software). It is important to clarify that not all software used within healthcare is qualified as a medical device. For example, “Simple search”, which refers to the retrieval of records by matching record metadata against record search criteria or to the retrieval of information does not qualify as medical device software (e.g. library functions). However, software which is intended to process, an alyse, create or modify medical information may be qualified as a medical device software if the creation or modification of that information is governed by a medical intended purpose. For example, the software which alters the representation of data for a medical purpose would qualify as a medical device software. (e.g. “searching image for findings that support a clinical hypothesis as to th e diagnosis or evolution of therapy” or “software which locally amplifies the contrast of the finding on an image display so that it serves as a decision support or suggests an action to be taken by the user”). However, altering the representation of data for embellishment/cosmetic or compatibility purposes does not readily qualify the software as medical device software. Software intended for non-medical purposes (excludi ng MDR Annex XVI devices), such as invoicing or staff planning, does not qualify as a medical device software. These software do not fall under the Medical Devices Regulations. 15 Article 2(1) of Regulation (EU) 2017/745 – MDR 16 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 7 of 28 A task such as e-mailing, web or voice messaging, data parsing, word processing, and back-up is by itself not considered as having a medical purpose. Additionally, software may run on different operating systems or in virtual environments. These operating systems or virtual environments do not impact the qualification criteria. It must be highlighted that the risk of harm to patients, users of the software, or any other person, related to the use of the software within healthcare, including a possible malfunction is not a criterion on whether the software qualifies as a medical device. 3.2. Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination , for a purpose as specified in the definition of a “medical device” in the MDR or IVDR, regardless of whether the software is independent or driving or influencing the use of a device. Note 1: MDSW may be independent , by having its own intended medical purpose and thus meeting the definition of a medical device or in vitro diagnostic medical device on its own (i.e. alone ) MDSW that uses maternal parameters such as ag e, concentration of serum markers and information obtained through foetal ultrasound examination for evaluating the risk of trisomy 21. MDSW that receives measurements from transrectal ultrasound findings, age, and in vitro diagnostic instruments and calculates a patient’s risk of developing prostate cancer. Mass Spectrometry MDSW intended to analyse LC-MS/MS data to be used for microorganism identification and detection of antibiotic resistance. MDSW smartwatch app, which is intended to send alarm notifications to the user and/or health practitioner when it recognises irregular heartbeats for the purpose of detecting cardiac arrhythmia. Note 2: If the software drives or influences a (hardware) medical device and also has a medical purpose, then it is qualified as a MDSW Melanoma image analysis software intended to drive a near-infrared laser light scanner. MDSW intended to measure and transmit blood glucose levels, calculate insulin dose required and drive the insulin pump to administer the calculated dosage (closed loop insulin delivery system). Note 3: Software may be qualified as MDSW regardless of its location (e.g. operating in the cloud, on a computer, on a mobile phone, or as an additional functionality on a hardware medical device). MDSW that is intended to operate a point of care test from a remote location. Note 4: MDSW may be intended to be used by healthcare professionals or laypersons (e.g. patients or other users).17, 18 MDSW that provides insulin dose recommendations to a patient regardless of the method of delivery of the prescribed dose, whether via an insulin pump, insulin pen or insulin syringe. 17 Where MDSW is intended to be used by a lay person, the manufacturer shall apply safety and performance requirements outlined in MDR Annex I. 22 and 23.4 (w); or IVDR Annex I. 9.4 and 20.4.2. 18 MDSW which can be considered as an IVD for self-testing shall be considered as a device intended to be used by laypersons. Page 8 of 28 Manufacturers must ensure that all regulatory requirements for placing on the market and conformity assessment have been fulfilled. As set out in Article 7 of MDR and IVDR, this also entails that any claims, relating to the intended medical purpose of their MDSW are supported by clinical evidence. If this is not the case, the software would not meet the requirements of the regulations and therefore may not be CE marked as a medical device, nor present said claims. 3.3. ‘Software driving or influencing the use of a medical device’ Is software intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device b) or supply output related to the (hardware) functioning of that device Note: Software that is driving or influencing the use of a medical device is covered by the medical devices regulations either as a part/component of a device or as an accessory for a medical device. (refer to Figure 2, box 2). Software that is intended to be used to operate a clinical chemistry analyser. Software with built-in electronic controls for IVD quality control procedures. These quality control procedures are intended to provide users with assurance that the device is performing within specifications. Decision steps for qualification of software as MDSW (Figure 1) Decision step 1 : if the product is software according to Section 2 (Definitions and Abbreviations) of this guidance, then it may be a medical device software, proceed to decision step 2; if the product is not software according to the definition of this guidance, then it is not covered by this guidance but may still be covered by the Medical Devices Regulations. Decision step 2 : if the product is an MDR Annex XVI device, or is an accessory for a medical device19, or is software driving or influencing the use of a medical device, then it must be considered as part of that device in its regulatory process or independently if it is an accessory. If it is not, proceed to decision step 3. Decision step 3 : if the software does perform an action on data, or performs an action beyond storage, archival, communication20, simple search, lossless compression (i.e. using a compression procedure that allows the exact reconstruction of the original data) then it may be a medical device software (Refer to section 3.1 for more guidance on these software functions) proceed to step 4. Decision step 4 : is the action for the benefit of individual patients? Examples of software which are not considered as being for the benefit of individual patients are those which are intended only to aggregate population data, provide generic diagnostic or treatment pathways (not directed to individual patients), scientific literature, medical atlases, models and templates as well as software intended only for epidemiological studies or registers. Decision step 5: Is the software medical device software (MDSW) according to the definition of this guidance? 19 According to Article 2(2) of the Medical Devices Regulation or In Vitro Diagnostic Medical Devices Regulation. 20 Communication: The flow of information from one point, known as the source, to another, the receiver; Source: IEEE 610.10-1994. Page 9 of 28 Page 10 of 28 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device Medical Device Software (MDSW) fulfilling the definition of an in vitro diagnostic medical device falls under the in vitro diagnostic medical devices Regulation (EU) 2017/746. Provided that MDSW is intended specifically by its manufacturer to be used together with an in vitro diagnostic medical device to enable it to be used in accordance with its in tended purpose, this MDSW falls under the scope of the in vitro diagnostic medical devices regulation and shall be treated as an In Vitro Diagnostic MDSW (IVD MDSW) in its own right. In cases when software is driving or influencing the use of a (hardware) device, the software should be considered as falling under the respective regulation of the driven or influenced (hardware) device. Software that analyses and interprets the optical density delivered by an ELISA reader, line or spot pattern of a blot. Such software takes raw data outputs and use clinical algorithms for diagnostic and/or prognostic purposes, in which case it qualifies as IVD MDSW. Decision steps for qualification of MDSW as either a medical device or an in vitro diagnostic medical device (Figure 2) Decision Step 1: Does the Medical Device Software (MDSW) provide information within the scope of the in vitro diagnostic medical device definition? MDSW which provides information according to Re gulation (EU) 2017/746 – IVDR Article 2(2) (a) to (f) should qualify as In Vitro Diagnostic Medical Device Software (IVD MDSW) (a) concerning a physiological or pathological process or state (by investigation of this process or state); or (b) concerning congenital physical or mental impairments (c) concerning the predisposition to a medical condition or a disease; (d) to determine the safety and compatibility with potential recipients; (e) to predict treatment response or reactions; (f) to define or monitoring therapeutic measures. A MDSW which falls under the definition set out in EU Article 2 (1) of Regulation (EU) 2017/745 – MDR should qualify as Medical Device Software (MD MDSW). In specific, the following considerations should apply on the prov ision of information by software on: (g) diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease (h) diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, (i) investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, (j) control or support of conception; (k) products specifically intended for the cleaning, disinfection or sterilization of devices as referred to in Article 1(4) and Annex XVI products. Decision Step 2 : Does the MDSW create information based on data obtained by in vitro diagnostic medical devices only? If the information provided is based on data obtained solely from in vitro diagnostic medical devices, then the software is an in vitro diagnostic medical device and is therefore an IVD MDSW. If the data analysed is obtained from a combination of both in vitro diagnostic medical devices and medical devices, proceed to step 3. Page 11 of 28 Decision Step 3 : Is the intended purpose substantially driven by data sources coming from in vitro diagnostic medical devices? If yes, then the appli cable legislation is Regulation (EU) 2017/746. If the intended purpose is substantially driven by data sources coming from medical devices, then the applicable legislation is Regulation (EU) 2017/745. In the condition where the intended purpose of the MDSW output data fulfils both the medical device and in vitro diagnostic medical device definitions set out in the MDR and IVDR (refer to Decision Step 2), a weighting of the data sources based on the significance of the information21 in relation to fulfilling the intended purpose should be conducted to aid the manufacturer in determining which regulation to apply. Annex II of this guidance offers some prescrip tive examples of how such a weighting may be performed. 21 A qualitative approach is intended to drive the weighting of data. The weighing aims to assess the contribution of each data towards achieving the result. Page 12 of 28 4. Classification of MDSW per MDR 2017/745 4.1. Implementing Rules All implementing rules in Annex VIII of Regulation (EU) 2017/745 shall be considered. Special considerations on Implementing Rule 3.3 and 3.5: The first sentence of implementing rule 3.3 of Annex VIII clarifies the regime applicable to software driving or influencing the use of a device: ‘Software, which drives or influences the use of a device, shall fall within the same class as the device’ The second sentence of implementing rule 3.3 of Annex VIII clarifies that the regime applicable to Independent MDSW: ‘If software is independent of any other device, it shall be classified in its own right’ This rule should also be considered at least as an orientation for finding the correct (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. Therefore, Medical Device Software that both achieves its own intended purpose and also drives or influences the use of a (hardware) device for a medical purpose is classified on its own, based on the intended purpose achieved. In such a case, however, the risk class shall not be lower than the risk class of the hardware medical device. Implementing rule 3.5 of Annex VIII is relevant for all devices and states that ‘If several rules, or if, within the same rule, seve ral sub-rules, apply to the same device based on the device’s intended purpose, the strictest rule and sub-rule resulting in higher classification will apply’ Melanoma image analysis software intended to be used with a near-infrared laser light scanner , which is considered class IIa per Rule 10. The software “drives or influences the use of” the near- infrared laser light scanner as it is intended to take control of the scanner by letting it execute proprietary multi-exposure programs for the detection of melanoma. As such, implementing rule 3.3 applies. However, Rule 11 would also apply based on the intended medical purpose of the software e.g. cancer diagnosis. The MDSW would be classified as class III based on Rule 11 (see section Classification Rules) and per implementing rule 3.5 of Annex VIII. 4.2. Classification Rules Rules 9, 10 and 12 mainly categorise the risks related to the exchange of energy/substances between the body and diagnostic or therapeutic active devices, taking into account the different healthcare situations (condition of patients). MDSW, in the majority of cases, does not (directly) relate to such risks. It relates to the consequences of indirect harm from failure to provide correct information. Therefore, in line with Recital 5 of the Medical Device Regulation and international guidance from the IMDRF (International Medical Device Regulators Forum)22, Rule 11 was introduced into the MDR and is intended to address the risks related to the information provided by an active device, such as MDSW. Rule 11, in particular, describes and categorises the significance of the information provided by the active device to the healthcare decision (patient management) in combination with the healthcare situation (patient condition). As software is defined as an active device, for the classification of active (hardware) devices, which also includes MDSW providing information for patient management, Rules 9, 10, 11, 12, 13, 15 and 22 IMDRF is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundational work of the Global Harmonization Task Force on Medical Devices (GHTF) and aims to accelerate international medical device regulatory harmonization and convergence. Page 13 of 28 22 of Annex VIII MDR 2017/ 745 should be considered. In line with implementation rule 3.5, the strictest rule or sub-rule should hence apply. MDSW should be classified in the same way, rega rdless of the software's location or the type of interconnection between the software and a (hardware) device. 4.2.1. Rule 11 – Software for decisions with diagnosis or therapeutic purposes or software intended to monitor physiological processes Rule 11 states: Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: death or an irreversible deterioration of a person's state of health, in which case it is in class III; or a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. The text of Rule 11 can be divided into what are essentially three sub-rules that are applied depending on the intended use/purpose of the MDSW: 11a: (3 first paragraphs of Rule 11) intended to provide information which is used to take decisions with diagnostic or therapeutic purposes; 11b: (Paragraph 4 of Rule 11) intended to monitor physiological processes or parameters; 11c: (Paragraph 5 of Rule 11) all other uses. Sub-rule 11a): The wording “intended to provide information which is used to take decisions with diagnosis or therapeutic purposes” describes, in very general terms, the “mode of action” which is characteristic of all MDSW. Therefore, this sub-rule is generall y applicable to all MDSW (excluding those MDSW that have no medical purpose). Sub-rule 11a), states that MDSW (which is intende d to provide information which is used to take decisions with diagnosis or therapeutic purposes) is classified as class IIa. There are two exceptions from sub-rule 11a) that ar e mainly intended to apply a risk classification based on the significance of the provided information and the potential impact of an (incorrect) decision made using information from the MDSW.23 Accordingly, MDSW that is intended to provide information which is used to take decisions with diagnosis and therapeutic purposes, is at a higher risk class where such decisions, if based on incorrect information from the MDSW, are reasonably likely to have an impact that may cause: i. death or an irreversible deterioration of a person's state of health, in which case it is in class III; ii. serious deterioration of a person's state of health or surgical intervention, in which case it is classified as class IIb. 23 Compare IMDRF/SaMD WG/N12FINAL:2014 which states that there are two major factors that provide adequate description of the intended use of software: A. - Significance of the information provided by the software to the healthcare decision and B. - State of the healthcare situation or patient condition. Page 14 of 28 The MDR contains several references to “serious deterioration of a person’s state of health” and “surgical intervention”, notably in the vigilance or clinical investigation context. Further horizontal guidance could be provided in the future and will be available at: https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en Rule 11 was also introduced to mirror the regulatory guidance developed at international level and notably in the context of the International Medi cal Device Regulators Forum (IMDRF). The IMDRF framework for risk categorisation of software as a medical device (SaMD) (“IMDRF Risk Framework”) categorises the risk of software based on the combination of the significance of the information provided by the software to the healthcare decision and the healthcare situation or patient condition. IMDRF also developed a table for assisting operators in identifying the appropriate risk category for their own product. Such a table could provide operators placing MDSW on the EU market with some useful indications on the risk class applicable to their products as a result of the application of Rule 11 of the MDR. For this purpose, a table is provided in Annex III to this document which lists the IMDRF risk categories and the possible corresponding MDR risk classes accor ding to Rule 11 of the MDR. It must be noted that this table does not take into account MDSW which is Class I. Sub-rule 11b): MDSW that is intended to monitor physiological processes will, under most circumstances, provide “information which is used to take decisions with diagnosis or therapeutic purposes and hence fall under sub-rule 11a. Sub-rule 11b) should therefore be considered as a specific rule for MDSW intended only for monitoring purposes. Sub-rule 11b) was introduced to ensure that MDSW which has the same intended purpose as (hardware) devices which would fall under rule 10, third indent, are in the same risk class. However, this sub rule applies to MDSW intended to be used for monitoring any/all physiological processes and not just vital physiological processes (equivalent to rule 10, third indent). Vital physiological processes and parameters include, for example, respiration, heart rate, cerebral functions, blood gases, blood pressure and body temperature. Sub-rule 11c): Sub-rule 11c) implies that all other MDSW is classified as class I. 4.2.2. Rule 12 – Active devices intended to administer and/or remove substances As software devices cannot physically administer and/or remove substances, please refer to the implementation rule 3.3 of Annex VIII for MDSW covered by this rule. 4.2.3. Rule 13 – All other active devices Taking into consideration all implementing and classification rules applicable to active devices, if no other rule applies, all other active devices are class I. 24 4.2.4. Rule 15 - Devices used for contraception Rule 15 applies to devices used for contraception or prevention of the transmission of sexually transmitted diseases. Software used for contraception will be classified as class IIb. 24 Specific implementation or classification rules for active Annex XVI devices (which might also include software) are expected to be provided together with the relevant Common Specifications for those devices. Page 15 of 28 4.2.5. Rule 22 – Closed loop systems Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. See also implementing rule 3.3 fo r MDSW covered by this rule. Further horizontal Guidance on the application of MD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . This is expected to provide useful orientation in relation to the application of non-software specific classification rules. 5. Classification and implementing rules per IVDR 2017/746 5.1. Implementing Rules: All implementing rules in Annex VIII of Regulation (EU) 2017/746 shall be considered. Special considerations on Implementing Rule 1.4 and 1.9: Implementing rule 1.4 is only applicable for software which drives or influences the use of an in vitro diagnostic medical device. This rule should also be considered at least as an orientation for finding the right (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. According to the second sentence of implementing rule 1.4 , if the software is independent of any other device, it shall be classified in its own right. Examples for applying this implementing rule under the in vitro diagnostic medical devices regulation:  Software that is exclusively intended to drive or influence the use of an instrument intended by the manufacturer specifically to be used for in vitro diagnostic procedures is classified in the same class as the instrument.  A software that is intended to operate (driving) a C-reactive protein (CRP) measuring analyser from a remote location is classified in the same class as the analyser i.e. if the analyser is a classified as class A then the software operating the analyser falls into Class A.  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring; this is an independent IVD MDSW and is classified on its own. Implementing rule 1.9 states that if several classification rules apply to the same device based on the devices’ intended purpose, the rule resulting in higher classification will apply. To classify In Vitro Diagnostic Medical Device Software (IVD MDSW) which is independent of any other device, see the MDCG Guidance on Classification of IVDs when available at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . 5.2. Classification Rules: In determining the proper classification of MDSW under the IVDR, the manufacturer shall consider all classification and implementing rules of Annex VIII of the IVD Regulation (EU) 2017/746. As spelled out by Implementing Rule 1.1 of Annex VIII of Regulation (EU) 2017/746, the application of the classification rules shall be governed by the intended purpose of the MDSW. Page 16 of 28 Guidance on the application of the IVD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en25 Examples for the classification of MDSW under the IVDR:  Software intended to be installed on a fully automated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA, intended to screen for and diagnose diabetes and monitor diabetic patients, should be in class C per Rule 3(k).  Software within a PAP stain automated cervical cytology screening system, intended to classify the PAP cervical smear as either normal or suspicious, should be in class C per Rule 3(h).  Software for the interpretatio n of automated readings of line immunoassay for the confirmation and determination of antibodie s to HIV-1, HIV-1 group O and HIV-2 in human serum and plasma, should be in class D per Rule 1.  Software that uses maternal parameters such as age, concentration of serum markers and information obtained through foetal ultrasound ex amination for evaluating the risk of trisomy 21, should be in class C per Rule 3(l). Classification examples in Annex IV are provided for guidance purposes and aim to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules must also be considered. 6. Considerations on placing on the market and conformity assessment of MDSW The type of interconnection between the MDSW and the device (e.g. embedded systems, wires, Wi-Fi, Bluetooth) does not affect the qualification of the software as a device under the MDR and IVDR (e.g. whether the software is incorporated in a device or is at a different location). However, MDSW can be placed on the market in two different ways: as a medical device or in-vitro diagnostic medical device in its own right or as an integral component or part of a hardware device. 6.1. Option 1: as a medical d evice in its own right MDSW may be placed on the market or put into service in its own right.  MDSW intended to be installed on a fully aut omated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW app that provides a 10-year risk of cardiovascular disease from data input by a lay user.  MDSW app that calculates anticoagulant dosage fo r patients in oral anticoagulant therapy, from INR test results input by IVD instrume nts and other manually entered patient data.  MDSW app that analyses digital images of stained HEp-2 cell substrates from a microscope, for detecting antinuclear antibody (ANA) patterns to guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. Conformity assessment: 25 Please note that at the time of the adoption of this document, the referenced Guidance on the application of IVDR classification and implementing rules was under finalisation. Page 17 of 28 MDSW placed on the market as a device or put into service in its own right shall undergo an appropriate regulatory process that shall take into consideration the qualification, classification and intended purpose of the MDSW. 6.2. Option 2: as an integral component/part of a device MDSW may be placed on the market or put into service as an integral component/part of a device.  MDSW contained within a blood gas analyser that enables a user to run tests on the instrument.  MDSW that is part of a handheld hardware device intended for near-patient testing (POCT: point of care testing) for the determinat ion of the blood glucose concentration.  A fully automated enzyme-linked immunosorb ent assay (ELISA) analyser, composed of hardware and MDSW, intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW that is part of a pulse oximeter intended to digitally filter the noise from low perfusion performance and motion artefacts, to calculate the ratio of red light/infrared light and to use a lookup table based on Beer-Lambert law to convert the ratio into the oxygen saturation in a person’s blood (SpO2). Conformity assessment: MDSW that is placed on the market or put into se rvice solely as an integral component/part of a (hardware) device may not have to undergo its own regulatory process. 26 In this case, the MDSW shall be assessed through the regulatory process applied to the device as a whole, as it is placed on the market. Applying the classification rules to these hardware devices, which is de-facto a combination of the hardware device and the MDSW, requires careful consideration of the intended purpose of the MDSW. This must also be analysed when later changes to the MDSW are done. Note: MDSW could be independent under both scenarios described in 6.1 and 6.2, despite the presentation in which it is placed on the market. 7. Modules Some medical device software may be segregated into a number of applications where each of these applications is correlated with a module. Some of these modules have a medical purpose, some not. Such modules may be intended to cover many needs, e.g.:  Collect and maintain administrative patient data;  Keep on file the medical history of the patient;  Invoicing and other accounting functions;  Provide a link to the social security system for reimbursement;  Provide a link to drug prescription systems (with possible link to drug dispensing outlets);  Provide expert system assistance for medical decision making (e.g. radiotherapy dose planner). 26 Note: MDSW that is intended specifically to replace a part or com ponent of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation (see Article 23.2 (2)). Page 18 of 28 This raises the issue as to whether the whole product can be CE marked when not all applications have a medical purpose. Computer programmes used in healthcare can have applications which consist of both medical device and non-medical device modules. The modules which are subject to the Medical Devices Regulations (figure 1 and 2) must comply with the requirements of the medical device regulations and must carry the CE marking. The non-medical device modules are not subject to the requirements for medical devices. It is the obligation of the manufacturer to identify the boundaries and the interfaces of the different modules. The boundaries of the modules which are subject to the medical device regulations should be clearly identified by the manufacturer based on the intended use. If the modules which are subject to the medical device regulations are intended for use in combination with other modules of the whole software stru cture, other devices or equipment, the whole combination, including the connection system, must be safe and must not impair the specified performances of the modules which are subject to the medical device regulations. 27 8. Consideration of changes to an MDSW Manufacturers shall evaluate the potential impact of any changes to the function, intended use, essential design, and manufacturing characteristics on the software’s qualification as MDSW and its classification (including the classification of the combination of the MDSW with another medical device). It is to be noted that a change to or the addition of functionality to a software may lead it to be qualified as MDSW, or a revision of the classificati on of the MDSW. Similarly, a module that is added to a software might be qualified as a MDSW on its own. When determining the risk class of a combinati on of a modified MDSW and a medical device, the intended purpose and functionality of that (new) combination must be considered. Note: For all MDSW, the manufacturer shall ensure safety and performance throughout the lifecycle of the software, through a continuous process of clinical and/or performance evaluation and risk management. 9. Annex I: Illustrative examples of qualification of software used in the healthcare environment Software for a medical purpose is rapidly evolving. Thus, the list of examples provided below is not exhaustive. The examples have been drafted in light of today’s state of the art, in order to give the reader a better understanding of the application of the principles set out in the guideline. The Manual on borderline and classification in the Community regulatory framework for medical devices contains many examples related to qualification of software and apps, under the current 27 i.e. general safety and performance requirements 14.1 of EU MDR 2017/745 and 13.1 of EU IVDR 2017/746 Page 19 of 28 Directives28. The Manual is currently under revision for adaptation to MDRs. In light of the technological progress, further examples will be regularly published in both the Manual and in this guidance. a) Hospital Information Systems Hospital Information Systems mean, in this context, systems that support the process of patient management. Typically they are intended for patient admission, for scheduling patient appointments, for insurance and billing purposes. These Hospital Information Systems are not qualified as medical devices. However, they may be used with additional modules, as described hereafter. These modules might be qualified in their own right as medical devices. b) Decision Support Software In general, these are computer based tools which combine general medical information databases and algorithms with patient-specific data. They are intended to provide healthcare professionals and/or users with recommendations for diagnosis, prognosis, monitoring and treatment of individual patients. Based on Figure 1, they are qualified as medical devices.  Radiotherapy treatment planning systems 29 are intended to calculate the dosage of ionizing irradiation to be applied to a specific patient . They are considered to control, monitor or directly influence the source of ionizing radiation and are qualified as medical devices.  Drug planning systems (e.g. chemotherapy) are intended to calculate the drug dosage to be administered to a specific patient and therefore are qualified as medical devices.  Computer Aided Detection systems are intended to provide information that may suggest or exclude medical conditions are qualified as medical devices (MDSW). For example, such systems would be able to automatically analyse x-ray images or interpret ECGs. c) Information Systems Information Systems that are intended only to transfer, store, convert, format, archive data are not qualified as medical devices in themselves. However, they may be used with additional modules which maybe qualified in their own right as medical devices (MDSW). c.1.) Electronic Patient Record Systems Electronic patient record systems are intended to store and transfer electronic patient records. They archive all kinds of documents and data related to a specific patient. The electronic patient records should not be qualified as a medical device, i.e. an electronic patient record that simply replaces a patient’s paper file does not meet the definition of a medical device. The modules used with electronic patient record system modules that might be qualified in their own right as medical devices (MDSW) are for example:  An image viewer with functionality for diagnosis based on digital images;  A medication module 28 http://ec.europa.eu/DocsRoom/documents/12867/a ttachments/1/translations/en/renditions/native 29 See EN 62083 “Requirements for the safety and radiotherapy treatment planning systems” Page 20 of 28 c.1.1.) Clinical Information Systems – CIS / Patient Data Manag ement Systems – PDMS A CIS/PDMS is a software-based system primarily intended to store and transfer patient information generated in association with the patient’s intensive care treatment (e.g. intensive care units). Usually the system contains information such as patient identification, vital intensive care parameters and other documented clinical observations. These CIS/PDMS are not qualified as medical devices. Modules that are intended to provide additional information that contributes to diagnosis, therapy and follow-up (e.g. generate alarms) are qualified as medical devices. c.1.2.) Pre-hospital Electrocardiograph (ECG) System A system for managing pre-hospital ECG is a software-based system intended for ambulance services to store and transfer information from patients to a doctor at remote location. Usually the system contains information about patient identification, vital parameters and other documented clinical observations. These Pre-hospital Electrocardiograph (ECG) Systems are not qualified as medical devices. Modules that create and provide new patient treatment information to the paramedics or to the doctor at a remote location to start the patient’s treatment while the patient is being transported are qualified as medical devices. c.1.3.) Picture Archive Communication System (PACS) The Manual on Borderline and Classification in th e Community Regulatory Framework for Medical Devices addresses the qualification of PACS. 30 The transposition of this Directive Guidance to the Regulations is currently underway and will be published at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en d) Communication Systems The healthcare sector uses communication systems (e.g. email systems, mobile telecommunication systems, video communication systems, paging, etc.) to transfer electronic information. Different types of messages are sent such as prescription, referrals, images, patient records, etc. Most of the communication systems handle types of messages other than medical information. This communication system is intended for general purpos es, and is used for transferring both medical and non-medical information. Communication systems are normally based on software for general purposes, and do not fall within the definition of a medical device. Communication system modules might be used with other modules that might be qualified in their own right as medical devices (MDSW). A software module generating alarms based on th e monitoring and analysis of patient specific physiological parameters is qualified as a medical device (MDSW). d.1) Telemedicine systems Telemedicine Systems are intended to allow monitoring and/or delivery of healthcare to patients at locations remote from where the healthcare professional is located. 30 https://ec.europa.eu/docsroom/documents/35582/attachments/1/translations/en/renditions/native Page 21 of 28 d.1.1.) Telesurgery Telesurgery is intended to conduct a surgical procedure from a remote location. Virtual reality technology may be used to support a remote surgeon to control a surgical robot performing the surgical procedure. Telesurgery systems should be qualified as medical devices according to Figure 2 of this document. Remote control software used in combination with telesurgery robots is a software that drives or influences the use of a medical device. Communication modules themselves are not medical devices. Other modules that are intended to influence the su rgery procedure are qualified as medical devices (MDSW). e) Web systems for monitoring of data A web system for the monitoring of clinical data typically interacts with a medical device (e.g. implanted devices or homecare devices), and uses a transmitter to send the information over the internet, a landline telephone or a mobile network. The information is collected and stored on a web server usually run by an external party who is generally the manufacturer of the system. The information can be reached by authorized health professionals or the patient through an internet connection.  Monitoring of performance of medical devices: Modules that are intended to monitor the medical performance of medical devices fall under the medical device regulations. This includes the clinical performance and failures that could affect medical performance of the device. One example of such a product is a web system for monitoring of active implants such as pacemakers or Intra Cardiac Defibrillators (ICDs).  Monitoring of non-medical performance of medical devices Modules that are intended to perform administrative monitoring of non-medical performance of medical devices do not necessarily fall under the scope of the medical devices regulations. Software for the monitoring of medical devices in hospital systems for the purpose of maintenance and repair. f) In vitro diagnostic medical device software f.1.) Laboratory Information Systems (LIS) and Work Area Managers (WAM) Laboratory Information System (LIS) and Work Area Managers (WAM) mean, in this context, systems that support the process from patient sample to patient result. Typically, they have pre- analytical functions for ordering, sorting and distribution of test samples. The main task is the management and validation of incoming information obtained from in vitro diagnostic medical device analysers connected to the system, such as calibration, quality control, product expiry and feedback (e.g. retesting of samples needed) through interconnections with various analytical instruments (technical and clinical validation). Finally the post-analytical process allows communication of laboratory results, statistics and optional reporting to external databases. The software normally supports the following functions:  Ordering of laboratory tests, samples with labels and sorting;  Technical and clinical validation, connection to analytic instruments;  Laboratory results and reports on paper, fax or electronic records that can be directly returned to e.g. the ordering clinic’s patient record;  Analytical instruments can be interfaced with Hospital Information Systems (HIS), Electronic Patient Record Systems, Infectious control databases, etc. Page 22 of 28 Note : software intended to modify the representation of available in vitro diagnostic medical device results is not considered an in vitro diagnostic medical device, e.g. basic operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function of time, and/or a comparison of the result to the limits of acceptance set by the user. The results are available, readable and understandable without the intervention of the software. Laboratory Information Systems (LIS) and Work Area Managers (WAM) are not qualified as medical devices in themselves. However, they may be used with additional modules. These modules might be qualified in their own right as medical devices. A module whose intended purpose is to assess the criticality of tests required and to perform automatic reprioritisation of the order based on patient data is qualified as a MDSW. f.2.) Expert system MDSW which is intended to provide information within the scope of the in vitro diagnostic medical devices definition by capturing and analysing together one or multiple results obtained for one patient by means of in vitro examination of body samples (possibly combined with information from medical devices and non-medical devices).  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring;  MDSW that uses an algorithm to characterise viral resistances to various drugs, based on a nucleotide sequence generated by genotyping assays. This software serves to generate new information (virus resistance profile) from avai lable information on the genotype of the virus;  MDSW intended to be used in microbiology for the identification of clinical isolates and/or the detection of antimicrobial resistances. Refer to Figure 2 of this guidance if data is obtained from both in vitro diagnostic medical devices and medical devices. f.3.) Interpretation of raw data In the case where MDSW is necessary to render raw data, readable for the user, obtained from an in vitro diagnostic medical device by means of in vitro examination of body samples, this MDSW is to be considered driving or influencing the use of the in vitro diagnostic medical device when it is specifically intended to be used together with this in vitro diagnostic medical device to enable it to be used in accordance with its intended purpose. MDSW intended for the analysis and interpretatio n of enzyme-linked immunosorbent assay (ELISA) reader optical density results, line patterns or spot patterns of a blot. f.4.) Home care monitoring, wired or mobile Software intended for archiving patient result s or for transferring results obtained from in vitro diagnostic medical devices from the home environment to the healthcare provider is not an in vitro diagnostic medical device. The results are available, readable and understandable by the user without the intervention of the software. f.5.) Image Management System (IMS) An IMS is a software-based system primarily intended to be networked with digital pathology systems, e.g., whole slide scanners, scanning microscopes, as well as LIS. It does not contain controls for the direct operation of the digital pathology syst ems, and is intended to access, display, annotate, manage, store, archive and share collections of digitised patient images. IMS may be configured to Page 23 of 28 provide limited or extensive capabilities to further visualise or analyse patient images acquired from networked digital pathology systems. An IMS only used for viewing, archiving and transmitting images are not considered medical devices in themselves. However, these IMS may be used with additional modules that might be qualified in their own right as medical devices (MDSW). IMS that incorporate functions to support post-processing of images for diagnostics purposes, e.g., image processing functions which alter image data or complex quantitative functions to aid in diagnosis, are qualified as MDSW. Page 24 of 28 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 Figure 1 - Example 1: A software module which runs on an in vitro diagnostic medical device instrument and tracks how the laboratory is performing in real-time on key operational metrics such as test volumes, turnaround times, pending tests, and quality control. Its intent is to improve a laboratory’s operations by providing real-time monitoring of performance metrics that can drive change management and continuous improvement initiatives within the lab. The software is configurable so that customers can choose the metrics on which they would like to focus. Qualification: Step 1 is concluded with a “yes” as the software is a product which uses a set of instructions (or algorithm) to process input data and create output data. Step 2 determines that the software is not an MDR Annex XVI device, nor is it an accessory for a medical device, nor a software driving or influencing the use of a medical device. Step 3 is answered “yes” since the software is doing more than storage, archival, communication or simple search of information. Step 4 is answered “no” as the software does not perform this action for the benefit of individual patients. The conclusion is that the software does not fall under the Medical Devices Regulations. This is appropriate since the software is intended to be a Laboratory Information Systems (LIS), which is not considered a medical device. Figure 2 - Example 2: MDSW intended to generate a risk score in order to trigger care processes to help reduce ICU transfers, readmissions, adverse events and length of stay. The risk score by default includes respiratory rate, heart rate, blood pressure and Sp O2, but a user can configure it to include other parameters, including in vitro diagnostic medical device results. Qualification: In decision Step 1, the MDSW can be understood to meet criteria (a), (f) and (h), it is therefore answered “yes”. Step 2 is answered with a “No” as an in vitr o diagnostic medical device result may be included in the in the calculation. Step 3 directs the significance of the medical device derived information as driving the intended purpose, re sulting in the qualification of the software as an MD MDSW (as the data received from the in vitro diagnostic medical device is not deemed decisive for the overall calculation result (output) achieved by the MDSW) Figure 2 - Example 3: A MDSW algorithm intended to provide information on the statistical predisposition for Down syndrome (Trisomy 21) and Edwards syndrome (Trisomy 18) in the first and second trimesters of pregnancy. 31 The MDSW analyses input data from various in vitro diagnostic medical device assays32 as well as, ultrasound measurements of the nasal bone or neck fold. The MDSW provides clinicians/obstetricians with a risk factor score for a foetus’s likelihood of having genetic mutations in the first or second trimester of pregnancy. The risk score suggests whether or not additional diagnostic testing is needed to confirm the genetic mutations of Trisomy 21, Trisomy 18. 33 Qualification: Step 1 can be answered “yes” as the software bears a medical purpose and fulfils the definition of MDSW. The MDSW meets criteria (c) as it provides information according to the in vitro 31 The software can also detect neural tube defects (NTD) in the second trimester as well as the risk for Patau’s syndrome (Trisomy 13). 32 AFP (LKAP, L2KAP), Unconjugated Estriol (LKUE3, L2KUE3), hCG (LKCG, L2KCG), free β-hCG (LKFB, L2KFB), PAPP A (LKPC, L2KPC) 33 or neural tube defects and Trisomy 13 Page 25 of 28 diagnostic medical devices definition. Decision step 2 is answered “no” as an imaging measurement is included in the calculation. Step 3 is answered “yes” as the intended purpose is substantially driven by in vitro diagnostic medical device data resulting in the qualification of the software as an IVD MDSW (as the data received from the in vitro diagnostic medical devices (markers) are deemed decisive for the overall calculation result (output) achieved by the MDSW). Figure 2- Example 4: A bioinformatics MDSW intended to analyse digi tal Next Generation Sequencing (NGS) raw data coming from sequenced patient’s cancer genomes. It allows the detection and visualisation of somatic genome alterations (such as substitutions, small insertions and deletions (indels), copy number alterations, and genomic rearrangements) across a selected number of genes. Additionally, it is also capable of determining genomic signatures* (such as microsatellite instability [MSI] and/or tumour mutational burden [TMB]). The types of somatic genome alterations and genomic signatures detected depend on the test chosen. The MDSW assists the user in identifying and visualising genomic alterations and is intended to identify somatic genome alterations to support diagnosis and treatment decisions. Qualification: Decision step 1 is concluded with a “yes” as the MDSW is intended for analysing congenital data to provide information on the predisposition to a medical condition or disease, thus meeting criteria (b) and (c) laid out in the decision step. As the MDSW processes data coming only from in vitro diagnostic medical devices into the calculation, then the software is qualified as an IVD MDSW according to Step 2. Page 26 of 28 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 34 The table below, which is intended for illustrative purposes only, may provide operators placing MDSW on the EU market with some useful indicative orientation on the risk class applicable to their products as a result of the application of Rule 11 a of the MDR. Note: MDR 2017/745 Sub-rule 11(a), point i., referr ing above to MDR class III, aligns with IMDRF risk category IV . Sub-rule 11(a), point ii.,, referring above to MDR class IIb, aligns with IMDRF risk category III products mentioned in section 7.2 of the mentioned IMDRF document. The IMDRF risk category II and IMDRF risk category I products are classified as MDR class IIa as per Rule 11. This table does not take into account MDSW which is Class I. Significance of Information provided by the MDSW to a healthcare situation related to diagnosis/therapy State of Healthcare situation or patient condition High Treat or diagnose ~ IMDRF 5.1.1 Medium Drives clinical management ~ IMDRF 5.1.2 Low Informs clinical management (everything else) Critical situation or patient condition ~ IMDRF 5.2.1 Class III Category IV.i Class IIb Category III.i Class IIa Category II.i Serious situation or patient condition ~ IMDRF 5.2.2 Class IIb Category III.ii Class IIa Category II.ii Class IIa Category I.ii Non-serious situation or patient condition (everything else) Class IIa Category II.iii Class IIa Category I.iii Class IIa Category I.i Table 1: Classification Guidance on Rule 11 34 Annex III and IV are not relevant for IVD MDSW. See sec tion 4.2 in order to classify IVD MDSW. MDCG Guidance on Classification of IVDs should also be considered. Page 27 of 28 12. Annex IV – Classification examples The examples are provided for guidance purposes only, to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules might also be considered. Moreover, the proposed classification reflects the specific intended purpose, or the healthcare context or situation, in which the device is used as described in the example itself. Any change to the intended purpose or the healthcare context/situation in which that same device is used might result in a different risk class.  MDSW intended to perform diagnosis by means of image analysis for making treatment decisions in patients with acute stroke should be classified as class III under Rule 11(a) - IMDRF Risk Category IV.i as the healthcare situation (stroke) is critical and the significance of the information is “treat or diagnose”.  Cognitive therapy MDSW that includes a diagnostic function which is intended to feed back to the software to determine follow-up therapy , e.g. software adapts treatment of depression based on diagnostic feedback, should be in class III per Rule 22 . When a specialist determines the necessary cognitive therapy base d on the outcome provided by the MDSW, the MDSW would be classified as class IIa per Rule 11(a). - IMDRF Risk Category II.ii as the healthcare situation is serious and the significance of the information is to “drive clinical management”.  Medical devices including MDSW intended to be used for continuous surveillance of vital physiological processes in anaesthesia, intensive care or emergency care should be classified as class IIb per (Rule 11(b)) .  Medical devices, including MDSW intended to monitor physiological processes that are not considered to be vital, and devices intended to be used to obtain readings of vital physiological signals in routine check-ups incl uding monitoring at home should be classified as class IIa (Rule 11(b)).  A mobile app intended to analyse a user’s he artbeat, detect abnormalities and inform a physician accordingly should be classified as class IIb per Rule 11(a) , if the information provided by the software is intended to guide the physician in the diagnosis. - IMDRF Risk Category III.i as the information drives clinical management.  Diagnostic MDSW intended for scoring depression based on inputted data on a patient’s symptoms (e.g. mood, anxiety) should be classified as class IIb under Rule 11(a) , - (IMDRF Risk Category III.ii) as the healthcare situation (depression) is serious and the significance of the information is “diagnosis”).  Ambulatory respiratory ventilation systems MD SW intended for long-term use (e.g. at home) that alert the user/operator to any disconnection or deviation to the programmed respiratory volume should be classified as class IIb per Rule 9 .  Active devices, such as electronic thermometers and stethoscopes, which include MDSW intended for direct diagnosis may be classified as class IIa per Rule 10 , third indent since body temperature and heart rate are considered decisive information for diagnosis (implementing rule 3.7), where the nature of the variations of these parameters would not result in immediate danger to the patient.  MDSW intended to rank therapeutic suggestions for a health care professional based on patient history, imaging test results, and patient characteristics, for example, MDSW that lists and ranks all available chemotherapy options for BRCA-positive individuals, should be classified as class IIa per Rule 11(a) Page 28 of 28 - IMDRF Risk Category II.i as it informs clinical management for cancer, a critical disease.  MDSW app intended to support conception by calculating the user’s fertility status based on a validated statistical algorithm. The user inputs health data including basal body temperature (BBT) and menstruation days to track and predict ovulation. The fertility status of the current day is reflected by one of three indicator lights: red (fertile), green (infertile) or yellow (learning phase/cycle fluctuation). This MDSW app should be classified as class I per Rule 11c.

md_mfr_factsheet.pdf.txt

Factsheet for Manufacturers of Medical Devices What you need to know!MEDICAL DEVICES CHANGE OF LEGISLATION This Factsheet is aimed at manufacturers of medical devices. For a general overview of the impact of the In-Vitro Medical Devices Regulation (IVDR) on manufacturers see the Factsheet for manufacturers of in-vitro diagnostic medical devices. Refer - ences to Annexes and Articles in this factsheet refer to the MDR (2017/745/EU). The new Medical Devices Regulation (2017/745/EU) (MDR) and the In-vitro Diagnostic Medical Devices Regulation (2017/746/EU) (IVDR) bring EU legislation into line with technical advances, chang - es in medical science, and progress in law making. The new Regulations will create a robust, transparent, and sustainable regulatory framework, recognised internationally, that improves clinical safety and creates fair market access for manufacturers. In contrast to Directives, Regulations do not need to be transposed into national law. The MDR and the IVDR will therefore reduce the risks of discrepancies in inter - pretation across the EU market. Transitional periods are planned to smooth the application of the new Regulations. However, you should bear in mind that con - sultants, in-house professionals, and Notified Bodies will all get busier as the deadline draws closer. Act now to be ready on time! Medical Devices Regulation (MDR) background The MDR will replace the existing Medical Devices Directive (93/42/EEC) (MDD) and the Active Implantable Medical Devices Directive (90/385/EEC) (AIMDD). The MDR was published in May 2017, marking the start of a three-year period of transition from the MDD and the AIMDD. During the transitional period the MDR will come into force gradually, start - ing with the provisions related to the designation of Notified Bodies and the ability of manufacturers to apply for new certificates under the MDR. The transitional period will end on 26 May 2020, the “Date of Application” (DoA) of the Regulation. From that date the MDR will apply fully. 1 Internal market, Industry, Entrepreneurship and SMEs Ref. Ares(2018)3873669 - 20/07/20182To avoid market disruption and allow a smooth transition from the Directives to the Regulation, several transitional provisions are in place (Article 120). Some devices with certificates issued under the Directives (AIMDD/MDD certificates) may continue to be placed on the market until 27 May 20241, and made avail - able until 27 May 20252 . During the transition phase, products certified under the Direc - tives and products certified under the Regulation will coexist on the market. Both will have equal status under the law, and no discrimination in public tenders may take place. What has changed? In terms of their impacts on manufacturers and products, the Directives and the MDR largely share the same basic regulatory requirements. No existing requirements have been removed, but the MDR adds new requirements. Compared to the current Directives, the MDR places more em - phasis on a life-cycle approach to safety, backed up by clinical data. The MDR brings more stringent requirements for the designation of Notified Bodies, with increased control and monitoring by the national competent authorities and the Commission. The MDR reclassifies certain devices and has a wider scope. For instance, the MDR explicitly covers all devices for cleaning, sterilising or disinfecting other medical devices (Article 2.1); re - processed single-use medical devices (Article 17)3; and certain devices with no intended medical purpose (Annex XVI). The MDR also covers internet sales of medical devices and med - ical devices used for diagnostic or therapeutic services offered at a distance (Article 6). The MDR introduces a clinical evaluation consultation procedure for some Class IIb devices and for implantable Class III devices by an independent expert panel (Article 54). A new Unique Device Identification system (Article 27) will significantly enhance the traceability and the effectiveness of post-market safety-related activities. The MDR will also provide increased transparency, with infor - mation on devices and studies being made public. The new Eu - ropean Database for Medical Devices – Eudamed – will play a central role in making data available and increasing both the quantity and quality of data (Article 33). 1 For definition see Article 2 paragraph 282 2 For definition see Article 2 paragraph 27 3 Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 4 EEA: European Economic Area What does this mean in practice? Scope (Article 1) The scope of the MDR has broadened, so as a manufacturer you must check your product portfolios to find out whether more of your devices fall within the scope of the Regulation compared to the Directives. Pay attention to products listed in Annex XVI, which will be covered by the Regulation once the respective Im - plementing Regulation setting out common specifications has been adopted. The list of products excluded from the scope can be found in paragraph 6. Some products that combined a medi - cal device and an in-vitro diagnostic device or a medicinal prod - uct follow specific rules (see paragraphs 7, 8, 9). It is now explicit that devices and services sold online fall under the scope of this Regulation (Article 6). Definitions (Article 2) The definition of a medical device has been slightly modified and there are more definitions of terms in the Regulation than in the Directives, in order to ensure a common understanding at EU level. Examples include: Unique Device Identifier (Definition 15), clinical data (Definition 48), clinical evidence (Definition 51), and serious incident (Definition 65). Obligations of manufacturers The obligations of the different actors and their relations are now clearly stated in the Regulation. According to Article 10, manufacturers shall have systems for risk management (paragraph 2) and quality management (paragraph 9); conduct clinical evaluations (paragraph 3); com - pile technical documentation (paragraph 4); and apply a confor - mity assessment procedure (paragraph 6). Manufacturers are also responsible for their devices once they are on the market (paragraphs 12, 13, 14). They must have systems in place to cover their financial responsibility for harm caused by defective devices (paragraph 16). Every manufacturer shall have a named person responsible for regulatory compliance (Article 15). Manufacturers of some implantable devices will have to provide an implant card for the patient (Article 18). Once they have completed all these obligations, manufacturers shall draw up a declaration of conformity (Article 19) and apply CE marking to their devices (Article 20). Manufacturers outside the EU/EEA shall have a contract with an authorised representative inside the EU/EEA4 (Article 11).3The obligations of authorised representatives (Article 11), importers (Article 13) and distributors (Article 14) are also clearly described. Risk classes of devices As a manufacturer you must check your portfolio of products to determine whether some of your devices will be reclassified or will need to be scrutinised by a Notified Body. Determining the risk class of a medical device is essential in specifying the steps required for CE marking (Article 51), especially in terms of the choice of conformity assessment procedure and clinical requirements. The MDR sets out 22 rules for determining risk classes (Annex VIII), compared to 18 rules under the Directive. You should pay special attention to rules regarding: invasive devices, surgically invasive devices and implantable devices (Section 5: Rules 5 to 8); active devices (Section 6: Rules 9 to 13, for example, soft - ware now falls under Rule 11); devices utilising tissues and cells (Rule 18); devices incorporating nanomaterials (Rule 19); and devices composed of substances (Rule 21). Notified Bodies (Chapter IV) Notified Bodies have to be designated under the new Regula - tion. They will be required to meet more stringent criteria, par - ticularly in terms of clinical competence. Notified Bodies can apply to be designated from 26 November 2017. The process of designation, which might take 12 months or more, involves assessors from different national and European authorities. This means that the first Notified Bodies designated under the new Regulation might be available by the end of 2018. The database of Notified Bodies (NANDO) can be found here. http://ec.europa.eu/growth/tools-databases/nando/ As a manufacturer you must verify whether your Notified Body will be designated under the new Regulation and whether the scope of its designation will cover all your products. You must also start working with your Notified Body to plan the timing of certification for your product portfolio, taking into account the availability of your Notified Body, the need for additional data on devices and the transitional provisions in the new Regulation. Device identification A system of unique device identifiers (UDIs) will enhance the identification (Article 27) and traceability (Article 25) of MDs. This is a completely new feature of the Regulation. Each MD – and as applicable, each package – will have a UDI composed of two parts: a device identifier (UDI-DI) specific to a device, and a production identifier (UDI-PI) to identify the unit producing the device.Manufacturers are responsible for entering the necessary data on the European database (Eudamed), which includes the UDI database, and for keeping it up to date. Conformity assessment (Chapter V Section 2) The assessment of the conformity of a device for CE marking varies according to the risk class and specific features of certain devices (Article 52). The intervention of a Notified Body is need - ed for all Class IIa, IIb and III devices, as well as some specific Class I devices (see paragraphs 7a5, b6, and c7). The different routes of assessment according to the class of the device are described in Article 52 and the Annexes IX, X, XI. In some cases manufacturers have some choice regarding the conformity as - sessment route. For certain Class III and Class IIb devices there is a new clinical evaluation consultation procedure to be carried out by an inde - pendent expert panel, based on the clinical evaluation assess - ment report of the Notified Body (Article 54). Annex I specifies the general safety and performance require - ments, while Annexes II and III specify the makeup of the tech - nical documentation. The scope of the Quality Management System (Article 10 para - graph 9) now includes clinical evaluation and post-marketing clinical follow-up (PMCF). A clinical evaluation plan must pre - cede the clinical evaluation itself (Annex XIV, Part A). Common specifications defining additional requirements may be put in place for certain devices (Article 9). Clinical requirements (Chapter VI) The new Regulation reinforces the requirements for clinical evaluation (Article 61), introducing some of the biggest changes compared to the previous regime. As under the Directives, it includes the collection of clinical data already available in the literature as well as the setting up of any necessary clinical investigations. The concept of equiva - lence with other devices for which clinical data already exists can still be used, but only in a limited number of situations, and the new rules are tighter (Article 61 paragraphs 4, 5, 6). Article 62 and Annex XV set out the new and more precise re - quirements for clinical investigations. With only certain excep - tions, implantable and Class III medical devices must now go through clinical investigations. For all Class III devices, and for Class IIb devices intended to administer a medicinal product (or remove it from the body), the manufacturer has the option to consult a group of European experts to obtain an upstream review of its intended clinical de - velopment strategy (Article 61 paragraph 2). 5 “Devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions”. 6 “Devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements”. 7 “Reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use”.4Summary of safety and clinical performance (Article 32) For Class III and implantable devices, manufacturers shall draw up a summary of their safety and clinical performance in a form that intended users (and patients, if relevant) can understand. This summary will form part of the technical documentation sent to the Notified Body Timing your transition to the new Regulation As a manufacturer, the timing of your transition to the MDR is up to you. From 26 May 2020, all new certificates will have to be delivered according to the Regulation. The certificates delivered under the Directives can be valid until their date of validity for a maximum of four years (27 May 20248 at the latest). However, in the latter case, the requirements of the new Regulation relating to post-mar - ket surveillance, market surveillance, vigilance, and the registration of economic operators and devices shall apply from the Date of Application (Article 120 paragraph 3). Class I devices (other than those that have a valid certificate under the Directive) will have to conform to the new Regulation from 26 May 2020. Class I (except sterile devices, devices with a measuring func - tion and reusable surgical instruments) and Class IIa might be easiest to start with. Classes IIb and III will be more challenging because of the more stringent requirements for clinical data. As a manufacturer, you can start now by making sure that: 1. all your products are classified appropriately; 2. all product documentation and evidence of compliance will be available in a timely fashion and conforms with the MDR; and 3. you have the necessary systems in place to handle clinical evaluation, quality management, post-market surveillance, and liability for defective devices. More information For more information on any of the above topics, please refer to the Medical Devices section on the DG GROW website. https://ec.europa.eu/growth/sectors/medical-devices_en Frequently asked questions Below you can find an extract from the FAQs of the Competent Authorities for Medical Devices. For a complete list, see: http://www.camd-europe.eu/sites/default/files/media/docu - ments/FAQ_MDR_180117_V1.0.pdf . When does the Medical Devices Regulation (MDR) apply? The MDR (EU) 2017/745 will apply from 26 May 2020 – the “Date of Application” (DoA). Some provisions of the MDR will come into force earlier (e.g. regarding Notified Bodies and the Medical Device Coordination Group). Some will apply later (e.g. regarding UDI labelling). When do the existing Directive cease to apply? In general, Directives 90/385/EEC and 93/42/EEC will be repealed on 26 May 2020 (the DoA). However, there are some exceptions, such as: • for the continued marketing of devices that comply with the Directives (see below); and • to serve as a backup in case Eudamed is not fully functional by the DoA. What is the applicable legislation up to 26 May 2020? Until the Date of Application, the laws and regulations adopted by Member States in accordance with the Directives will contin - ue to apply. However, there are some exceptions. Is it possible to place devices on the market that are compliant with the MDR prior to the DoA? Yes, you may certainly place MDR-compliant devices on the market before the end of the transitional period. This applies to devices in all risk classes, and includes, for example, cus - tom-made devices, systems and procedure packs. However, devices subject to the “clinical evaluation consultation procedure”, which covers certain devices in Classes IIb and III, may not be placed on the market before the Medical Device Coordination Group (MDCG) and the expert panels have been established. Depending on the risk class of the device, conformity assess - ment may involve an appropriate Notified Body. This require - ment may create further delays before such devices can be marketed due to the delays in the availability of appropriate Notified Bodies for all technologies. 8 There are some exceptions described in Article 120 paragraph 25As a manufacturer, which obligations of the Regulation do I need to fulfil in order to place compliant devices on the market before the DoA? You should meet as many obligations as possible, bearing in mind that the complete MDR infrastructure, including Eudamed, is unlikely to be complete before the Date of Application. Both the device and the manufacturer must comply with the MDR. You should assess the conformity of your device – a pro - cess that may require the involvement of a Notified Body. Other important points include: • Clinical evaluation • Risk management • Quality Management System (QMS) • Post-market surveillance • Technical documentation and other reports • Liability for defective devices. Until Eudamed is fully operational, some parts of the Directives will have to substitute for the corresponding requirements of the Regulation. These include the registration of devices and economic operators. A person responsible for regulatory compliance needs to be available but not necessarily registered until Eudamed is operational. Do certificates issued by Notified Bodies under the existing Directives remain valid after the DoA? Yes, AIMDD/MDD certificates will generally remain valid un - til their indicated expiry dates. This applies to all the certifi - cates commonly issued by Notified Bodies, including the EC Design- Examination Certificates, Certificates of Conformity, EC Type Examination Certificates, the EC Certificate Full Quality Assurance System, and the EC Certificate Production Quality Assurance.However, all certificates issued after 25 May 2017 will be void at the latest by 27 May 2024. After this date there will be no more valid AIMDD/MDD certificates. Is it possible to have valid MDR and AIMDD/MDD certificates in parallel until 27 May 2024? Yes. Can manufacturers still place on the market/put into service Directive-compliant devices after the end of the transition period? Yes, under certain conditions there will be an option to con - tinue placing on the market/putting into service devices that comply with the Directives until their existing certificates ex - pire. This may avoid the immediate need for a new certificate under the MDR. To use this option, all the existing certificates will have to be val - id (including, for example, the QMS), the purpose and nature of the device must not change, and you must follow the new MDR rules for registration, surveillance and vigilance. What is the “sell-off” provision about? The “sell-off” provision is intended to limit the time during which devices that are compliant with the Directives and have already been placed on the market may be made available. Any devices that are still within the supply chain and that have not reached their final user as being ready for use, for example a hospital, on 27 May 2025 are no longer marketable and must be withdrawn. Once a Directive-compliant device has been made available to the final user by the deadline, the further making available of this device is not subject to/covered by the Regulation. © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89634-7 DOI: 10.2873/614436 ET-03-18-102-EN-N

cnd_general_principles_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 13 The CND Nomenclature ‘Classificazione Nazionale Dispositivi medici’ Table of Contents 1. Background and General Principles ................................ ................................ ................................ ...... 2 2. The CND structure ................................ ................................ ................................ ................................ .. 4 Anatomic Categories – by anatomical area of use: ................................ ................................ ................... 6 Functional Categories – by intended use or clinical method: ................................ ................................ .... 6 Special Categories – by other criteria: ................................ ................................ ................................ ....... 6 Groups: the second hierarchical level ................................ ................................ ................................ ........ 7 Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) ........... 7 3. External links ................................ ................................ ................................ ................................ ........... 8 The purpose of this document is to provide information regarding the basic principles and the structure of the Italian “Classificazione Nazionale Dispositivi medici” (CND) . In March 2019, an d according to the criteri a set out by the Medical Device Coordination Group1 (MDCG) , the CND was selected as the basis for the future European M edical Device Nomenclature (EMDN ). The EMDN will support the functi oning of EUDAMED as stated by the MDCG and in accordance with Articles 23 of Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 2 of 13 1. Background and General Principles2 In 2005, the Italian Ministry of Health set out that the CND would be the official Italian medical device classification and nomenclature. Since then, t he CND has been implemented not only in Italy, but also in Portugal and Greece. About 15.000 manufacturers3 from various countries have used the CND for the registration of medical devices and in vitro diagnostic medical devices in the Italian database. The distribution of manufacturers of medical devices and in vitro diagnostic medical devices per countr y is reported below in Figure 1. Fig. 1 Distribution of manufacturers of medical devices per countr y The CND nomenclature is one of the tools used in the governance of the medical device sector and is characteri sed by its refined and hierarchical structure . It aims to support the improvement of patient safety and the quality of health systems by enabling information to be communicated in a standard ised manner . Updates and maintenance of CND: 2 The principles and rules presented thereafter are the ones historically established/followed when building the CND nomenclature u p to the last update in 2018. This is without prejudice to the new rules that will govern the EMDN which will be established by th e MDCG. 3 Source NSIS: data updated on 10 August 2019 31,6% 15,2% 10,2% 9,8% 3,9% 3,6% 2,7% 2,5% 2,0% 18,5% 0,0%5,0%10,0%15,0%20,0%25,0%30,0%35,0%Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 3 of 13 The construction of the CND , its subsequent updates and maintenance have been based on three fundamental principles. A) Participative approach: For the update and maintenance of a qualitative nomenclature, highly differentiated and qualified expertise is required. As the medical device sector is acknowledged for its heterogeneity and complex ity, a broad participation of all stakeholders (economic operators and healthcare professional from NHS - at all levels of its organisation ) is essential. B) Qualified validation of proposals : Nomenclature and Classification proposals are technically validated based on assessment s of actual need . Factors taken into consideration are:  other existing nomenclature and classification systems available at international level  consumption and expense information  assessment with sector experts from the different disciplines C) Formal adoption and free public availability: The CND system , which represents the basis of the whole information system on medical devices is formally approved and thus constitutes an offici al reference, freely available to all stakeholders. More information on previous updates of the CND up to 2018 can be found in Annex I of this document. The following pr oducts are currently not included in the CND :  Medicinal products  Cosmetics products  Human blood and its derivatives;  Organs, tissues and cells of human origin, products including human tissues and cells and products derived therefrom.  Organs, tissues and cells of animal origin except medical devices manufactured using animal devitalized tissues o r devitalized products derived from animal tissue.  Individual Protection Devices Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 4 of 13 2. he CND structure The CND is characterised by its alphanumeric structure that is established in a multi -level hierarchical tree . It clusters medical devices in three main levels:  Category: the first hierarchical level  Group: the second hierarchical level  Type: the third hierarchical level (which if necessary, expands into several levels of detail (1°, 2°, 3°, 4° e 5°)) Each medical device is classified by an alphanumeric code consisting of a letter referring to the “Category”, a couple of numbers referring to the “Group” and a series of other couples of numbers referring to the “Type” (whose amount depends on the level o f detail) up to a maximum of 7 levels . Each level isidentified by: •an alphanumeric code (max 13 digits ) A ## ## ## ## ## ## Level 1: C ategoriesLevel 2: GroupsLevel from 3 to 7: TypesMedical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 5 of 13 Categories: the first hierarchical level The first hierarchical level of the CND is defined as a “Category”. There are 22 categories, each identif ied by a letter of the alphabet: Each “Category ” includes devices regulated under Directive 93/42/EEC, 90/385/EEC or 98/79/EC or following a dedicated prescription from reimbursement rules in Italy. These “categories” are used for the same specific apparatus, anatomical district or organ or as a replace ment of them (anatomical categories), or devices characterised by similar use, intended use or clinical m ethod (functional categories). Considering these criteria and the ramified tree structure with different detail level, the following Anatomic (8), Fun ctional (9) and Special (5) Categories have been defined: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 6 of 13 Anatomic Categories – by anatomic al area of use: • B – HEMATOLOGY AND HEMOTRANSFUSION DEVICES • C – CARDIOCIRCULATORY DEVICES • F – DYALISIS DEVICES • G – GASTROINTESTINAL DEVICES • N – DEVICES FOR NERVOUS AND MEDULLAR SYSTEMS • Q – DENTAL, OPHTALMOLOGIC AND ENT DEVICES • R – RESPIRATORY SISTEM AND ANAESTHESIA DEVICES • U –UROGENITAL APPARATUS DEVICES Functional Categories – by intended use or clinical method: • A – DEVICES FOR ADMINISTRATION, COLLECTING AND PICKING • D – DISINFECTANTS, ANTISEPTICS AND P ROTEOLYTICS FOR MEDICAL DEVICES (regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • H – SUTURE DEVICES • K – ENDOTHERAPY AND ELECTROSURGICAL DEVICES • L – REUSABLE SURGICAL INSTRUMENT S • M – DEVICES FOR GENERIC AND SPECIALISTIC MEDICATION • S – STERILIZATION DEVICES • T – PROTECTION DEVICES AND INCONTINENCE AIDS ( regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • V – MEDICAL DEVICES - VARIOUS Special Categories – by other criteria : • J – ACTIVE -IMPLANTABLE DEVICES : MDs regulated by Directive 385/90 EEC • P – IMPLANTABLE PROSTHETIC DEVICES AND OSTEOSYNTHESIS DEVICES : non-active implantable MDs • Y – SUPPORTS OR TECHNICAL AIDS FOR DISABLED PERSONS • W – IN VITRO DIAGNOSTIC DEVICES MDs regulated by Directive 98/79 EEC • Z – MEDICAL EQUIPMENT AND RELATED ACCESSORIES AND MATERIALS Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 7 of 13 Groups : the second hierarchical level The second hierarchical level s are called “Group s”. There are 146 anatomical/functional Medical Devices Gr oups 4, which represent the various differentiations that distinguish devices contained in the Categories. They are identified by two -digit nu mbers from 01 to 99 for each Category. Number “90” identifies the gr oups of devices having various characteristics that are not related to existing gro ups. Number “99” “Altri – Others” is reserved to medical d evices that are not included in already existing Groups and will be categori sed in later updates. Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) The “Type” represents the third hierarchical level . If necessary, it expands into several level s of detail (1°, 2°, 3°, 4° and 5°). The group of every type includes medical devices characteri sed by a high affinity of use, intended use or s imilar clinical method. In case of doubt, the peculiar characteristics of the medical device under examination should be considered for a proper collocation or search proces s (i.e. the anatomic -functional characteristics and/or the intended use declared by the manufacture r). As explained, the term “ot hers” marked with the code “99 ”on the first detail level is suitable for devices not included i n existing types. The “99” types will be submitted for later updates. Th e code reserved to the generic term “others” must be used by users only if it is not possible to classify the medical device in existing typologies . This type is subject to continuous checks and monitoring. Regarding accessories, e very accessory follows the CND classification code of the medical device that it is associated with , according to the intended use given by the manufacturer . If an accessory can be used with multiple medical devices belonging to several group s, it must be placed in the prevalent type. 4 Updated as of the Italian Ministerial Decree of 13 March 2018. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 8 of 13 3. External links For more information, please consult the Italian Ministry website at: http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=328&area=dispositivi - medici&menu=classificazione The fo llowing documents may also be of use :  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 ( PDF format)  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 (XLSX format)  English translation of National Classification of Medical Devices Codes (as modified by Minister ial Decree 13.03.2018 -pdf, format).  English translation of National Classification of Medical Devices Codes (as modified by Ministerial Decree 13.03.2018 -XLSX format).  Search code and description of the CND  Search in alphabetical order Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 9 of 13 Annex I – CND updates up to 2018 The periodical updating process of the CND was schematically subdivided into four main phases:  Phase 1: Collection of proposals This phase is open to all stakeholders who submit proposals for the definition of new classifications or for the revision of existing ones.  Phase 2: Preliminary technical evaluation and elaboration of the proposal. The MoH MD Technical Team (MDTT) analyses th e collected proposals, the existing systems and the contents of the medical devices database to identify elements useful for classification.  Phase 3: “Widespread validation” of the proposal. The proposal is formally evaluated in three steps: A) the regional levels of the NHS involving clinical professionals in technical sessions B) Technical Health Committee - medical devices section of the Ministry of Health C) State - Regions Conference  Phase 4: Formal adoption of the proposal Finally, the proposal is approved by formal MoH act and published on the Italian Official journal as well as the website of the Italian MoH Most of the inputs adopted for updating purposes are listed below:  The analysis of the terminal typologies "90" and "99": Implemented and consolidated, it originates from the analysis of information within the Italian databank and consider s data from all the medical device s registered and classified in the CND terminal types with code " 90" ( - various) and "99" ( - other) of specific categories or groups identified. In fact, the classification system had already foreseen ab origine that medical devices that are not placed in a specific “typology” are classified in the generic typologies in dicated with the codes 90 and 99.  Manufacturer requests: When a manufacturer is unable to classify a medical device in an appropriate way inside the CND terminal level, a specific request for the introduction of a new CND class is required, with a communic ation to the MoH of a rationale and the technical characteristics and / or intended use that differentiate the device from the specific terminal classes already represented in the CND.  The analysis of CND coming from vigilance system: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 10 of 13 Market surveillance and the vigilance system are part of the institutional activities of the MOH. The lack of classificatory level can emerge in order to identify products that need particular attention for public health. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 11 of 13  The analysis of consumption by the NHS: The revision of the CND made through the processing of the consumption data of the Monitoring Database is based on identification of medical devices with great economic relevance or price variability.  The analysis coming from HTA Report s: Health Technology Assessment documents are periodically published by the Ministry of Health. These reports are considered when evaluating the revision of the CND. The following principles were considered in the revision of the CND:  the number of levels in the CND structure can be inc reased up to a maximum of seven, by coherently applying the homogeneity of the classification rules and of the coding system defined for the first CND structure.  for the definition of a new CND branch the number of manufacturers manufacturing the medical devices that will be placed in the new typology of the CND should be more than 1;  significant characteristics of medical devices detected by NHS professionals should be evaluated  the proposal of relocation of medical devices placed in class 90 or 99 should be consistent.  for the definition of a new CND branch significant differences of price between similar medical devices could be considered if necessary:  for the definition of a new CND branch an assessments related to the use of medical devices is conside red (quantity and number of users in NHS); For each update proposal of the CND, the information associated to the devices registered in the Italian database were analysed and, if necessary, the information detect ed by the “Consumption Monitoring Database” were processed. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 12 of 13 Annex II – CND VERSIONS Art. No. 57 of the Italian Law n° 289 of the 27 December 2002 stated the requirement of the establishment of a Commission on Medical Devices (CUD) as a technical advisory board to the Ministry of H ealth. The CUD has the task of defining and updating the repertoire of medical devices and classifying all medical devices in specific classes and sub -classes. The CUD d efined the first version of the Classificazione Nazionale dei Dispositivi Medici (CND) on July 2005 (Italian Ministerial Decree of 22 Sept .2005). In Vitro Diagnostic Medical Devices (regulated by European Directive No. 98/79 EEC and Italian Legislative De cree No. 332/2000) were not included in the first version of the Classification , although they belong to a class of Medical Devices. The Italian Financial Law of 2006 (Law No. 266 of the year 2005, art. 1, par. 409) established that the CND has to be appr oved by a decree of the Minister of Health in agreement with the State - Regions Conference. The CUD considered it appropriate to review and update the CND with the inclusion of in vitro diagnostic medical devices before proceeding with the State -Regions Con ference . Therefore, on 20 February 2007 , and after a revision of the classification, the Health Minister decreed the approval of the Classificazione Nazionale dei Dispositivi Medici (CND) drawn up by the CUD. The classification refers to the medical device s regulated by Italian legislative decrees N°. 507/92, N°. 46/97, N°. 332/2000 and subsequent amendments. In 28 March2013, the Italian D.P.R. n.44, replaced the Commission on Medical Devices (CUD) with the Technical Committee section F on medical devices. The Classification represented the first step towards the establishment of the Italian Repertoire of the Medical Devices. According to the art. N° 2 of The Italian Financial Law No. 266, the Technical Committee section F (previously CUD) , review the CND a nd make the necessary changes and updates. Every update is approved by a Ministerial Decree: 1. Decree of the Italian Ministry of Health (13 Mar 2008) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in th e Official Gazette - GU No. 125 of 29/05/2008. Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_2_file.pdf Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 13 of 13 www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_3_file.xls 2. Decree of the Italian Ministry of Health (12 Feb 2010) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.119 of 24/05/2010. Links: http://www.salute.gov.it/imgs/C_1 7_pagineAree_328_listaFile_itemName_5_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_7_file.xls 3. Decree of the Italian Ministry of Heal th (7 Oct 2011) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.259 of 7/11/2011.Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_9_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_10 _file.xls 4. Decree of the Italian Ministry of Health (29 July 2013) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No. 258 of 04/11/2013). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_16_file.pdf www.sa lute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_17_file.xlsx 5. Decree of the Italian Ministry of Health (8 J une 2016 ) regarding Modification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, n. 242 del 15/10/2016). 6. Decree of the Italian Ministry of Health (13 march 2018) regarding Mod ification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, No. 116 del 21/05/2018). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_15_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_18_file.xlsx

emdn_eudamed_nomenclature_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 1 The European Medical Device Nomenclature (EMDN) The European Medical Device Nomenclature (EMDN) will be the nomenclature of use by manufacturers when registering their medical devices in the EUDAMED database. Founded on pre-established criteria and requirements1 and based on orientations provided by the Medical Device Coordination Group (MDCG) , the European Commission decided in favour of the use of the ‘Classificazione Nazionale Dispositivi medici (CND)’2 as the basis for the EMDN . Currently, a n extrao rdinary revision of the CND is ongoing so that to release the first version of the EMDN, which will be i ntegrated in EUDAMED for use by operators. The EMDN will be fully available and accessible to any operators and will be copyright free. To the extent possible, t he Commission will map the EMDN to the G lobal Medical Device Nomenclature (GMDN) . This task has been undertaken with th e hopes of possibly facilitating EMDN code search by operators current ly using GMDN . The correspondence between the nomenclatures is intended to be visible to operators and incorporated in the future database in the form of a searching tool. Therefore, and in cooperation with GMDN, t he mapping exercise is currently ongoing . The level of quality and reliability of this mapping is dependent on the commitment of all relevant parties to work together in ma pping and validating the result s. A sub -group of the MDCG on nomenclature which includes experts from National Competent Authorities and stakeholders has been established to oversee regulatory activities linked to nomenclature . The sub -group will aim to define the rules and processes related to the creation, update , maintenance and use of the European Medical Device Nomenclature. Additionally, t he Commission is currently collaborating with the World Health Organisation (WHO ) in the context of their work and activities on a future international medic al device nomenclature. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements 2 CND is currently used in Italy, Portugal and Greece.

FAQ_MDR_180117_V1.0-1.pdf.txt

Page 1 of 13 CAMD Transition Sub Group FAQ – MDR Transitional provisions Disclaimer : The information presented in this document is for the purpose of general information only and is not intended to represent legal advice to any individual or entity. It reflects the outcome of discussions within the Transition Sub Group (TSG) of the CAMD (established in May 2017) to establish recommendations on the interpretation of transition -related provisions. It is not intended to be a guidance document . We recommend that you should obtain your own legal advice before taking any action based on information given here. The content of this FAQ table will be updated cont inuously. While we strive to provide the following information in as timely and accurate a manner as possible , this document does not make any claims or guarantees about the accuracy, completeness or sufficiency of its contents. Participants of the Transit ion Sub Group, authors and reviewers of this document expressly disclaim liability for any errors and omissions in the contents. Page 2 of 13 Glossary: • AIMDD/MDD compliant device = device that is compliant with Directive 90/385/EEC/ Directive 93/42/EEC • AIMDD/MDD certificates = certificates in accordance with Directive 90/385/EEC/ Directive 93/42/EEC • DoA = date of application of the MDR • MDR = Medical Device Regulation (EU) 2017/745 • MDR compliant de vice = device that is compliant with the MDR • MDCG = Medical Device Coordination Group • MFR = manufacturer • PRRC = person responsible for regulatory compliance • NB = notified body • “old” NB = NB that has issued an AIMDD/MDD certificate • The Directives = Directives 90/385/EEC, 93/42/EEC Document History Version Publication Note V1.0 17/01/18 Original publication Conten ts: I - Issue: Transition in general ................................ ................................ ................................ ................................ ................................ .............................. 3 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) ................................ ................................ ............. 4 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) ................................ ................. 7 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR ................................ ................................ ................................ ................................ .. 11 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) .... 12 Page 3 of 13 I - Issue: Transition in general 1 Question: When does the Medical Devices Regulation (EU) 2017/745 (= MDR) apply? Answer: The MDR shall apply from 26 May 2020 (= date of application (DOA)) , see Art. 123 para 2 MDR . There are however exceptions to that general rule. Some provisions apply earlier (e.g. regarding notified bodies or the Medical Device Coordination Group), some later (e.g. regarding UDI labelling). For the exceptions, see Art. 123 para 3 MDR (earlier application: a -c, i; p ostponed application: d –h). 2 Question: When do the Directives 90/385/EEC , and 93/42/EEC [= the Directives] cease to apply ? Answer: In general the Directives 90/385/EEC and 93/42/EEC are repealed with effect from 26 May 2020 (= DoA), see Art. 122 MDR . However there are some exceptions , e.g. • in order to deal with devices that are compliant with the Directives or • to serve as a “back up” in case EUDAMED is not fully functional at DoA (see Art. 122 MDR). 3 Question: What is the applicable legislation until 26 May 2020 (= DoA )? Answer: Laws and regulations adopted by Member States in accordance with the Directives (= Directives regime). There are however exceptions (see for example Art. 123 para 3 a – c, i MDR and Art. 120 para 5 and 6 MDR ). Page 4 of 13 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) 4 Question: Is it possible to place a device, which is compliant with the MDR (= MDR compliant device ), on the market prior to 26 May 2020 (= DoA) ? Answer: Yes, see Art. 120 para 5 MDR. Manufacturer s (= MFR ) are – until 26 May 2020 (= DoA) normally required to place devices on the market that comply with the Directives (= AIMDD/MDD compliant devices) , however Art. 120 para 5 MDR offers the option to place MDR compliant devices on the market before DoA. 5 Question: Is it possible for all types of devices (for all different risk classes I – III) compliant with the MDR (= MDR compliant device) to be placed on the market prior to 26 May 2020 (according to Art. 120 para 5 MDR )? Answer: Yes, all types of devices - regardless of their risk class – may be placed on the market according to Art. 120 para 5 MDR. This includes for example custom made devices (Art. 2 para 3 MDR ) and system s and procedure packs (Art. 2 para 10 and para 11 MDR). However , devices being subject to the “clinical evaluation consultation procedure” according to Art. 54 MDR (= certain class III and class IIb devices) may not be placed on the market in ac cordance with Article 120 para 5 MDR before the Medical Device Coordination Group ( MDCG ) and the expert panels have been established (see Art. 120 para 7 MDR) . Depending on the risk class of the device, conformity assessment may requir e the involvement of a NB designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). In this c ase, such devices cannot complete a conformity assessment, and therefore may not be placed on the market, before NBs have been designated and notified under the MDR. Page 5 of 13 6 Question: As a MFR , which obligations of the MDR do I need to fulfil in order to place a MDR compliant device on the market before the DoA according to Art. 120 para 5 MDR? Answer: As many obligations as are possible , while taking into account that • EUDAMED is not fully functional and • the MDR is not fully applicable at that point in time . Generally speaking, that is to say that: • first, the device as such needs to be MDR compliant (see Annex I) and • second, the MFR has to comply with the MDR. In particular, the MFR shall undertake an assessment of the conformity of that device in accordance with the applicable conformity assessment procedures set out in Art. 52 MDR . This may, depending on the risk class of the devic e, necessitate the involvement of a notified body designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). The following requirements of the MDR need to be fulfilled by t he MFR (non -exhaustive list) : • clinical evaluation • risk management • QMS • Post-market surveillance • Technical documentation and other reports • Liability for defective devices Page 6 of 13 However, exceptions /adaptations are possible /necessary , particularly due to the fact that EUDAMED may not be fully functional before the DoA . For example : • in the absence of a fully functional EUDAMED some requirements of the Directives shall – where necessary - apply in place of the relevant provisions of the Regulation (e.g. registration of d evices and economic operators). • A person responsi ble for regulatory compliance (PRRC, Art. 15 MDR) needs to be available but not necessarily registered until EUDAMED is available . . • The assignment of an UDI (Art. 27 para 3 MDR) is not possible as long as there are - no issuing entities designated by the Commission according to Art. 27 para 2 MDR or - as long as the legal fiction according to Art. 120 para 12 does not apply (it shall apply from 26 May 2019 , see Art. 123 para 3 i MDR ). It is of no significant use as long as there is no UDI database . • An implant card and the information according to Art. 18 MDR need to be provided, however without the UDI related content (as the requirement to place the UDI carrier on the devices will be stepwise introduced after the DoA). 7 Question: Are MDR compliant devices placed on the market according to Art . 120 para 5 MDR subject to the so called “sell off” provision in Art. 120 para 4 MDR (see below)? Answer No, the possibility of their being made available/put into service is not time-limited. Page 7 of 13 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) 8 Question: Do certificates issued by notified bodies in accordance with the Directives (= AIMDD/MDD certificates ) prior to 25 May 2020 remain valid after the DoA? Answer: Yes, as specified in Art. 120 para 2 MDR. In general , they remain valid until the end of the period indicated on the certificate. Certain AIMDD/MDD certificates (Annex 4/IV, refer to Art. 120 para 2 first sentence MDR) become void at the latest on 27 May 2022, others (refer to Art. 120 para 2 second sentence MDR) on 27 May 2024 at the latest. In other words, after 27 May 2024 there will be no more valid AIMDD/MDD certificates. 9 Question: What kind of certificates remain valid according to Art. 120 para 2 MDR? Answer: All certificates which are commonly issued by Notified Bodies with reference to the Council Directives MDD and AIMDD. That is [see for example NBOG BPG 2010 -3, similar NB-MED/2.5. 1Rec 4]:  EC Design -Examination Certificate (Annex II section 4 MDD, Annex 2, section 4 AIMD)  Certificate of Conformity (Annex IV MDD, Annex 4 AIMD)  EC Type Examination Certificate (Annex III MDD; Annex 3 AIMD)  EC Certificate Full Quality Assurance System (Annex II excluding section 4 MDD; Annex 2 section 2 AIMD)  EC Certificate Production Qualit y Assurance (Annex V MDD, Annex 5 AIMD) Page 8 of 13  EC Certificate Product Quality Assurance System (Annex VI MDD) 10 Question: May a “ declaration of conformity ” be considered as a “certificate” according Art.120 para 2 MDR? Answer: No, since it is not a certificate issued by a NB. 11 Question: Is it possible for a MFR to have valid MDR and valid AIMDD/MDD certificates in parallel until the 27 May 2024 expiry date? Answer: Yes. 12 Question: May devices, that are compliant with the Directives (= MDD/AIMDD compliant devices ), be placed on the market/put into service after 26 May 2020 (= DoA) ? Answer: Yes, under certain conditions (see answer on question 1 7) as specified in Art. 120 para 3 MDR. In general , after 26 M ay 2020 , devices need to comply with the MDR in order to be placed on the market/put into service (see Art. 5 MDR) . However , for a limited time (depending on the validity of the MDD/AIMDD certificates) there is the option to continue to place devices on the market that are compliant with the Directives. Making use of this option may postpone the immediate need for a new certificate under the MDR. 13 Question: May MFR s of class I devices , that are compliant with the Directives , make use of the derogation in Art. 120 para 3 MDR (= be placed on the market after the DoA)? Answer: No, they must comply with the MDR , unless the device concerned is a class I device with measurement function or in sterile condition covered by a valid MDD certificate . Page 9 of 13 14 Question: May devices that are excluded from the scope of the MDR (e.g. via Art. 1 para 6 lit h) nonetheless benefit from Art. 120 para 3 MDR ? Answer: No, these devices do not fall under the MDR, thus Art. 120 para 3 MDR is not applicable. 15 Question: May MDD/AIMDD compliant devices , which under the MDR will be subject to an “upgrade” in risk class (“up- classification”) , e.g. formerly class IIa -> then class III , benefit from Art. 120 para 3 MDR ? Answer: Yes, under the conditions specified in Art. 120 para 3 MDR (e.g. valid AIMDD/MDD certificate ). Devices which are in a different respectively higher risk class in MDR than under the Directives are not as such excluded from the scope of Art. 120 para 3 MDR . 16 Question: If, according to Art. 120 para 3 MDR, a MFR intend s to place a MDD/ AIMDD compliant device on the market after the DoA, that , under the MDR , will be subject to an “upgrade” in risk class (“up-classification”) , what is the relevant risk class with regard to the applicable MDR requirements listed in Article 120 para 3 MDR (e.g. PSUR)? Answer: The risk class under MDD/AIMDD . 17 Question: What are the requirements for the placing on the market/putting into service of MDD/AIMDD compliant devices according to Art. 120 para 3 MDR after DoA? Answer: See Art. 120 para 3 MDR. In short: 1. A valid AIMDD/MDD certificate according to Art. 120 para 2 MDR [All certificates necessary for the placing on the market of the device in question need to be valid , e.g. a class III device needs to have a valid QMS as well as product specific certificate .] 2. Continuous compliance of the device with the Directives Page 10 of 13 3. No signif icant changes in the design and intended purpose [If there is a significant change in either the design or the intended purpose , Art. 120 para 3 MDR cannot be claimed . Qualification of a change as “significant ” according to Art. 120 para 3 MDR shall be determined on a case by case basis. However, - limitations of the intended purpose - design changes related to corrective actions assessed and accepted by the Competent Authority are not considered “ significant ” in the sense of Art. 120 para 3 MDR. . 4. Appl ication of MDR requirements in place of the corresponding requirements of the Directives with regard to: a. Registration of economic operators and of devices (see Art. 31 MDR and Art. 29 MDR) b. Post market surveillance (PMS) (see Art. 83 -86, 92 MDR including Annex III but without the PMS having to be an integral part of the QMS) c. Market surveillance (see Art. 93 – 100 MDR, but device s tandards to be met = Directives ) d. Vigilance (see Art - 87-92 MDR) However exceptions are possible in the case that EUDAMED is no t fully functional in time (then see Art. 123 para 3 d and e MDR). Moreover, the “old” NB which issued the AIMDD/MDD certificate shall continue to be responsible for the appropriate surveillance of all the applicable requirements relating to the devices it has certified. This should be agreed on between the “old” NB and the MFR on a contractual basis . Page 11 of 13 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR 18 Question: What is the so called “sell off” provision (Art. 120 para 4 MDR) about? Answer: It is intended to limit the time during which AIMDD/MDD compliant devices, that have already been placed on the market (either before the DoA or by virtue of Art. 120 para 3 after the DoA) , may be made available e.g. by a distributor . After May 27, 2025 these devices may not be made available/put into service (= deadline) . If such devices are still within the supply chain by this date - i.e. have not reached the final user as being ready for use (e.g. the hospital) - they are not “marketable” any more. This provision is thus primarily dealing with the “making available” of AIMD/MDD compliant devices once they have been placed on the market , e.g. within the supply chain . It does not apply to the “placing on the market” of these devices by the MFR . Please also note, that this provision is not intended to apply to second hand sales (see recital 3). This means , once a device has been made available to the final use r (e.g. the hospital) as being ready for use, the further making available of this device is not subject to/covered by the MDR. 19 Question: Does Art. 120 para 4 MDR enable MFRs to place MDD/AIMDD compliant devices on the market until May 27, 2025? Answer: No. Art. 120 para 4 MDR is not applicable to the “placing on the marke t” of MDD/AIMDD compliant devices (see question 18). The only way to place MDD/AIMDD compliant devices on the market after DoA is Art. 120 para 3 MDR (see question s 12-17). Given th at MDD/AIMDD certificate s will no longer be valid after May 27 2024 , this option ceases to exist from that date onwards . Page 12 of 13 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) 20 Question: Do all devices have to be registered according to Art. 29 para 4 MDR by the DoA? Answer: No. Even if EUDAMED is fully functional at the DoA there will be a n 18-month “interim phase ” (= EUDAMED fully functional but Art. 29 para 4 MDR not yet applicable) during which the different devices to be placed on the market may be registered “step by step” in EUDAMED accordin g to Art. 29 para 4 MDR instead of nationally according to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR) . However , at the end of this “interim phase ” it must be ensured that all devices of a MFR’s portfolio have been registered in EUDAMED. If EUDAMED is not fully functional until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). 21 Question: Must NBs have entered all the certificate related information of all devices according to Art. 56 para 5 MDR into EUDAMED by the DoA ? Answer: No. Even if EUDAMED is fully functional at the DoA there will be an 18-month “interim phase” (= EUDAMED fully functional but Art. 56 para 5 MDR not yet applicable) during which the relevant information according to Art. 56 para 5 MDR may be registered in EUDAMED “step by step = certificate by certificate” instead of nationally acco rding to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR). However , at the end of this “interim phase” it must be ensured that all the relevant data regarding all certificates have been registered in EUDAMED. If EUDAMED is not fully functio nal until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). Page 13 of 13 22 Question: What happens if EUDAMED is not fully functional at the DoA? How does this affect the application of obligations and requirements of the MDR that relate to EUDAMED ? Answer: The relevant provisions to refer to are mainly Art. 123 para 3 d and e . Art. 123 para 3 d MDR: The different Articles listed in Art. 123 para 3 d (= dealing with e.g. the registration of devices and economic operators, clinical investigations, notified bodies, vigilance, post -market surveillance, market surveillance) are not fully postponed with regard to their applicati on but generally remain applicable from the DoA. However , their application is postponed as far as the obligations and requirements within these Articles relate to EUDAMED (which is not fully functional yet). To that extent they shall apply from the date c orresponding to 6 months after the date of notice of full functionality . Meanwhile ( until EUDAMED is fully functional ) the corresponding provisions of the Directives regarding exchange of information continue to apply . The principle is that the derogation applies to the electronic exchange of information/upload to EUDAMED. If the derogation is applicable this does not necessarily mean that the information itself does not need to be prepared/exchanged. This exchange of in formation e.g. reports will have to be done by other means in lieu of exchange via EUDAMED (Directives regime ). The underlying idea behind this paragraph was to ensure compliance with the new obligations and requirements via the “old” systems as far as pos sible. The actual practical implication of this concept with regard to the different Articles listed in Art. 123 para 3 d MDR needs a closer look and further guidance , which is in progress. Art. 123 para 3 e MDR : For the application of Art. 29 para 4 MDR and Art. 56 para 5 MDR in the case that EUDAMED is not fully functional in time, see question 20 and 2 1.

ivd_mfr_stepbystep.pdf.txt

MEDICAL DEVICES CHANGE OF LEGISLATION Internal market, Industry, Entrepreneurship and SMEs1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the IVDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (IVDR Classes A–D) and confirm conformity assess - ment routes for existing and future products. Check the requirement for involving the Notified Bodies Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 56) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market performance follow-up plan (PMPF, Annex XIII Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for IVDs under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know!Implementation Model for In-Vitro Diagnostic Medical Devices Regulation Step by Step Guide Ref. Ares(2018)3873813 - 20/07/20182Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs related to the new risk classification system and the need of involving a Notified Body and costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the IVDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, re - source requirements and a steering group, and ensure overall responsibility for IVDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transi - tional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through IVDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (performance evaluation, technical documentation, relations with other economic operators, Unique Device Identifica - tion, labelling, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for IVDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the IVDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the IVDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89124-3 DOI: 10.2873/41862 ET-04-18-659-EN-N

scheer_o_015.pdf.txt

Final Version Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices Scientific Committee on Health, Environmental and Emerging Risks SCHEER GUIDELINES on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties The SCHEER adopted this document at plenary meeting on 18 June 2019 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 2 ABSTRACT The SCHEER was requested to provide Guidelines on the benefit -risk assessment (BRA) of the presence, in the medical devices specified in the regulation , of phthalates , which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction (CMR) or endocrine -disrupt ing (ED), according to the criteria outlined in the legal obligation section from the mandate. Phthalates are widely used in industry as plastici sers of polymers, in a variety of applications such as coated fabrics and roofing membranes, as well as in me dical devices, adhesives, paints, inks and enteric -coated tablets. Di -(2-(ethylhexyl) phthalate (DEHP) is the most widely used phthalate in medical devices. Dimethyl phthalate (DMP) and diethyl phthalate (DEP) are not used as plasticis ers but e.g. as addit ives in cosmetics, medical devices, and household products. The interaction of phthalates with the polymers they are embedded in is weak, so they may be released from the plastic product into the environment and into the human body if the product is in con tact with it. The Medical Device Regula tion, Regulation (EU) 2017/745 allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w. when a proper justification can be provided (Annex I, Chapter II Section 10.4). Fo r such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the risk associated with such alternatives should be weighed against the risk of the u se of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1 . However, the risk by itself is not the only parameter to consider: also the impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device shall be evaluated. These Guidelines describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices and/or or parts or materials used therein at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alternatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. The approach of these Guidelines may also be used for a BRA of other CMR/ED substances present in medical devices. During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices, SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data needed for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices. Pending on new scientific evidence, it is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Keywords: Guidelines, benefit -risk assessment , CMR/ED phthalates, medical devices, SCHEER . Guidelines to be cited as: SCHEER (Scientific Committee on Health, Environmental and Emerging Risks), Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are ca rcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties, final version adopted at SCHEER plenary on 18 June 2019. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 3 ACKNOWLEDGMENTS Members of the Working Group are acknowledged for their valuable contribution to this opinion. The members of the Working Group are: SCHEER members: Teresa Borges Rodica Mariana Ion Wim H. de Jong (Chair and Rapporteur) Demosthenes Panagiotakos Emanuela Testai Theo Vermeire SCCS members: Ulrike Bernauer Christophe Rousselle External experts: Stéphane Bégué (Etablissement Français du Sang, EFS, Paris, France) Hilde B. M. Kopperud (Nordic Institute of Dental Materials, Oslo, Norway) Maria Rosaria Milana (Istituto Superiore di Sanità, Dip. Ambiente e Salute, Roma, Italy) Tanja Schmidt (Ansbach University of Applied Science, Ansbach, Germany) Experts from EU Agencies : Francesco Pignatti (European Medicines Agency ) Evgenia Stoyanova (European Chemicals Agency ) Katarina Volk (European Food & Safety Authority ) All Declarations of Working Group members are available at the following webpage: http://ec.europa.eu/health/scientific_committees/experts/declarations/scheer_wg_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 4About the Scientific Committees (2016 -2021) Two independent non -food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commissio n's attention to the new or emerging problems which may pose an actual or potential threat . They are: the Scientific Committee on Consumer Safety (SCCS) and the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER). The Scientific Comm ittees review and evaluate relevant scientific data and assess potential risks. Each Committee has top independent scientists from all over the world who are committed to work in the public interest. In addition, the Commission relies upon the work of other Union bodies, such as the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCHEER This Committee, on request of Commission services, provides Opinions on questions concerning health, environmental and emerging risks. The Committees addresses questions on: -health and environmental risks related to pollutants in the environmental media and other biological and physical factors in relation to air quality, water, waste and soils. -complex or multidisciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health, for example antimicrobial resistance, n anotechnologies, medical devices and physical hazards such as noise and electromagnetic fields. SCHEER members Roberto Bertollini, Teresa Borges, Wim de Jong, Pim de Voogt, Raquel Duarte -Davidson, Peter Hoet, Rodica Mariana Ion, Renate Kraetke, Demosthen es Panagiotakos, Ana Proykova, Theo Samaras, Marian Scott , Remy Slama, Emanuela Testai, Theo Vermeire, Marco Vighi, Sergey Zacharov Contact European Commission DG Health and Food Safety Directorate C: Public Health, Country Knowledge, Crisis management Unit C2 – Country Knowledge and Scientific Committees Office: HTC 03/073 L -2920 Luxembourg SANTE- C2-SCHEER@ec.europa.eu ISBN 978-92-76-15387-0© European Union, 2020 ISSN 2467-4559 doi: 10.2875/784367 EW-CA-20-001-EN-N The Opinions of the Scientific Committees present the views of the independent scientists who are members of the committees. They do not necessarily reflect the views of the European Commission. The Opinions are published by the European Commission in their original language only. http://ec.europa.eu/health/scientific_committees/policy/index_en.htm Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 5 TABLE OF CONTENTS ACKNOWLEDGMENTS ................................ ................................ ................................ ........... 3 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine -disrupting phthalates used in medical devices ................................ ................................ .............................. 6 1. Introduction ................................ ................................ ................................ .............. 7 2. Framework for Benefit -Risk Assessment ................................ ................................ ..... 10 3. Assessment of the presence of phthalates in a medical device ................................ ....... 15 4. Assessment of possible alternative substances, materials, designs or medical treatments . 18 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates ................................ ................................ ........ 23 6. Justification for the use of CMR/ED phthalate ................................ .............................. 25 7. Benefit assessment ................................ ................................ ................................ .. 27 7.1 Material benefit ................................ ................................ ................................ ....... 28 7.2 Clinical benefits ................................ ................................ ................................ ....... 28 8. Methodologies for Benefit –Risk Assessment ................................ ............................... 29 9. Uncertainty analysis ................................ ................................ ................................ . 30 10. Conclusions ................................ ................................ ................................ ............. 34 11. Consideration of the responses received during the public consultation process ............... 35 B. REFERENCES ................................ ................................ ................................ ........... 36 C. ANNEXES ................................ ................................ ................................ ................ 40 Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates ........... 40 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances ......... 44 Annex 3: Definitions/descriptions – References - Glossary ................................ ....................... 45 Annex 4: CMR and/or ED substances ................................ ................................ .................... 51 Annex 5: Legislation on CMR and/or ED phthalates ................................ ................................ . 53 Annex 6: Use of phthalates in medical devices ................................ ................................ ....... 57 Annex 7: Approaches for Benefit -Risk Assessment ................................ ................................ .. 60 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 6 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine - disrupting phthalates used in medical devices Scope The Regulation (EU) 2017/745 on m edical devices (MDR), Annex I “General Safety and Performance Requirements”, Chapter II “Requirements regarding design and manufacture”, Section 10.4 deals with the presence of substances that may be released from a medical device. Annex I Chapter II Section 10.4.1 state s that substances that are carcinogenic, mutagenic, or reprotoxic (CMR) of category 1A and 1B, or substances having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans, shall only be present in device s, or parts thereof or those materials used therein , above 0.1% weight by weight (w/w) when justified according to a set of criteria listed under Section 10.4.2. These Guidelines1 describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alt ernatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. These Guidelines apply to those medical devices and components thereof indicated in Annex I section 10.4.1.of the MDR . They do not provide information for the BRA of the use of a medical device itself . However, the BRA as described can be integrated within the risk management system for individual medical devices. For the BRA of medical devices in general, stakeholders are referred to section A7.2. of MEDDEV 2.7/1, revision 4. Additional information may be found elsewhere, for example in the following documents FDA 2 016, 2018, EN ISO 14971, ISO/TR 24971. It should be noted that the acceptability of any risk is evaluated in relation to the benefit of the use of the medical device. When the word “patient” is used in these Guidelines, this also covers professional users and other persons (e.g. donors in case of blood donation) exposed to the medical device as well. Annex 1 to these Guidelines describes the mandate, Annex 2 describes Annex I Chapter II Section 10.4. of the MDR regarding the use of substances that could be released from the medical device and pose a risk to patients, and Annex 3 describes the definitions used in these Guidelines. 1 It should be noted that, in accordance with Regulation (EC) 2017/745, Annex I, Chapter II Section 10.4.3. and 10.4.4., updates of these Guidelines might be available in the future. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 7 1. Introduction Placing medical devices on the market, making them available on the market and putting them into service are all activities governed by Regulation (EU) 2017/745 that replaces Directive s 90/385/EEC and 93/42/EEC . Medical devices are defined in the MDR as presented in the text box below: For the purposes of this Regulation, the following definitions apply (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes : — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anat omy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended a ction by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conce ption; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. As a general requirement , the medical device shall perform acc ording to its intended purpose and be safe for professional users and patients , or where applicable other persons (e.g. donor s) on which the device is used. The conformity of medical devices shall be evaluated against the requirements of the Regulation (EU) 2017/745. They shall be presumed to be in conformity with this Regulation if they are in conformity with EU - harmonised standa rds or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union. Although not mandatory, these standards provide a route to comply with the MDR. For medical devices the horizontal standards EN ISO 14971 and EN ISO 10993 -1 are especially relevant. EN ISO 14971 describes the application of a risk management process for medical devices, whereas EN ISO 10993 -1 deals with the biological evaluation and t esting of medical devices within a risk management process. According to EN ISO 10993 -1, evaluation of the biological safety of a medical device should be a strategy Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 8 planned on a case -by-case basis to identify the hazards and estimate the risks of known hazards. In Annex A of EN ISO 10993 -1, a series of endpoints is indicated from which a selection can be made for the biological evaluation of a medical device. The selection is based on the nature of the device's contact with the body (device category: surfa ce device, external communicating device, or implant device; type of contact: skin, mucosal membrane, compromised surface, blood, tissues, organs; duration of the contact: limited ≤24 h, prolonged >24 h to 30 days, permanent >30 days). A systematic literat ure review is part of the biological evaluation of a medical device in order to avoid unnecessary testing (EN ISO 10993 -1). This systemic literature review should also be performed for a CMR/ED phthalate or potential relevant alternatives identified for a given in a medical device. In addition to EN ISO 10993 -1, a series of EN ISO 10993 standards has been published describing various assays and approaches for the evaluation of the endpoints identified in EN ISO 10993 -1 for the biological evaluation of medic al devices. Assays described in the various standards include cytotoxicity, sensitisation, irritation, systemic toxicity, implantation, haemocompatibility, genotoxicity, and carcinogenicity endpoints. Additionally immunotoxicity and organ -specific toxiciti es need to be considered, if appropriate. In addition, reproductive and developmental toxicity should be addressed for novel materials, materials containing substances with a known reproductive or developmental toxicity, medical devices with relevant targe t populations (e.g. pregnant women), and/or medical devices where there is the potential for local presence of device materials in the reproductive organs (EN ISO 10993 -1:2018). For the risk assessment EN ISO 10993 -17 describes determination of allowable l imits for leachable substances, whereas EN ISO 10993 -18 describes methods for chemical characterization of materials used in medical devices. In addition to the horizontal standards, vertical i.e. device specific standards and standards for clinical investigation are available ( e.g. EN ISO 14155). Furthermore, the EU also provides guidance in MEDDEV documents (e.g. MEDDEV 2.7/1 rev.4 for clinical evaluation of medical devices). The MDR states that substances that are classified as carcinogenic, muta genic, or toxic to reproduction (CMR) of category 1A or 1B, or substances identified at EU level as having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans (CMR/ED substances, in this text) , shall only be present in a device s or parts thereof or those materials used therein above 0.1% weight by weight (w/w) when justified. Annex 4 provides further information on the classification of CMR and on identification of ED substances. The justificatio n for the use of CMR/ED substances in a medical device above 0.1% w/w, shall be based on an analysis of potential patient and user exposure, availability of possible alternatives, an argumentation why possible alternatives are appropriate or inappropriate, and on the most recent Guidelines of this Scientific Committee. Phthalates are a group of substances widely used in medical devices. When used as plastici sers they may comprise a substantial part of the medical device. A typical concentration of Bis(2 -ethylhexyl) phthalate (DEHP; CAS 117 -81-7) in plastici sed polyvinyl chloride (PVC) can be 30% based on weight (ECB 2008, SCENIHR 201 5). For many years the reproductive toxicity and the possible endocrine disrupting activity of certain phthalates has been a source for debate. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 9 Phthalates currently classified as reproductive toxicants category 1B under the Classification, Labelling and Pa ckaging (CLP) regulation (EC 1272/2008) and identified as substances of very high concern (SVHC) under Article 57 (c) of REACH Regulation (EC) 1907/2006 are listed in Annex 5 of this document . This list may be updated, so it is recommended to consult the An nex VI of the CLP Regulation. In addition, the Commission Implementing Decision (EU) 2017/1210 and Commission Implementing Decision (EU) 2018/636 identified some phthalates as substances of very high concern (SVHC) according to Article 57(f) of REACH Regu lation (EC) 1907/2006, due to their endocrine disrupting properties with probabl e serious effects to humans, namely Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) , Diisobutyl phthalate (DIBP) , and Dicyclohexylphthalate (DCHP) . Bis(2- ethylhexyl) phthalate (DEHP), was also identified in 2014 as a substance of very high concern in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) because it is a substance with endocrine disrupting prop erties for which there is scientific evidence of probable serious effects to the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) of Article 57 REACH. https://echa.europa.eu/documents/10162/21837b30 -0318-8b45-92db-9e8c39f89dee SCENIHR adopted an Opinion on the safety of medical devices containing DEHP - plasticised PVC in 2008, and a revision of this Opinion in 201 5 (SCENIHR 2008, 201 5). The main source for DEHP exposure of the general population was determined to be food. In addition, the use of medical devices can increase the exposure considerably in the course of specific medical treatments, for e xample during massive blood transfusions, haemodialysis, and in neonatal intensive care units (NICU) for prematurely born neonates (SCENIHR 201 5). Although quite a number of alternative substances were available for DEHP, for some of them serious data gaps were observed regarding hazard identification and exposure estimation (Bui et al., 2016, SCENIHR 201 5). The Danish EPA assessed different alternatives and concluded that to various degrees some substances can be considered to be relevant alternatives to DEHP in terms of human health hazards, especially regarding the endpoints reproductive and developmental toxicity (Nielsen et al. 2014). However, for a number of possible alternatives the data set was limited. Some alternatives showed a low migration rate and some of them are already used as substitutes in medical devices for traditional DEHP -applications. For example, four additional plasticisers for PVC (BTHC, DEHT, DINCH, and TOTM) used in medical devices have recently been included in th e updated chapters of the European Pharmacopoeia (Council of Europe, EDQM 2018). Phthalates classified as CMR of category 1A or 1B according to the procedure described in Annex 4 are listed in Annex VI of the CLP regulation (CLP -Regulation (EC) No 1272/200 8, OJ L353). According to article 57 (f) of REACH (Regulation (EC) 1907/2006) or the Biocides Regulation ( Regulation (EC) 528/2012) phthalates can be identified as having ED-properties when there is scientific evidence of probable serious effects to human health . These Guidelines provide a framework of how to perform a BRA for the presence of such CMR and/or ED phthalates in medical devices or parts or materials used therein at percentages above 0.1% weight by weight (w/w) , and shall be used by all relevant stakeholders, e.g. manufacturers and notified bodies, and regulatory bodies for the justification of the presence of CMR/ED phthalates . The evaluation according to the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 10 Guidelines should be performed by a multidisciplinary team including amongst others e.g. a material scientist, medical device specialist, toxicologist and clinician. A justification for the use of a CMR/ED phthalate can also be based on an already availabl e justification relating to a medical device for which equivalence with the device in question can be demonstrated according to the MDR Annex XIV Section 3. The existing justification can be used as a reference, and the data used for this justification sho uld be available . The approach of these Guidelines can also be u sed for a BRA of other CMR/ED substances present in medical devices. Other descriptions for BRA may be “benefit -risk analysis” or “benefit -risk determination” as defined in the MDR. As Annex I Section 10.4.3 indicates a benefit -risk assessment this terminology is used in these Guidelines. 2. Framework for Benefit -Risk A ssessment The MDR allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w when a proper justification can be provided ( MDR Annex I, Chapter II Section 10.4). For such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the r isk associated with such alternatives shall be weighed against the risk of the use of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1. However, the risk is not the only parameter to consider . The impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device should also be evaluated. The justification for the presence of CMR 1A or 1B and/or ED phthalates for which there is scientific evidence of probable serious effects on humans should be based on a number of considerations as described below and in Figure 1 . In order to perform the BRA as indicated above , it is important to describe the terminology to compare the risk s of the presence of the phthalates to be evaluated (see text box below). Annex 3 provides a selection of definitions as present in the MDR and/or the OECD Substitution and Alternatives Assessment Toolbox. (http://www.oecdsaatoolbox.org/ ) For the purpose of these Guidelines the following definition for "alternatives" is used: “alternatives are defined as substances, materials, designs and medical treatments that can be used to replace the use of CMR and/or ED substances in medical devices” The alternative therefore is not limited to a possible substitute substance or material but could also be another device design (e.g. coating/production process/ techniques /lower concentration of substances) or medical treatment (e.g. procedure, device) or a combination of technical and substance alternatives that can substitute or eliminate the use of the CMR/ED phthalate (modified from the ECHA REACH guidance on the preparation of an application for authori sation). The functionality and performance of the alternative should be comparable to the extent that there would be no clinical ly relevant difference foreseen in the performance of the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 11 device or in the outcome of the alternative medical procedure. Conside rations of functionality and performance shall be based on proper scientific justification. In order to justify the use of a CMR 1A or 1B and/or ED phthalate, the manufacturer shall clearly demonstrate that the identified alternative(s) are not appropriate to maintain the functionality, performance and benefit -risk ratios of the medical device. A number of aspects need to be considered for the justification of the presence of a phthalate classified as CMR category 1A or 1B and/or identified as ED above content > 0.1% w/w in a medical device , or parts thereof or those materials used therein, as intended to be used. In summary, these aspects can be considered by a stepwise approach given below and presented in Figure 1. Further details and examples on the steps used in the Guidelines are given in the following chapters. Assessment of the CMR/ED phthalate (CMR/ED scenario) Step 1: Description and characterisation of the composition of the medical device (or parts or materials thereof) . Identif ication of the presence and concentration of CMR/ED phthalate (s) in weight by weight percentage (% w/w) . Step 2: Description of the use and function of the CMR/ED phthalate used in medical device. 2a. Description of functionality/performance provided by the presence of the CMR/ED phthalate. 2b. Description of the benefit (material and/or clinical) of the presence of CMR/ED phthalate in the medical device. Step 3: Assessment of the risks of the CMR/ED phthalate. 3a. Determin ation of the patient exposure based on realistic worst -case2 use scenario in the intended use . 3b. Identif ication of biocompatibility, general toxicological and specific CMR/ED hazards associated with the phthalate. 3c. Determin ation of the maxim um tolerable/ acceptable exposure for the patient, based on pre -clinical and clinical information (if available). 3d. Determination of the risks for various intended use scenarios and patient groups. Assessment of possible alternative (s) (non CMR/ED phthalate scenario) Step 4: Inventory of possible alternative (s). 4a. Substances. 4b. Materials. 2 Realistic worst case is the situation where the exposure is estimated us ing a range of factors (i.e. duration, amount, exposure controls), where applicable, the ones that would be expected to lead to maximum amount of exposure (e.g. exposure might be assessed under realistic simulated -use scenarios by EN ISO 10993 -12 and EN IS O 10993 -18 or a non-volatile residue test (USP <661>)). The realistic worst case does not include deliberate misuse. (EU Biocides Regulation 528/2012). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 12 4c. Designs and/or medical treatments3. Step 5: Identification of the potential relevant candidates for assessment as alternatives to CMR/ED phthalates and justification for the selection and exclusion of possible alternatives. This also includes assessment of the availability of the potential alternative (s). Step 6: Description of identified potential relevant alternative(s). 6a. Description of functionality and performance of the potential alternative(s). 6b. Description of the benefit (material and/or clinical) of the use o f the potential alternative(s). Step 7: Assessment of the risk of identified potential relevant alternative (s). 7a. Determination of patient exposure o f the alternative based on a realistic worst -case use scenario in the intended use. 7b. Identification, where available, of biocompatibility, toxicological and CMR/ED hazards associated with the alternative. 7c. Determination of maximum tolerable/acceptabl e exposure of the alternative for patient (if available). 7d. Determination of risk of potential alternatives for various use scenarios and patient groups. Assessment of potential relevant alternative (s) versus CMR/ED phthalate Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Step 9: Comparison of hazard (s) of original CMR/ED phthalate as used in the medical device with hazard (s) of identified potential relevant alternative (s). Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. In addition to patients, the same approach shall be used for the justification of the presence of CMR/ED phthalate in medical devices to evaluate the risk for professional users and for other persons (e.g. donors) exposed to the CMR/ED phthalates. When alternative designs or medical treat ments were identified as potential alternatives in step 5, adequately adopted endpoints for risks and benefits shall be chosen. It should be noted that scientific developments may be available after the initial assessment regarding the use of alternatives for CMR/ED phthalates . Therefore, a 3 It should be noted that for alternative designs and/or medical treatments, appropriate endpoints for r isks and benefits shall be selected. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 13 revision of the BRA of the presence of the CMR and/or ED phthalate may be necessary. Revisions of the above indicated BRA shall occur as indicated in the relevant sections of MDR for the general risk assessment of the me dical device. Figure 1 illustrates the BRA and is based on Eliason and Morose (2011), EMA (2014), FDA (2016) and a critical selection from the OECD Substitution and Alternatives Assessment Toolbox ( http://www.oecdsaatoolbox.org ). It presents the stepwise approach described above including a general description of factors to consider when performing a BRA. Figure 1 presents a use scenario in which the CMR/ED is used in a medical device versus a non -use scenario in which a proper potential alternative is evaluated. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 14 Figure 1 . BRA for evaluation of presence of CMR/ED phthalates and their potential alternatives in medical devices (relevant sections between brackets) . Step 3 (3) Use scenario Assessment of the risks of phthalate 3a. Exposure assessment patient 3b. Biocompatibility, hazard assessment 3c. Maximum tolerable /acceptable dose 3d. Risk characterisation Step 4 (4) Inventory of possible alternatives 4a. Substitute substances 4b. Substitute materials 4c. Alternative designs/treatmentsDefine aim and scope Step 1 (3) Description and characterisation of composition of medical device, IdentifIcation of presence and amount of CMR/ED phthalate Step 2 Description of phthalate 2a. Use, functionality and performance of phthalate (3) 2b. Benefit (7)Step 5 (4) Identification of potential candidates for alternatives and justification for the selection and exclusion Step 6 Description of identified potential relevant alternatives 6a. Functionality, performance (4) 6b. Material and clinical benefit of the use (7) Step 7 (4) Assessment of the risks of Identified potential relevant alternative(s) 7a. Exposure assessment patient or user 7b. Biocompatibility, hazard assessment 7c. Maximum tolerable /acceptable dose 7d. Risk characterisation Step 8 (5) ComparIson of functionality, performance of use and non- use scenario Overall summary report Justification for continued use of CMR/ED phthalate (6)Step 9 (5) Comparison of hazard(s) of use and non-use scenario Step 10 (5,7, 8) Comparison of benefit and risk of use and non-use scenario Uncertainty analysis (9)Non-CMR/ED phthalate scenarioCMR/ED phthalate scenario Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 15 3. Assessment of the presence of phthalates in a medical device4 It is already necessary to provide most of the information as indicated for the use of CMR/ED phthalates in order to prove compliance with the general safety and performance requirements for the phthalate containing medical device. When more than one CMR/ED phthalate is used simultaneously in the medical device, a justification shall be provided for each of the phthalates and their combination. Some risk assessment data regarding the combinat ion of phthalates are available, as EFSA has recently proposed a Group TDI for some of them, having a similar Mode of Action (MOA) in vivo (EFSA 2019, see Annex 5). Information on assessment of combined exposures to phthalates can be found for example at the report by the National Research Council Committee on the Health Risk of Phthalates (2008) and the ECHA website on the restriction of f our phthalates ( https://echa.europa.eu/registry -of-restriction -intentions/ - /dislist/details/0b0236e180d73895 ) and EFSA guidance on cumulative expos ure (EFSA, 2019 https://doi.org/10.2903/j.efsa.2019.5634 ) Step 1: Description and characterisation of the composition of the medical device. Provide a description of the medical device and its composition including identification and the concentration of each CMR/ED phthalate in the device , and the type of chemical /physical binding of the phthalate in the formulation/device, when there is an impact on leakage. Use available chemical information for identifying target phthalates (e.g. CAS Nº; EINECS Nº; IUPAC name). The chemical composition of a medical device can be evaluated by using e.g. EN ISO 10993 -18 (FDIS published in 2019) . Step 2: Use and function of CMR/ED phthalates in the medical dev ice. Characterise the function and use of the CMR/ED phthalates in the medical device and the properties it imparts to the device. Provide a description of the intended use, functionality and performance of the medical device containing the CMR/ED phthala te and how the use of the phthalate is critical for its functionality and performance . For example, for PVC consider, with regard to the performance of the medical device, maintenance, flexibility, durability and for the phthalate viscosity and PVC compatibility. Provide a description of the patients targeted (e.g. with respect to sex, age, probable vulnerable groups5). Provide a description of use types of the medical device for which it is intended (e.g. single vs repeated exposure ). Other aspects that can be relevant include the critical properties (e.g., flexibility), the conditions of use, critical quality criteria, process/treatment and performance constraints (e.g., sterilization, device/drug interactions), regulatory or clinical or other requi rements that the CMR/ED phthalates and the phthalate -containing device need to deliver. Key criteria for the function, 4 The analysis presented in section 3 (steps 1 -3) describes the current use scenario of the CMR/ED phthalate, i.e., the scenario that would continue in the future if no additional action (other than, e.g., a planned regulatory action entering into force) is taken to limit, substitute or eliminate the presence of the CMR/ED phthalate in the medical device. The current scenario can also be referred to as baseline, business as usual or continued use scenario. 5 Vulnerabl e Groups (in these Guidelines): vulnerable groups of the population such as children and individuals with increased susceptibility due to pre -existing disease, medication, compromised immunity, pregnancy or breastfeeding, women and men in reproductive age. These vulnerable groups also include infants, elderly people or people with poor health conditions. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 16 performance and overall use should be outlined and applied as the basis for an identification and screening of possible alternatives and a more detailed assessment of potential alternatives. Justification for the selection of these criteria should be provided. Benefits of the device with CMR/ED phthalates should also be considered e.g. treatment of specific patients groups due to tuning of flexibility of the medical device . Present an inventory of the benefits of the CMR/ED phthalates in the medical device for the patients (separately for vulnerable groups). More detailed information on the benefit assessment is presented in section 7. Step 3: Assessment of the risks of the CMR/ED phthalate. Perform a risk assessment of the CMR/ED phthalate present in the medical device. The risk assessment should contain a description of the potential phthalate exposure of various patient groups for which the medical device is intended (e.g. single vs repeated exposure ). This should separately include vulnerable groups. EN ISO 10993 -1 provides information on use type in terms of exposure potential (e.g. limited ( ≤24h), prolonged (>24h to 30d) and permanen t (>30d)) that slightly differs from the duration of use as defined in the MDR (Annex VIII, 1, transient <60 minutes, short term 60 minutes to 30 days, long term >30 days). Exposure estimation Provide information , preferably based on data from direct measurement or, when not available, an estimation based on worst -case scenario or from scientific literature , on the release of the CMR/ED phthalate from the medical device when used in various clinical modalities. For data generation , analytical contact conditions for the evaluation of leaching of substances from medical device s, should consider fo r example temperature, contact duration and frequency, polarity of contact liquids, flow rates, contact surface, and volume of contact liquids (EN ISO 10993 -1, EN ISO 10993 -12, EN ISO 10993 -18, USP 661). The contact conditions should be set to represent realistic worst -case conditions taking into account the intended use of the medical device. Estimate exposure to the phtha late(s) considering data on the release of the substance from the device. Consider repeated use scenarios (e.g. dialysis, apheresis donation, chronic treatment) and different population groups. The combined exposure to different CMR/ED phthalates also needs to be considered when present in a medical device. More details on the use of phthalates in medical devices are presented in Annex 6. Risk management measures in place and their effectiveness should be described and taken into account in the assessme nt (EN ISO 14971, EN ISO 10993 -1). In addition, data from biomonitoring programs may become available that could also provide information on exposure levels of phthalates in the general population and more specifically during medical treatment. Hazard id entification Describe hazards associated with the CMR/ED phthalate by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity. EN ISO 10993 -1 provides information on hazard endpoints to be considered depending on the exposure and use category of a medical device, whereas allowable limits can be determined according to EN ISO 10993 -17. Possible hazardous effects of combined exposure should Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 17 also be assessed. Identify an adequate point of departure (PoD) for risk ass essment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no-observed - adverse -effect -level (NOAEL ) or lowest -observ ed-adverse -effect -levels (LOAEL ), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non -threshold effects (e.g. in the case of genotoxic carcinogens or for certain substances acting via an ED -mediated MoA), such a dose descriptor could be a T256 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the analysis could refer to these derived figures without referring to detailed assessment how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). However, as some of these data may have been derived in the past, relevant up -to-date scientific evidence (based upon a systematic li terature review) and up -to-date risk assessment methodology for all relevant toxicological endpoints needs to be considered . If such DNEL/DMELs are not used in the assessment, a justification should be presented (e.g. new information /studies). Some of thes e other legislations are defined under Annex 4. In addition, information can also be obtained in the SCENIHR 201 5 Opinion on DEHP. The ED property of the phthalate can be described according to the recently published EFSA/ECHA guidance document . https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2018.5311 This includes impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental effects, and other effects associated with the CMR/ED phthalates. Describe risk (risk characterisation) The risk can be described by comparing exposure levels that are considered safe with the expected exposure (worst -case scenario) to obtain a risk characterisation ratio (RCR). Starting points (points of departure, PoD) for exposure levels that are considered safe could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) for threshold substances. For non -threshold substances, a T25 value or the benchmark dose associated with a 10% response (BMD10) could be used. From these PoDs, acceptable expo sure values can be derived such as “Der ived No -Effect Level ” (DNEL), “Derived Minimum Effect Level” (DMEL) or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE). As such data are often obtained in rat studies, th e use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited p eriod of time. EN ISO 10993 -17:2002 7 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, acceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors . Specifically for ED effects additional assessment factors might be considered as proposed recently (Hass et al., 2019). 6 Animal dose -descriptor; chronic dose rate that will give 25% of the animal's tumours at a specific tissue site after correction for spontaneous incidenc e (Dybing et al., 1997) 7 EN ISO 10993 -17:2002 is currently under revision. It is discussed to replace in the updated version TE by TI. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 18 The risks can also be described by calculation of the Margin of Safety (MoS), which is the ratio between the lowest PoD and the expected exposure (worst case scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18). Perform this evaluation for e very group (patients/donors) for which the device is intended to be used. Determine and describe in which situation the risk can be acceptable for the use of the CMR/ED phthalate in the medical device. The benefit -risk assessment for the use of the CMR/ED phthalate can be performed using for example MEDDEV 2.7/1rev4 and EN ISO 14971 (see also Section 8). The MDR considers a risk acceptable when outweighed by the benefit of using the device in patients (Chapter I of MDR , Chapter VI Article 62 ). In addition to potential CMR/ED effects, discuss any other potential hazards associated with the composition of the device (e.g. by using the EN ISO 10993 series of standards). Evaluate if such effects are associated with the use of the CMR/ED phthalates i n the device. Note: It should be noted that for some genotoxic carcinogens a no effect level is assumed not to exist. Similarly, a scientific debate is ongoing about whether this also applies to ED activity. The assessment of the risk should be accompan ied by an estimation of the impact of uncertainties in the described outcomes (see section 9). 4. Assessment of possible alternative substances, materials, designs or medical treatments8 In general a similar risk assessment as presented in step 3 above has to be performed for the alternative (substance s, material s, designs or medical treatment ). An inventory should be prepared in order to be able to evaluate possible alternative s. An alternative could be another substance/material or device design modifi cation or it could be a clinical procedure (e.g. a process, technique, treatment or modification) or a combination of technical and substance alternatives. Step 4: Inventory of possible alternatives Prepare a list of possible alternatives ( such as substances, materials, designs or medical treatments)9. A description of the alternative scenario (CMR/ED phthalate "non -use scenario”) needs to be presented including identification of alternative substances , materials, designs or medical treatment , e.g. by includ ing consideration of all available information, such as alternative medical devices available on the market, information about independent research, published peer-reviewed studies, systematic literature reviews, risk assessment reports or scient ific opinions from relevant scientific committees and the results of in - 8 The analysis presented in section 4 constitutes the non -use scenario or the scenario that would transpire if the CMR/ED phthalates would no longer be used in the medical device. 9 Information source for alternatives might be the European Pharmacopoeia. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 19 house research and development. The identif ication of possible alternatives should be properly documented. Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates The MDR indicates that an analysis of all possible alternatives shall be performed. However, when many alternatives are available it would not be feasible to do an extensive evaluation of all alternatives. It is therefo re recommended to select a number of potential relevant alternatives based on screening against key criteria for function, performance, toxicity, and overall use in the medical device in question (see below). In addition, analysis of availability and technical feasibility might affect choices for alternatives as well. A preliminary analysis of possible alternative substances, materials or designs or medical treatments should be performed . This preliminary analysis should include a description of their possible use as alternative substance , material , designs or medical treatment s. Justification on how and why alternatives are rejected for further assessment by defining inclusion and exclusion criteria should be provided. Information/data on functionalit y (e.g. level of flexibility in tubes) as well as performance and/or chemical safety assessment (e.g. hazard profile) may be used for rejection of the less likely alternatives (see below ) and no further risk assessment for the alternative is required. The rejection of the less likely alternatives requires justification and documentation. The chemical safety assessment should be done after assessment of the functionality and performance. In addition to the comparison in terms of functionality, technical per formance and risks to patients and users, which are critical elements for the benefit -risk assessment, Annex I Section 10.4.2 of the MDR states that the justification for the presence of CMR/ED substances should also be based on an analysis of the availabi lity of possible alternatives. Availability has several aspects, including for example the availability of necessary quantity (volumes) of the alternative on the market within a required timeframe and the ability to gain access to alternatives that may be proprietary (e.g., via licensing). If potential alternatives can be identified, a shortlist of the potential alternatives can be established for further detailed assessment with regard to technical feasibility, health benefits, comparison of risks, exist ing legal requirements, availability (e.g. sufficient availability or accessible to the manufacturer), and technical performance. In the event that no alternative is identified, i nformation should be presented on the actions undertaken to identify alternat ives. A compilation of resources and elements in support of chemical substitution and an assessment of alternatives can be found on the OECD webpage : http://www.oecdsaatoolbox.org/ Step 6: Description of identified potential relevant alternative(s) and conclusion on their technical feasibility CMR/ED phthalates are present in medical devices for a specific purpose depending on the intended use of the medical device. For example, phthalates offer the possibility for fine tuning the flexibility (e.g. optimal flexibility without kinking) of a PVC -based medical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 20 device. In addition, DEHP has a stabilising effect on red blood cells in blood bags (SCENIHR 201 5). Technical feasibility of an alternative is based on the alternative fulfilling the function of the CMR/ED phthalate. Therefore, the assessment of the functional properties in relation to the intended use of the medical device is essential. Besides functionality, performance under intended use conditi ons should also be considered. Argumentation shall be provided for justifying why possible substances and/or material substitutes, if available, or design or medical treatment changes, if feasible, are inappropriate in relation to main taining the functionality and/or performance of the medical device. For example, it might be the case that replacement is possible for one specific functional use whereas for another functionality the use of the CMR/ED phthalate remains necessary . Also oth er aspects related to performance of the alternatives need to be considered like material processing conditions (Crespo et al., 2007), material quality after sterilisation (Burgos and Jiménez 2009), and possible interaction with drugs in therapeutic infusi on systems (Treleano et al. , 2009, Salloum et al. , 2015, Tortolano et al., 2018). The benefit(s) should also be considered. An inventory of the benefit(s) of the potential alternative substances, materials, designs or medical treatments for patient populations (separately for vulnerable patient groups) should be presented (see section 7 ). The evaluation of the identified potential relevant alternatives can be done in a tiered way to avoid full assessments for each candidate alternative. For example, based on the outcome of the functionality evaluation, the choice of the potential relev ant candidates might be reconsidered and some might be discarded before performing the risk assessment (see Step 7). The ECHA guidance on the preparation of an application for authorisation and ECHA formats for Analysis of Alternatives provide more detailed information on how to conduct an initial screening of possible alternatives and to assess the technical feasibility of potential alternatives. Submitted applications for authorisations contain a number of examples (https://echa.europa.eu/applying -for-authorisation/preparing -applications -for- authorisation ) of technical feasibility assessment for uses of substances of very high concern. Step 7: Assessment of the risk of identified potential relevant alternatives The risk assessment of alternatives is comparative in nature. Its aim is to assist in the conclusion in section 5 whether the transition to the alternatives would lead to lower benefit and/or risk to human health for patients when compared to the current u se of the CMR/ED phthalates in the medical device. Th e methodology of the assessment in this step is similar to that in step 3 as performed for the phthalate to be evaluated with reference to the alternative. If potential relevant alternative s were identified under Steps 1 -6, a risk assessment of these potential relevant alternative substance/material or designs or medical treatments should be performed. The risk assessment should contain a description of the potential substance/material (alternative medical procedure) exposure of various person groups (e.g. including patients, donors, professional users) for which the medical device is intended to be used (considering single or repeated use). This should include separately Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 21 vulnerable groups . For each subgroup a different level of risk may be accepted based on the potential benefit of the medical device for that particular group . Risk management measures (EN ISO 14971, EN ISO 10993 -1) and their effectiveness to reduce exposure should be described and t aken into account in the assessment. Exposure estimation Estimate the potential release of the alternative substance(s) when used in various treatment modalities. Consider also the rate of leaching to estimate the potential exposure to the alternative substance. Multiple use scenarios (including various types of possible contact) should be considered for the exposure estimation of the alternative substance (e.g. frequent use of dialyzer) and different population groups. Hazard identification Identify hazards based on literature, supplier documentation and other information (such as risk assessments performed by regulatory bodies). Describe hazards associated with the alternative substance/material by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity including human data. Identify an adequate point of departure (PoD) for risk assessment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non - threshold effects (e.g. in the case of genotoxic carcinogens or for substances acting via an ED -mediated MoA), such a dose descriptor could be a T25 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Hazards should preferably be evaluated by a relevant exposure route for the intended use of the assessed medical device. For the hazard identification special attention should be on the determination of any potential CMR and/or ED property of the alternative substance used . For further information purposes, a procedure is described in ECHA Guidance on the application of the CLP criteria https://echa.europa.eu/documents/10162/23036412/clp_en.pdf/58b5dc6d -ac2a-4910- 9702-e9e1f5051cc5 or by searching Annex VI of CLP regulation. ED propert ies of the alternative substance/material can be described according to the recently published EFSA/ECHA guidance document . https://echa.europa.eu/documents/10162/23036412/bpr_guidance_identif_ed_en.pdf/1a 4d2811 -3faa-fe61-1de2-3cbce8fd4d95 These effects include impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental eff ects, and other potential toxic effects associated with phthalates with ED properties and reprotoxic effects category 1A/B. It needs also to be considered that the potential alternative (substances, materials, designs or medical treatments) could also have other hazards than those of the CMR/ED activity. These other hazards and their possible associated risks should be discussed for example by using the EN ISO 14971 and the EN ISO 10993 series. See also Table 1. Descri ption of risk (risk characteri sation) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 22 The risk can be described by comparing exposure levels that are considered safe with the expected exposure (realistic worst case use scenario). Exposure levels that are considered safe could be “Derived No Effect-Levels” (DNEL s) for threshold substances, “Derived Minim um Effect Levels” (DMEL s) for non -threshold substances or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE ). As such data are often obtained in rat studies, the use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited period of time. EN ISO 10993 -17:2002 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, a cceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors. For medical devices allowable limits of their chemical constituents can be determined by EN ISO 10993 -17. The risks can also be described by calculation of the Margin of Exposure (MoE) or the Margin of Safety (MoS) due to the substances present in a medical device , which is the ratio between the lowest PoD and the expected exposure (e.g. realistic worst case use scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18 ). Perform this evaluation for every patient group for which the device is intended to be used. Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the assessment could refer to these derived figures without referring to a detailed assessment of how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). Data on the relevant exposure route of the medical device application (e.g. intravenously) are preferred (see also Table 1A, EN ISO 10993 -1). The risk can be described by the so -called risk characterisation ratio (RCR), being a ratio between the exposure and the DNEL /DMEL . If such DNEL/DMELs are not used in the assessment, a justification should be stated (e.g. new information /studies). Determine and describe acceptability of the risk for the use of the potential alternative s. Risks may be acceptable when they are outweighed by the benefits for the patient. Consider any known adverse events associated with the operation of the device using the phthalate, and whether the potential alternatives might affect these adverse event s. These considerations can be based upon a systematic literature review (see MEDDEV 2.7/1rev4) . This exercise has to be performed for each potential relevant alternative substance and/or materials . A large number of phthalates exist and some may be potential relevant alternatives for the CMR/ED phthalate used in the medical device. However, a number of these phthalates are also classified as CMR and/or designated ED (see above and Table 1 Annex 5 ). Such phthalates might be identified as alternatives when the CMR/ED risk is reduced compared to the phthalate intended to be used. In addition, different substances , have also been proposed as alternative plastici sers. In 201 5 SCENIHR published an updated Opinion of potential alternative plastici sers for DEHP (SCENIHR Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 23 2015). Although many alternatives were potentially available, it was also observed that for many of them the information on potential risks and the necessary risk assessment was rather limited precluding their use as alternative s. For DEHP an extensive amount of literature is available, allowing a very careful evaluation of the risk associated to its use . In the event that the risk assessment of a potential relevant alternative cannot be performed due to lack of information, document ation should be presented on the actions undertaken to obtain information to characterise the risk, including the outcome (for example, QSAR /read across could be performed). Note shall be taken that alternative designs or medical treatments might lead to adaptation of endpoints for the benefit -risk assessme nt when compared to the toxicological endpoints of CMR/ED phthalates. The assessment of the risk should be accompanied by an estimation of the uncertainties in the described outcomes which might be qua ntitative (e.g. confidence interval, standard deviation) or qualitative (see section 9). Conclude the analysis of the potential relevant alternative(s) with a summary describing the possible scenario(s) ( see Fig ure 1). 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates Based on the information obtained above a decision can be made on the appropriateness of potential relevant alternative s (substance, material , design or medical treatment ). In this evaluation several factors need to be included such as weighing of technical feasibility, benefits and risks . And, if possible, quantification of benefits and risks. These steps entail a comparison of the CMR/ED phthalate “use-scenario” (summarised in step 3) with the “Non-use scenario ” (summarised in step 4) as shown in Figure 1. Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Compare the functionality and performance of CMR/ED phthalate in the medical device and the potential relevant alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 8 for each candidate identified as the potential relevant alternative in section 4. If several potential relevant alternatives have a similar functionality and hazard profile, exposure conditions and possibilities for Risk Management Measures (RMM) res ulting in risk reduction should be considered (see below). Risk management is described in EN ISO 14971. In this comparison also additional issues not directly related to the functionality and performance of the alternative itself, like technical possibili ties, sterilisation effects and Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 24 interactions with infusion liquids, are important for the application of the alternative and the comparison with the CMR/ED phthalates, and thus should be considered. Step 9: Comparison of risk(s) of CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives. Compare the risk of both CMR/ED phthalate and alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 9 for each potential relevant alternative. There may be difficulties in comparing the risks of a substance e.g. a phthalate, and the risks of a technical alternative such as medical design or medical treatment. For example, there may be risks as sociated with alternative technologies but these may not be of the same nature of the risk of the phthalate. However, the potential relevant alternative must represent a reduction in the overall risks to human health (Step 10) . Therefore, a comparison of risks must be conducted and the applicant will need to consider how these different risks might be compared in terms of risks to human health. Note that an alternative medical design or medical treatment may also result in expo sure to other risks previously not present in the treatment modality. Possible risks of these substances will also need to be considered in the assessment. The comparison with technological alternatives such as a medical design or medical treatment can nor mally not be fully quantitative (i.e. with directly comparable numeric values), as the hazards and associated risks will not be expressed in similar terms, but will in most cases be qualitative or semi -quantitative. Nevertheless, a clear and transparent de scription can give a good basis to conclude whether overall risks are reduced or not (Step 10) . Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Present summary/overvi ew of comparison of benefit and risk of CMR/ED phthalate used in the medical device with the potential relevant alternatives, including uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters presented. The summary should contain various aspects of functionality, performance, risk and benefit of the use of the original CMR/ED phthalate used in the medical devic e and the potential relevant alternative (s). In section 6 below the justification of the use of a CMR/ED phthalate is described based on the summary table comparing an alternative with the CMR/ED phthalate. Perform step 10 for every potential relevant alternative. Each of the assessments performed in steps 1 to 1 0 is associated with uncertainties. Certain uncertainties can be described by the use of measures like the standard deviation or confidence interval. For other uncertainties , a description may be necessary to explain the extent of the uncertainty and its impact on the final outcome . Benefit and risks should be described and weighted against each other in the use of the potential alternative substance /material in the medical device (or designs or medical treatments by choosing adequate endpoints) similar to the procedure for the CMR/ED phthalate (see step 2). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 25 6. Justification for the u se of CMR/ED phthalate Based on the comparison of functionality, performance, availability, risk and benefit, an argumentation can be built as to why a possible substance and/or material alternative, if available, or changes in designs or medical treatment, if feasible, are inap propriate in relation to maintaining the functionality, performance and the benefit -risk ratio or profile (quantitative/semi -quantitative or qualitative) of the medical device containing a CMR/ED phthalate. Explain the importance of any difference in ter ms of benefits and risks between the CMR/ED phthalate to be used in the medical device and potential relevant alternatives using value judg ements and explain how the use of the CMR/ED phthalate can be justified over the alternatives by describing the accep tability of trade -offs in the achievement of some criteria against others. Any advantage in benefits needs to be weighed against possible disadvantages in terms of functionality and risks. Both differences in benefits and risks need to be considered jointly. In building the argumentation for the use of a CMR/ED phthalate, note can be taken of the Memorandum on weight of evidence and uncertainties of SCHEER (SCHEER 2018). This Memorandum describes a methodology that classifies the strength of evidenc e in the human health risk assessment based on integration of different lines of evidence into strong, moderate, weak, uncertain and inconclusive (no suitable evidence available). Any weight of evidence evaluation needs to show the overall confidence in t he assessment. The argumentation should specifically take into account the intended use of such devices. This should include consideration and discussion of possible high risk groups such as children or pregnant or breastfeeding women, and other patient groups considered particularly vulnerable to such substances and/or materials. In addition, where applicable and available, any future update of these Guidelines shall be considered. A Table with the most relevant information and values should be used to p resent an overview of the performed assessment comparing the CMR/ED phthalate with potential alternative(s). A non-exhaustive example of such Table is presented below. The Table should be extended depending on the number of criteria evaluated and the numbe r of potential alternatives identified. Table 1: Example for a comparison of CMR/ED phthalate with potential relevant alternative(s). Assessment criteria Description (examples) Reference phthalate Alternative I Alternative II etc. Identification of substances/material etc Name and CAS number Chemical information CAS 117-81-7 Functionality/performance Used as plasticiser e.g. DEHP Clinical benefit/performance Treatment possibility e.g. Flexibility of tubing / red blood Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 26 cells storage Material benefit Concentration (% w/w) Leaching from medical device for relevant conditions e.g. media, temperature, etc (mg per hour/day) Exposure estimation (realistic worst case use scenario ) for relevant route of exposure Hazard identification Local and systemic acute and repeat -dose toxicity, ED - properties, organ toxicity, CMR properties, biocompatibili ty, and others Identification of a point of departure for risk assessment ( LOAEL, NOAEL, BMD, T25, BMD10) Identification of dose levels associated with minimal or negligible risk (e.g. DNEL, DMEL, TDI , TE, TI) Risk characterisation (MoE, MoS, RCR) Confidence estimation (see Table 2) Technical feasibility Other This Table shall be completed for every component of the medical device that contains CMR/ED phthalate(s ) above the 0.1% w/w level. For some medical devices used as a system (e.g. blood bag system) the whole system might be evaluated. Note that in case of alternative designs or medical treatments adequate endpoints for the comparison shall be chosen. These endpoints may represent risks that may be of a different nature than that of the risk of the phthalate. When the outcome of the comp arison shows that the alternative fulfils a comparable or better intended functionality as well as performance and shows a reduced risk, the use of a CMR/ED phthalate is not possible. The risk assessment should also indicate whether there would be a reduce d hazard concerning CMR and/or ED properties, and/or reduced exposure overall resulting in reduced risk. In this evaluation, other toxicities (e.g. for any Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 27 other organ or system ) of the potential relevant alternatives shall also be considered. So, the full toxicological profile of the potential relevant alternatives shall be taken into account. A balanced weighing of the benefit versus the risk has to be performed . For example it is possible to use a combination of a CMR/ED phthalate and PVC/material with h igh intrinsic toxicological hazards, thus accepting a risk from a toxicological perspective, in case the clinical benefit is very high . In contrast, a minor loss in medical functionality might be acceptable if there is a large reduction or even absence of risk. Each comparison of a potential alternative for the use of a phthalate should be based on the combination of functionality , risk and benefits for patients. In this final evaluation , the assessment of uncertainties associated with the alternatives (e.g. on the nature of the risks; assumptions made) should also be considered (see Table 2 below section 9). Therefore, where possible, quantitative results should be collected and compared (e.g. NOAEL, estimated exposure in mg/kg) and their uncertainties should be reported. Also a qualitative description of the uncertainties may be useful (see Table 2 below sec tion 9). Their impact on the conclusions should also be discussed. Although not the main subject of these Guidelines, it should be realised that availability and accessibility on the market might be a limitation for the introduction of an alternative subst ance/material. Some chemicals proposed as alternatives are widely available (e.g. BTHC, DEHT, DINCH, and TOTM) however, this may not be the case for other alternatives identified . The lack of the availability of a potential alternative for a medical device might result in the conclusion that replacement is not feasible and that the use of a phthalate with CMR and/or ED property continues in order to keep the device available for pat ients. So, besides technical feasibility in terms of functionality and risk reduction (risk assessment of the phthalate versus the alternative), also availability and accessibility on the market needs to be considered. The BRA of the CMR/ED phthalate shoul d be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated. A plan to perform an update of the relevant part of the technical file of the device needs to be submitted during the certification process (post -market surveillance plan referred to in Article 84, the requirements are set out in Section 1.1 of Annex III MDR) and this should also cover upd ates needed on the justification for the presence of CMR/ED phthalates . 7. Benefit assessment These Guidelines do not provide information for the benefit -risk assessment of the use of a medical device itself but are limited to the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates in a medical device above 0.1% (w/w). The evaluation of the overall benefit -risk assessment of a medical device is presented in other documents (e.g. MEDDEV 2.7/1 rev4, EN ISO 14971). The benefits of the CMR/ED phthalate use in a medical device need to be compared to the benefits of the potential relevant alternatives, with the focus of the analysis being on Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 28 the net or incremental benefits of use of the CMR/ED phthalate in comparison to the alternatives. These benefits may include material or clinical benefits. Uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters need to b e presented. 7.1 Material benefit A medical device does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but may be assisted in its function by such means. For the use of phthalates in medical devices, additional functionalit ies need to be considered. One of the functionalit ies is the fine -tuning of the flexibility of PVC when used as plasticiser s e.g. in intubation devices. For blood bag materials other requirements are , for example, resistance to heat and chemicals, especially during sterili sation, and permeability of gases to assure that pH and oxygen levels remain stable . In addition, DEHP has an additional property namely the stabilising effect on red blood cells (RBCs) (SCENIHR 2015). A number of alternatives were evaluated as alternative for DEHP in blood bags (Simmchen et al., 2012, SCHENIR 2015). Platelets are extremely sensitive to changes in the pH of the medium in which they are suspended, so sufficient gas permeability to O2 and CO 2 has to be assured in the containers devoted to their storage (Simmchen et al. , 2012). For this reason, DEHP has been almost fully replaced with BTHC, DINCH, and/or Trioctyltrimellitate (TOTM or Tri( 2 - ethyl hexyl)trimellitate (TEHTM) ) (Simmchen et al. 2012, Prowse et al. 2014). A better gas exchange has been found in bags plasticised with these chemicals . Also other materials, like polyolefins, are currently used for platelet storage bags (Prowse et al. 2014). This potentially will allow the stor age of platelet concentrates for up to 7 days, if measures to prevent bacterial contamination can be safely implemented. It should be noted that the benefit of phthalates in terms of material functionality and performance may differ from device to device. An alternative may be available for one application while this may not be available for another in view of added or specific demands on the functionality of the p hthalate . 7.2 Clinical benefits Clinical benefit of medical devices is defined in the MDR as follows: ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnos is, or a positive impact on patient management or public health; (Regulation (EU)2017/745: Article 2 Definitions: (53)): This “clinical benefit” has to be substantiated by the manufacturers in the “clinical evaluation” of the medical device, which includes a number of considerations. These include a discussion and overall conclusions covering safety and performance results, assessment of risks and clinic al benefits, discussion of clinical relevance in accordance Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 29 with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device and limitations of the investigation. A ”clinical benefit ” could include any meaningful, measurable, patient -relevant outcome as presented below. SCHEER identified the following examples that may be relevant for the use of phthalates (list not exclusive):  Improved survival rates  Improved length of hospital stay  Improved time of intervention  Improved time of placing ( among others in tubes and catheters)  Improved product quality/ clinical performance ( among others in tubes and catheters) in terms of: o Improved leakage rates o Improved breakage rates o Improved knotting rates o Improved blockage rates o Improved bending performance rates o Improved release rates of toxic substances o Improved release rates of (nano -)particles  Improved displacement rates  Improved possibilities for sterili sation  Reduction of diameters in relation to performance  Possibility to produce “multiple -purpose” devices, (e.g. inclusion of additional sensors), and therefore reduction of over -all patient -stress and patient -impact  Improved observability (safety) in terms of translucence, printability, radiopaque lines included, identifiab ility, traceability, etc. ( among others in tubes and catheters)  Fewer adverse events , e.g. r educed mucosal or endothelial irritation or injury rates ( among others in tubes and catheters)  Fewer serious adve rse events and serious incidents The benefit of the use of the CMR/ED phthalate should always be judged with respect to the “intended use” of the medical device and the exposed patient -group to the medical device and weighed in its clinical impact (“clinically relevant difference”). These aspects should be judged by clinical experts. Quantitative information on the benefits should be provided where possible or at a minimum qualitative description of their magnitude. Information on the probability of the benefit to occur and/or the duration of the benefit should also be included. 8. Methodologies for Benefit –Risk A ssessment In general, a Benefit - Risk A ssessment (BRA) aims to evaluate the desired effects of therapeutic mean s, medicine s or device s, against their undesired effects, i.e., risks for human health. An appropriate BRA can contribute to a more objective analysis and help conformity verification bodies and authorities towards a more objective and transparent decision -making process. Weighi ng the benefits and risks can be a complex task. It may involve the evaluation of a large amount of data that should be as accurate as possible , Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 30 without methodological weaknesses and biases. There is always some uncertainty around the actual benefits and r isks, because they can only be determined by looking at the information that is available at a given point in time which may contain various sources of uncertainty. For the BRA of medical devices in general, guidance is available in section A7.2. of MEDDEV 2.7/1, revision 4 “Clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC” . EN ISO 14971 (FDIS published in 2019) and the accompanying ISO/TR 24971 provide information on the risk benefit analys is to be performed within a risk management process. Additional information may be found elsewhere, for example in the documents of the FDA 2016, 2018,. It should be noted that the acceptability of any risk is weighted against the benefit of the use of the medical device. Several methodologies for BRA have been proposed (Guo et al, 2010 , Mt-Isa et al. 2014), of which most methodologies are so far , mainly used for pharmaceutical products. However, it should be underlined that f or medical devices the quantitative determination of a benefit -risk ratio may be rather difficult to be made and expressed in a figure. In such cases a qualitative approach of weighing the benefit based on expert judgement might be used. One methodology, namely the multi criteria decision analysis (MCDA), can be generally applied to various areas of BRA. Therefore, this methodology might also be suitable for performing the BRA of medical devices (see Annex 7). The MCDA methodology has its origins in decisi on theory aiming to evaluate multiple conflicting criteria in decision making. These criteria can include the benefits and risks of the use of a medical device on human health. The final BRA of both the used CMR/ED phthalate and potential relevant alterna tives should contain all aspects as indicated in the framework above. A quantitative or semi - quantitative description of the risks (e.g. MoS, RCR) and of the benefits of a medical device containing a CMR/ED phthalate or alternative should be the basis for a BRA. However, a lthough quantitative approaches for a BRA are preferable, a qualitative description of the value judgements about the balance of benefits and risks might also be an acceptable approach when justified (see step 10). 9. Uncertainty analysis Uncertainty plays an important role in medical decision making. It is widely accepted that, despite the methodological and technological improvements that were achieved in the past decades, there is never absolute certainty regarding the safety, effective ness, or performance of a medical treatment or use of a device. Therefore, the degree of certainty and thus uncertainty of the benefits and risks of a medical device is a factor that should always be considered when making BRA. There are various sources of uncertainty in bio -medical studies; a major source of uncertainty is the biological differences among individuals. Another source of uncertainty is the intra - and inter - variability of the laboratories, with respect to equipmen t, reagents, and methods used. It is also accepted that diagnostic tools which evaluate benefit and risk share several limitations , giving false negative and false positive results in a variety of cases. Observer variation occurs quite often and should alw ays be taken Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 31 into account. Other factors that may influence the degree of uncertainty include: the type of clinical information available (e.g., clinical investigation data, observational studies, evidence derived from registries or use experience), the re presentativeness of the information (e.g., sample size, relevance of the sample to the referent population exposed to the device), as well as the statistical inferences derived from the information. A number of techniques for uncertainty analysis are descr ibed in t he Guidance for Socio - Economic Analysis of ECHA (ECHA 2011). The aim is to determine whether uncertainties in the estimation of impacts could affect the overall conclusions. More accurately , the techniques shown can be used to either reduce the va riability of estimates, or to help test whether uncertainties affect the conclusions drawn. The only way to actually reduce uncertainty is through better data, better understanding and knowledge of the uncertainties and through further analysis. However, i n most cases residual uncertainties will remain. Recently EFSA published a guidance on uncertainty analysis (EFSA 2018 a) and a description of the principles and methods behind the guidance for uncertainty analysis (EFSA 2018 b). The EFSA Guidance recogni ses that the form and extent of uncertainty analysis, and how the conclusions should be reported, vary widely depending on the nature and context of each analysis and the degree of uncertainty that is present. Therefore it is important to identify appropriat e options for each BRA. The EFSA documents provide a flexible framework for uncertainty analysis within which different methods may be selected, according to the needs of each BRA. It seems likely that also for medical devices a similar flexibility is need ed in view of the broad range of medical devices used. EFSA describes a number of main elements of uncertainty that need to be considered in the uncertainty analysis: EFSA: Main elements of uncertainty analysis  Identifying uncertainties affecting the assessment. This is necessary in every assessment and should be done in a structured way to minimise the chance of overlooking relevant uncertainties. In assessments that follow standardised procedures, it is only necessary to identify nonstandard uncertai nties.  Prioritising uncertainties within the assessment plays an important role in planning the uncertainty analysis, enabling the assessor to focus detailed analysis on the most important uncertainties and address others collectively when evaluating overa ll uncertainty. Often prioritisation will be done by expert judgement during the planning process, but in more complex assessments it may be done explicitly using influence analysis or sensitivity analysis.  Dividing the uncertainty analysis into parts. In some assessments, it may be sufficient to characterise overall uncertainty for the whole assessment directly, by expert judgement. In other cases, it may be preferable to evaluate uncertainty for some or all parts of the assessment separately and then comb ine them, either by calculation or expert judgement.  Ensuring the questions or quantities of interest are well -defined. Each question or quantity of interest must be well -defined so that the true answer or value could be determined, at least in principle. This is necessary to make the question or quantity a proper subject for scientific assessment, and to make it possible to express uncertainty about the true answer or value clearly and unambiguously. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 32 Some assessments follow standardised procedures, within which the questions and/or quantities of interest should be predefined. In other assessments, the assessors will need to identify and define the questions and/or quantities of interest case by case.  Characterising uncertainty for parts of the uncertainty analysis. This is needed for assessments where assessors choose to divide the uncertainty analysis into parts but may only be done for some of the parts, with the other parts being considered when characterising overall uncertainty.  Combining uncertainty f rom different parts of the uncertainty analysis. This is needed for assessments where the assessors quantify uncertainty separately for two or more parts of the uncertainty analysis.  Characterising overall uncertainty. Expressing quantitatively the overall impact of as many as possible of the identified uncertainties, and describing qualitatively any that remain unquantified. This is necessary in all assessments except those standardised assessments where only standard uncertainties are identified (e.g. inter-and intra -species uncertainty factors).  Prioritising uncertainties for future investigation. This is implicit or explicit in any assessment where recommendations are made for future data collection or research, and may be informed by influence or sensit ivity analysis.  Reporting uncertainty analysis. Required for all assessments, but extremely brief in standardised assessments where only standard uncertainties are identified. A number of methods that can be used in the uncertainty analysis include:  Sensitivity analysis  Scenario analysis  Expert judgement  Monte Carlo Simulations Some of these techniques can be used in combination (e.g. scenario analysis together with expert judgement to establish ranges for key variables) but also together with less commonly used techniques such as risk -risk analysis, Delphi techniques and portfolio analysis, which can be used to help reduce the variability of estimates but are not discussed in these Guidelines. After performing the uncertainty analysis , the observed overall confidence associated with a BRA can be expressed as a probability score. This score gives the risk assessor an indication what the uncertainty is in the BRA. In situations where sufficient data are available, a quantitative categori sation of probability levels is preferred. If this is not possible, the manufacturer should give a qualitative description. A good qualitative description is preferable to an inaccurate quantitative description ( EN ISO 14971). EFSA (EFSA, 2018 b) and SCHEER (2018) use a rather detailed probability scale of 9 and 7 probab ility levels, respectively. EFSA stresses that this scale may be used as an aid to support the development of judgements and that other ranges or qualitative descriptions can be used as well. EFSA (2018 b) also argues that presenting the numerical probabilities alongside verbal expressions of probability, e.g. ‘Likely (> 66% probability)’, increases the consistency of interpretation. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 33 A detailed scale does not seem to be applicable for the uncertainties that can be obtained during a BRA evaluation of medical devices. For medical devices, a probability scale as indicated in Table 2 may b e used EN ISO showing a 5-level scale recommended by ISO for semi -quantitative assessments ( EN ISO 14971, Table D4 ). Table 2 further show s the verbal terms and subjective probability ranges that are based on a simplification of the EFSA/SCHEER scales. Table 2: Probability scale for (semi -)quantitative description of the overall confidence ISO probabil ity term Subjective probability range Probability term Frequent Probable Occasional Remote Improbable > 90% 66-90% 33-66% 10-33% <10% very l ikely likely as likely as not unlikely very unlikely Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 34 10. Conclusions These G uidelines are intended to be used for a BRA of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties . The Guidelines can be used for the justification of the use of CMR/ED phthalates in a medical device according to the Regulation (EU) 2017/745 on medical devices. They also provide a framework on how to assess and compare possible alternative substances, materials , designs or medic al treatments to the use of CMR/ED phthalates in medical devices. Major aspects include the functionality of phthalates, the performance of the medical device using the phthalate or the potential relevant alternative for the phthalate, as well as the risk assessment of the phthalate or the alternative s. In the end , the benefit (s) shall be weighed against the possible risk s of the use of the CMR/ED phthalate and of the alternative substance, materials , desig ns or medical treatments . This overall analysis will determine whether it is justified or not to use a CMR/ED phthalat e in a medical device. In view of the concern of the CMR/ED properties of phthalates, further research to possibilities to replace these p hthalates in medical devices is highly encouraged by the SCHEER . During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices , SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices . As the BRA of the presence of phthalates may have an impact on the conclusions of the "overall" benefit -risk determination of the medical device, a periodic update of the BRA of the medical device may be needed. The BRA of the presence of the CMR/ ED phtha late should be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated . A plan to perform an update of the general BRA for the medical device should be included in the dossier before marketing the device, and this should also include a plan regarding the necessary updates on the evaluation of alternatives for CMR/ED phthalate s. Pending on new scientific evidence, i t is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 35 11. Consideration of the responses received during the public consultation process A public consultation on these Guidelines was opened on the website of the non -food scientific committees from 18 March to 29 April 2019 . Information about the public consultation was broadly communicated to national authorities, international organisation s and other stakeholders. A to tal of 197 submissions from 19 contributors (providing 378 comments and additional references ) provided input to different chapters and subchapters of the document. The vast majority of comments came from industry and were requesting clarifications . Each submission was carefully considered by the SCHEER and the scientific opinion has been revised to take account of relevant comments. The literature has been accordingly updated with relevant publications. The SCHEE R expresses their thanks to all contributors for their comments and for the literature references provided during the public consultation. The text of the comments received and the response provided by the SCHEER is available at: https://ec.europa.eu/health/scientific_committees/consultations/public_consultations/sch eer_consultation_08_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 36 B. REFERENCES  Bui TT, Giovanoulis G, Cousins AP, Magnér J, Cousins IT, de Wit CA. Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ. 2016 Jan 15;541:451 -467. do i: 10.1016/j.scitotenv.2015.09.036 .  Burgos N, Jiménez A.Degradation of poly(vinyl chloride) plasticized with non - phthalate plasticizers under sterilization conditions. Polymer Degradation and Stability 94 (2009) 1473 –1478.  Crespo JR, Balart R, Sanchez L, López J. 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EFSA Journal 2018;16(1):5123, 39 pp. (https://doi.org/10.2903/j.efsa.2018.5123 .)  EFSA Scientific Committee, Benford D, Halldorsson T, Jeger MJ, Knutsen HK,More S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V, Solecki R, Turck D, Younes M, Craig P, Hart A, Von Goetz N, Koutsoumanis K, Mortensen A, Ossend orp B, Germini A, Martino L, Merten C, Mosbach -Schulz O, Smith A and Hardy A, 2018. Scientific Opinion on the principles and methods Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 37 behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. 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Benefit -Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics. Guidance for Industry and Food and Drug Administration Staff. September 25, 2018. Washington , USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM404773.pdf  FDA. US Food and Drug Administration. Factors to Consider Regarding Benefit - Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions. Guidance for Industry and Food and Drug Administration Staff. December 27, 2016. Washington, USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM506679.pdf  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report of the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 38  Hass U, Christiansen S, Andersson A -M, Holbech H, Bjerregaard P. Report on interpretation of knowledge on endocr ine disrupting substances (EDs) – what is the risk? Danish Centre on Endocrine Disruptors, Denmark . (http://www.cend.dk/files/ED_Risk_report -final-2019.pdf)  Katsikantami I, Sifakis S, Tzatzarakis MN, Vakonaki E, Kalantzi OI, Tsatsakis AM, Rizos AK. A global assessment of phthalates burden and related links to health effects. Environ Int. 2016;97:212 -236. doi: 10.1016/j.envint.2016.09.013  Mariana M, Feiteiro J, Verde I, Cairrao E. The effects of phthalates in the cardiovascular and reproductive systems: A review. 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Impact of the nature and concentration of plasticizers on the ability of PVC to sorb drug. International Journal of Pharmaceutics 496, 664 –675, 2015.  SCHEER 2018 Memorandum on weight of evidence and uncertainties. Revision 2018. https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/s cheer_o_014.pdf  SCENIHR Opinion on The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). 2015 https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_047. pdf  Simmchen J , Ventura R , Segura J . Progress in the removal of di -[2-ethylhexyl] - phthalate as plasticizer in blood bags. Transfus Med Rev. 2012; 26(1):27 -37. doi: 10.1016/j.tmrv.2011.06.001. Epub 2011 Aug 5.  Tortolano L, Matmati H, Bourhis M,Manerlax K, Lemare F, Saunier J,Yagoubi N. DinCH and ESBO actual migration from PVC infusion tubings used in an oncopediatric unit. J. Appl. Polym. Sci. 135, 46649, 2018. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 39  Treleano A,Wolz G,Brandsch R, Welle F. Investigation into the sorption of nitroglycerin and diazepam intoPVC tubes and alternative tube materials during application . Intl JPharmac 369, 30 –37, 2009.  Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008 ; 118(4):1479 -90. doi: 10.1172/JCI34241. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 40 C. ANNEXES Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates 1. Background What are phthalates? Phthalates are the esters of 1,2 -benzenedicarboxylic acid (o -phthalic acid) and their chemical structure consists of one benzene ring and two ester functional groups linked with two consecutive carbons on the ring10. The hydrocarbon chains of the ester groups are either straight or branching; they give each substance its name and they are responsible for the different properties amo ng phthalates. Phthalate esters (PEs) may be categori sed into three distinct groups according to the length of their carbon chain. High molecular weight (HMW) phthalates include those with 7 –13 carbon atoms in their carbon chain and low molecular weight (L MW) those with 3 –6 carbon atoms in their backbone. DEHP is classified as a LMW phthalate. A third group includes dimethyl phthalate (DMP) and diethyl phthalate (DEP)11. What are they used for? Phthalates are widely used in industry as plastici sers of polym ers such as polyvinyl chloride (PVC). HMW phthalates are used in a variety of applications such as coated fabrics and roofing membranes. LMW phthalates are used in medical devices, adhesives, paints, inks and enteric -coated tablets. DEHP is the most widel y used phthalate in medical devices. DMP and DEP are not used as plastici sers but e.g. as additives in cosmetics, medical devices, and household products. Potential CMR or endocrine -disrupting properties The interaction of phthalates with the polymers the y are embedded in is weak, so they may migrate from the plastic product into the environment and into the human body if the product is in contact with it. Correlation between exposure to a range of phthalates and adverse health effects has been documented in animals and humans (see for example tables in Mariana et al. 2016 and Katsikantami et al. 2016). A number of phthalates are suspected of and/or have been classified or identified as having CMR or endocrine -disrupting properties. 10 A global assessment of phthalates burden and related links to health effects. Katsikantami et al., Environ Int. 2016 Dec;97:212 -236. https://www.ncbi.nlm.nih.gov/pubmed/?term=katsikantami 11 Footnote added by SCHEER. It should be noted that there are hundreds of phthalates of which only a limited number is used as plasticiser in polymers. Phthalates can be categorised according to the length of the carbon chain and one of these categorisations is mentioned in the mandate of DG GROW. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 41 Previous work of Commission Scientific Committees on phthalates Previous opinions on the most commonly used phthalate DEHP [di -(2-(ethylhexyl) phthalate] in medical devices were issued by EU Scientific Committees in 2002 (SCMPMD), 2008 and 2015 (SCENIHR). The 2008 Opinion concluded that "So far, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans", but noted that "newborn and pre -term born male infants are of special concern" . In the 2015 Opinion, SCENIHR additi onally identified that "patients subject to haemodialysis procedure may be at risk of DEHP induced effects" . The Committee noted that "Food is the primary source of exposure to DEHP for the general population." In both opinions, the Committee emphasised th at "the benefit of the medical devices must also be considered" and in the 2008 Opinion the Committee states that "each alternative to DEHP, however, must also be evaluated with regard to their functionality in respect to medical devices. The risk and bene fits of using alternative plasti cizers should be evaluated case by case." In the 2015 opinion, the Committee states that “The potential for replacement of DEHP in these products should be considered against their efficiency in the treatment, as well as the toxicological profile and leaching properties of the alternative materials.” The legal obligation Article 5 paragraph 2 of the Regulation 2017/745 on medical devices stipulates: "A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose." Accordingly, Section 10.4 of Annex I, which deals with substances in medical devices, states that "Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device." Particular substances of concern are those which (a) are carcinogenic, mutagenic or toxic to reproduction (CMR), of category 1A or 1B,12 or (b) have endocrine -disrupting properties (ED)13. The Regulation states that: "Devices, or those parts thereof or those materials used therein that:  are invasive and come into direct contact with the human body,  (re)administer medicines, body liquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body" 12 in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 13 identified as such in accordance with the relevant provisions of Regulation (EC) No 1907/2006 or respectively of Regulation (EU) No 528/2012 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 42 shall only contain any such substance ab ove the concentration of 0.1% weight by weight where justified pursuant to Section 10.4.2. The justification shall be based on several elements, including the latest relevant scientific committee guidelines on benefit -risk assessment of the presence of suc h substance in devices. According to Section 10.4.3, the Commission shall provide a mandate to the relevant scientific committee to prepare such guidelines for phthalates which are subject to these provisions. These guidelines are explicitly requested by t he Regulation to be available at the latest on the date of application of the Regulation, and are to be updated whenever appropriate on the basis of the latest scientific evidence, or at least every five years. 2. Terms of reference The Scientific Committee is requested to provide guidelines on the benefit -risk assessment of the presence, in the medical devices specified below, of phthalates which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction or endocrine -disrup ting, according to the criteria outlined in the previous section. The devices covered, or those parts thereof of those materials used therein, are those which:  are invasive and come into direct contact with the human body,  (re)administer medicines, body l iquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body. The guidelines shall include guidance on how, for an individual device, to:  analyse and estimate potential patient or user exposure to the substance,  analyse possible alternative substances, materials, designs, or medical treatments,  to justify why possible substance and/or material substitutes, if available, or design change s, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratios of the product, including taking into account if the intended use of such devices includes treatment of children or treatment of pregnan t or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials. In addition, the Scientific Committee is requested to :  identify any relevant knowledge gap , and  to give consideration to what extent of new evidence would be deemed appropriate to justify an update of these guidelines before the maximum period of five years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 43 In order to ensure the appropriateness of this guidance the Scientific Committee should inter alia :  involve at the appropriate level the notified bodies active in the field of medical devices, or other relevant stakeholders such as Competent Authorities, professional and patient associations, industry associations, while maintaining scientific independence ,  involve to the necessary extent the relevant EU Agencies and Scientific Committees. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 44 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances The requirement for justification of the presence of CMR 1A or 1B and/or ED hazardous substances is described in Annex I 10.4.2 as presented in the text box below. 10.4. Substances 10.4.1. Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as fa r as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine -disrupting properties for which there is scientific ev idence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been ad opted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established the rein. 10.4.2. Justification regarding the presence of CMR and/or endocrine -disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the subs tance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer -reviewed studies, scientific opinions from relevant scientific committees and an analysis of the avail ability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratio s of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances an d/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3 and 10.4.4. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 45 Annex 3: Definitions/descriptions – References - Glossary Definitions ( Regulation (EU) 2017/745 ) Benefit -risk determination: means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer. Performance: means the ability of a device to achieve its intended purpose as stated by the manufacturer. Clinical performance: means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteri stics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer. Clinical benefit: means the positive impact of a de vice on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health. Risk: means the combination of the probability of occurrence of harm and the severity of that harm. Adverse event: means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or othe r persons, in the context of a clinical investigation, whether or not related to the investigational device. Serious adverse event: means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subjec t, that resulted in any of the following: (i) life -threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitali sation or prolongation of patient hospitali sation, (iv) medical or surgical intervention to p revent life -threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) fetal distress, fetal death or a congenital physical or mental impairment or birth defect. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 46 Incident: means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use -error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesir able side -effect. Serious incident: means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a pati ent's, user's or other person's state of health, (c) a serious public health threat. Serious public health threat : means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time. Device deficiency: means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer. Regulation (EU) 2017/745 Annex XIV Clinical evaluation and post -market clinical follow -up. Part A “Clinical evaluation” Section 3 describes the characteristics that shall be considered for demonstration of equivalence . “A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. T he following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: Technical : the device is of similar design; is used under similar conditions of use; has similar specifications and pr operties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and cr itical performance requirements; Biological : the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including de gradation products and leachables; Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 47 Clinical : the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has simila r relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in or der to justify their claims of equivalence. ” Definitions on assessment of alternatives (OECD Toolbox Glossary) Note: The term "chemical" is used synonymously with "substance" Alternativ es assessment : A process for identifying and comparing potential chem ical and non -chemical alternatives that can be used as substitutes to replace chemicals or technologies of high concern1 Chemical substitution : The process of replacing a chemical of concern with a safer chemical, material or product, or technology/process that eliminates the need to use that chemical Cost/benefits and availability : The negative (cost) and positive (benefit) implications, direct and indirect, resulting from some actio n. This includes both financial and non - financial information. Availability refers to the production of an alternative and its market accessibility3 Functional use approach : This approach starts with identifying the function that is desired. The concept is applied in two ways: first and foremost, to characteri se the purpose a chemical or mixture serves, or the properties it imparts in a product or process (functional use), and second, to eva luate the function of the product and how its use may influence the assessment of alternatives4, 5 Material substitution : The process of replacing a material containing a chemical of concern with a safer chemical, material, product or technology/process that eliminates the need to use that chemical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 48 Mixture : A composition of at least two chemicals in which they do not react6 Technical feasibility : The determination as to whether the performance or functional requirements of a chemical, material or product could be fulfilled or replaced by eliminating or using an alternative chemical, material, product, process or technology, while considering any need for process adaptations and changes3 Process modification : Changes in manufacturing processes to eliminate, reduce or substitute chemicals of concern. Such changes may include synthesis pathways, waste reduction, and manufacturing procedures where chemicals are used. Product performance : The ability of a product to meet identified performance requirements. The boundaries of performance characteristics are defined by the user3 Product substitution : The process of replacing a product containing a chemical of concern with a chemical, material or product or technology/process that eliminates, reduces or substitutes the need to use that chemical. 1 Adapted from Alternatives Assessment Guide, version 1.0 . 2013. Interstate Chemicals Clearinghouse. 2 REACH. Title I, Chapter 2, Article 3. 3 Current Landscape of Alternatives Assessment Practice: A Meta -Review. Organisation for Economic Cooperation and Development. 2013. 4 U.S. EPA. 2006. National Pollution Prevention and Toxics Advisory Committee (NPPTAC) Recommendation to the EPA Administrat or and Deputy Administrator on Incorporating the Functional Use Approach into OPPT Activities. 5 Lavoie, E. T., et al. 2010. "Chemical Alternatives Assessment: Enabling Substitution to Safer Chemicals." Environmental Science & Technology 44(24): 9244 -9249. 6 Adapted from U.N. Global Harmonized System of Classification and Labelling of Chemicals . 2003. 7 ECHA, 2008. Guidance on Socio -Economic Analysis - Restrictions. 8 Adverse event means pre -clinical and clinical occurrences of an effect whereas incident indicates a clinical effect occurring during post -market surveillance. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 49 Reference s  ECHA (2011) Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  EFSA (2019) Draft update of the risk assessment of di -butylphthalate 1 (DBP), butyl-benzyl -phthalate (BBP), bis(2 -2 ethylhexyl)phthalate (DEHP), di - isononylphthalate (DINP) 3 and di -isodecylphthalate (DIDP) for use in food contact 4 materials http://www.efsa.europa.eu/en/consultations/call/190221 .  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report o f the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66. Glossary BBP Benzylbutylphthalate BMD Bench Mark Dose BRA Benefit -Risk Analysis BTHC Butyryl -tri-n-hexylcitrate CAS Chemical Abstracts Service CEN European Committee for Standardization CLP Classification Labelling and Packaging regulation (EC No 1272/2008) CMR Carcinogenic, Mutagenic, toxic to Reproduction (Reprotoxic) DBP DiButylphthalate, DCHP Dicyclohexylphthalate DEHP Diethylhexylphthalate DIBP Diisobutylphthalate DIDP Di isodecyl phthalate) DINCH 1,2- cyclohexan edicarboxylic acid, di isononyl ester) DINP Di isononyl phthalate) DIPP Diisopentylphthalate DMEP Bis(2-methoxyethyl)phthalate DNHP Dihexylphthalate DHNUP 1,2-Benzenedicarboxylic acid, di -C7-11-branched and linear alkyl esters DPP Dipentyl phthalate DMEL Derived Minimum Effect Level DNEL Derived No Effect Level EC European Commission ECB European Chemicals Bureau (now ECHA) ECHA European Chemicals Ag ency (formerly ECB) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 50 ED Endocrine Disruptor EEC European Economic Community EMA European Medicines Agency EFSA European Food Safety Authority EN-ISO CEN and ISO combined published document FDA Food and Drug Administration (USA) FDIS Final Draft International Standard ISO International Organization for Standardization LOAEL Lowest Observed Adverse Effect Level MCDA Multi Criteria Decision Analysis MDD Medical Device Directive (Council Directive 93/42/EEC) MDR Medical Device Regulation (EU 20 17/745) MoA Mode of Action MoE Margin of Exposure MoS Margin of Safety NICU Neonatal Intensive Care Unit NOAEL No Observed Adverse Effect Level OECD Organization for Economic Cooperation and Development PoD Point of departure PVC Polyvinyl chloride RBC Red Blood Cell RCR Risk Characterisation Ratio REACH Registration, Evaluation, Authorisation and restriction of CHemicals. SCHEER Scientific Committee on Health, Environmental and Emerging Risks SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks T25 25 % increase of the tumour rate over controls TDI Tolerable Daily Intake TE Tolerable Exposure (EN ISO 10993 -17:2002 in mg/day) TEHTM Tri( 2 -ethyl hexyl)trimellitate also TOTM Trioctyltrimellitate TI Tolerable Intake TOTM Trioctyltrimellitate also TEHTM Tri( 2 -ethyl hexyl)trimellitate TWI Tolerable Weekly Intake Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 51 Annex 4: CMR and/or ED substances CMR substances are substances identified and classified as carcinogenic, mutagenic or toxic for reproduction of different categories based on the intrinsic toxic properties of a substance for which categories 1A and 1B apply to these Guidelines. In Europe, classification for these endpoints is harmonised through harmonised classification and labelling (CLH). Details can be found at https://echa.europa.eu/regulations/clp/understanding -clp. For a specific substance to be classified as CMR 1A, 1B or 2 a dossier needs to be prepared and if the Commission finds that the proposed classification is appropriate, it submits a draft decision concerning the inclusion of that substance in Part 3 of Annex VI to the CL P Regulation (Regulation (EC) 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures).  Category 1A means that the substance is a known human carcinogen, mutagen or reproductive toxicant based on human evidence.  Category 1B means that the substance is a presumed human carcinogen, mutagen or reproductive toxicant based on animal studies.  Category 2 means that a substance is considered as suspected carcinogen, mutagen or reproductive toxicant based on limited evidence from ani mal studies or humans (not part of these Guidelines) . Documents on the classification are publicly available , and a tutorial to search entries is given here: http://www.chemsafetypro.com/Topics/EU/Annex_VI_to_CLP:_List_of_Harmonised_Class ification_and_Labelling_for_Certain_Hazardous_Substances.html Guidance for the identification of endocrine disrupto rs (ED) in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009 has been published on 7th June 2018 by ECHA and EFSA (doi: 10.2903/j.efsa.2018.5311; EFSA Journal 2018;16(6):5311) which can be accessed via: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2018.5311 This EFSA/ECHA Guidance describes when a substance shall be considered as having endocrine disrupting properties. “A substance shall be considered as having endocrine disrupting properties if it meets all of the following criteria: a) it shows an adverse effect in [an intact organism or its progeny]/[non -target organisms], which is a change in the morphology, physiology , growth, development, reproduction or life span of an organism, system or (sub)population6 that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other in fluences; b) it has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system; c) the adverse effect is a consequence of the endocrine mode of action. It should be highlighted that the ‘endocrine mode of action ’ as stated in point (b) should be interpreted as ‘endocrine activity ’ while the term ‘endocrine mode of Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 52 action’ in point (c) covers the link between the adverse effect and the endocrine activity identified in points a) and b), respectively. Keeping this in mind point (b) abo ve should be understood as (differences from above in italics ): it shows endocrine activity, i.e. it has the potential to alter the function(s) of the endocrine system; Consequently point (c) above should be understood as (differences from above in italics ): the substance has an endocrine disrupting mode of action, i.e. there is a biologically plausible link between the adverse effect and the endocrine activity. ” EDs identified with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 concern ing the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), will finally enter the REACH candidate list of substances of very high concern for potential inclusion in REACH Annex XIV. The information can be found in the respecti ve decision document accessible via : https://echa.europa.eu/candidate -list-table. For substances having endocrine -disrupting properties as indicated above, there is currently no information concer ning whether it is foreseen to publish them in central lists or annexed to a Regulation. EDs identified by the delegated act pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products, can be accessed through the Biocidal Products Committee opinions on active substance approval which can be accessed via ECHA’s website (https://echa.europa.eu/regulations/biocidal -products -regulation/approval -of-active - substances/bpc -opinions -on-active -substance -approval ). Substances undergoing an ED assessment under the REACH or Biocidal Products regulations that have been brought for discussion to ECHA’s ED Expert Group are included in ECHA’s endocrine disruptor (ED) assessment list: https://echa.europa.eu/ed - assessment . For each substance, the table shows the assessing or evaluating Member State (submitter), the outcome and the suggested follow -up for the assessment, and the date of the latest update to the list entry. Recently the Commission Implementing Decision (EU) 2017/1210 was published that identified some phthalates (Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) and Diisobutyl phthalate (DIBP)) as substances of very high concern due to their endocrine disrupting properties with probable serious effects to humans (European Commission 2017). https://publications.europa.eu/en/publication -detail/ -/publication/357b3d45 -620f-11e7- 9dbe-01aa75ed71a1/language -en/format -PDF For completeness, even if not relevant for the purpose of this guidelines, Bis(2 - ethylhexyl) phthalate (DEHP) was also identified in 2014 as a substance of very high concern due to its endocrine disrupting properties with probable serious effects to the environment. In addition, Commission Implementing Decision (EU) 2018/636 identified Dicyclohexylphthalate (DCHP) as subs tance of very high concern (SVHC) according to Article 57(f) of REACH Regulation (EC) 1907/2006, due to its endocrine disrupting Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 53 properties with probable serious effects to humans. https://eur -lex.europa.eu/legal - content/EN/TXT/PDF/?uri=CELEX:32018D0636&fr om=EN Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 54 Annex 5: Legislation on CMR and/or ED phthalates Due to their reprotoxic properties and additionally since 2014 for DEHP due to their endocrine disrupting properties for the environment and since 2017 for DEHP, BBP, DBP, and DIBP due to their endocrine disrupting properties for human health , a considerable number of phthalates have been identified as substances of very high concern (SVHC) and therefore included in the candidate list for the inclusion in Annex XIV of the REACH regulation (Annex XIV of REACH EC 1907/2006 , see https://echa.europa.eu/de/candidate -list-table for the most recent update of the candidate list). Eight phthalates are also listed on the Authorisation list (Annex XIV of REACH), namely DEHP, BBP, DIBP, DBP, DIPP (diisopentylphthalate), Bis(2 -methoxyethyl) phthalate, dipentyl phthalate, and N -pentyl -isopentylphthalate. Since February 2015 DEHP, BBP, DIBP, and DBP cannot be used within the European Union withou t authorisation. The same provision would apply to the remaining four phthalates on Annex XIV from July 2020. To date, applications for authorisation have been submitted for DEHP and DBP only. However, imported articles do not come under the authorisation requirement. For the purpose of evaluating applications for authorisation, the ECHA Committee for Risk Assessment (RAC) has developed reference DNELs for several substances, including DEHP, BBP, DBP, and DIPP. (See Evaluating Applications table/Ref erence D NELs on ECHA’s website: https://echa.europa.eu/applying -for-authorisation/evaluating -applications .) Risks to human health arising from the use of an Annex XIV substan ce in medical devices regulated by Directives 90/385/EEC, 93/42/EEC or 98/79/EC are exempted from authorisation requirements under Title VII of the REACH Regulation14. ECHA is currently preparing a recommendation on the inclusion of the ED properties for environment for DEHP in Annex XIV to REACH .15 If DEHP is included on Annex XIV for environmental hazards , applications for authorisations may need to be prepared for uses of the substance in medical devices in the future. REACH Annex XVII (entry 51) also restricts the placing on the market of articles containing DEHP, BBP, DBP, and DIBP in concentration greater than 0.1% weight by weight of the plasticised material, individually or in combination in a range of articles. These articles include toys16 and childcare articles, as well as other primarily consumer and professional use articles whic h lead to dermal or inhalation exposure. (For risk assessment conclusions, including derivation of a DNEL for DIBP, see Compiled RAC & SEAC opinion and background document on ECHA’s website: https://echa.europa.eu/previous -consultations -on-restriction -proposals/ -/substance - rev/13919/term .) 14 These Regulations will be replaced by:  Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC •Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU 15 https://echa.europa.eu/draft -recommendation -for-amendment -of-authorisation -list-entries -previous - consultation 16 The Toy Safety Directive (2009/48/EC) stipulates that chemicals that are susceptible to cause cancer, change genetic information, harm fertility or harm an unborn child (CMR substances) are no longer allowed in accessible parts of toys beyond the concentration limits set in the CLP Regulation ((EC) No 1272/2008). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 55 REACH Annex XVII (entry 52) restricts the placing on the market and the use of DINP, DIDP, and DNOP, as a substance or in mixture, in concentrations greater than 0.1% weight by weight of the plasticised material in toys and childcare articles which can be placed in the mouth of children. In 2010, the European Commission requested ECHA to review the scientific evidence on the risks posed by articles containing these phthalates with the view to conclude on the need or not for further actions under REACH. The report and RAC risk assessment conclusions (including information on the derivation of DNELs) can be foun d on ECHA’s website: https://echa.europa.eu/consultations -draft-review - report -previous -consultations/ -/substance -rev/1108/term . EFSA recently launched a consultation on its updated 2005 risk assessments of DBP, BBP, DEHP, DINP and DIDP which are authorised for use in plastic FCM, by using the same database as ECHA for its 2017 assessment of certain phthalates. The draft update of the ri sk assessment can be found here: http://www.efsa.europa.eu/en/consultations/call/190221 In addition to the REACH legislation, there is also product -specific legislation which regulates certain phthalates, i.e. the Cosmetic Products’ Regulation (EC/1223/2009) and the Regulation on materials and articles intended to come into contact with food ( Food Contact Materials, Regulation EC 1935/2004 , as general framework regulation and Regulation EU 10/2011 specific for plastic materials and articles destined to be in contact with foodstuffs , recently amended by Regulation 2018/831 ). Both in the MDD (93/42/EEC) and the more recent MDR (2017/745), phthalates are specifically mentioned for their use in medical devices. For a number of phthalates there is legislation available that might contain information relevant for the use of phthalates in medical devices. Of specific relevance for medical devices may be the Regulation EU 10/ 2011, which also incl udes provisions for the use of phthalates in food contact materials and articles with respect to migration limits. This may be a parallel with migration (and thus potential internal exposure) of phthalates as present in polymers used for medical device man ufacturing. In Annex I of the Regulation EU 10/2011 all substances are listed, which are authorised for the use as starting material or additive for plastic layers in plastic materials and articles. Each substance must not exceed its specific migration lim it (SML). The following phthalates and other plastici sers17 are authorised for use as additives: DBP (SML) = 0.3 mg/kg food only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical supp ort agent in polyolefins in concentrations up to 0.05% in the final product BBP, SML = 30 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles; 17 Not exhausti ve examples for other than phthalates Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 56 (b) plasticiser in single -use materials and articles in contact with non -fatty foods, not for contact with infant formulae and follow -on formulae (Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Direc tive 2006/125/EC); (c) technical support agent in concentrations up to 0.1% in the final product. DEHP, SML = 1.5 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical su pport agent in concentrations up to 0.1% in the final product. DINP SML = 9 mg/kg food (cumulative with DIDP) only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Di rective 2006/125/EC) (c) technical support agent in concentrations up to 0.1% in the final product. DIDP, SML = 9 mg/kg food ( cumulative with DINP) Only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Directive 2006/125/EC) (c) te chnical support agent in concentrations up to 0.1% in the final product. Furthermore, for certain plasticizers listed in Regulation (EU) 10/2011, including a number of phthalates, applies a group restriction (Group restriction number 32), that is, the sum of these substances must not exceed an SML of 60 mg/kg foodstuff. DEHP, BBP, DBP and DIBP must not be contained in homogenous materials above the concentration of 0.1% w/w from July 2019 on according to the Restriction of Hazardous Substances Directive in electrical and electronic equipment RoHS2 (2011/65/EC). For medical devices and in vitro diagnostic products this restriction takes effect in July 2021. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 57 Table 1 CMR Classification*) and ED designation**) of phthalates (status Jan 2019) Phthalate Abbreviation CAS number CMR Classification* ED identification** bis(2- methoxyethyl)phthalate DMEP 117-82- 8 Repr 1B - bis (2-ethylhexyl)phthalate DEHP 117-81- 7 Repr 1B ED dibutyl phthalate DBP 84-74-2 Repr 1B ED 1,2- benzenedicarboxylic acid, dipentylester, branched and linear 84777 - 06-0 Repr 1B - n-pentyl - isopentylphthalate PIPP No CAS 776297 - 69-9? Repr 1B - di-n-pentyl phthalate DnPP 131-18- 0 Repr 1B - diisopentylphthalate DiPeP 605-50- 5 Repr 1B - benzyl butyl phthalate BBP 85-68-7 Repr 1B - ED diisobutylphthalate DIBP 85-69-5 Repr 1B ED dihexylphthalate DHP 84-75-3 Repr 1B dicyclohexylphthalate DCHP 84-61-7 Repr 1B ED *) as indicated in Annex VI to CLP_ATP10 (in force from 1 December 2018). **) according to the ECHA Candidate List of substances of very high concern for Authorisation published in accordance with Article 59(10) of the REACH Regulation https://echa.europa.eu/candidate -list-table As substances of concern, knowledge on the exposure to phthalates is important and biomonitoring of populations provides important information. For some of the phthalates already human biomonitoring assessment values, namely Biomonitoring equi valents (BE) or human biomonitoring (HBM) values, have been derived – these are concentrations of biomarkers (metabolites) in urine, which reflect an acceptable chronic exposure, since the basic assumption is an equilibrium between external exposure and in ternal burden (Angerer et al. 2011, Apel et al. 2017). In the course of the work done within the HBM4EU project, Human Biomonitoring Guidance Values (HBM -GVs) could be derived for DEHP and DINCH (see HBM4EU Deliverable D5.2, https://www.hbm4eu.eu ). In addition, HBM-GVs for the following SVHC phthal ates are finalised in September 2019 (Deliverable D5.6) and will also be published on the website: BBzP, DiBP, and DnBP. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 58 Annex 6: Use of phthal ates in medical devices Phthalates are abundantly used in polyvinyl chloride (PVC) medical devices such as blood bags, intravenous bags, nutrition pockets, tubing, catheters, respiratory masks or disposable gloves. More than 40% of all plastic -based disposable medical devices are made from PVC. Di -2-ethylhexyl phthalate (DEHP) has been for many years the most commonly used phthalate ester plasticiser in medical devices. A survey among the Danish Medical Device Industry found that 95% of the products contained DEHP [Huntley P, edit or The classified phthalates should be phased out of medical devices. Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark]. Safety concerns have been expressed for several high -risk patients groups, s uch as neonates, infants, pregnant and breast -feeding women exposed to DEHP. The SCENIHR in its Opinion of 201 5 indicated that “a lack of evidence of causation between DEHP -PVC and any disease or adverse effect does not mean that there are no risks”. This lack of evidence applies to all phthalates classified as CMR and/or identified as ED. Therefore the requirement of patient subgroup analysis for the target patient groups as defined in the “Intended Use” of a medical device is now included in the Regulatio n (EU) 2017/745. For the use of DEHP, high risk groups were identified including patients undergoing haemodialysis, extracorporeal membrane oxygenation (ECMO), and prematurely born infants in Neonatal Intensive Care Units (NICU), (SCENIHR 201 5). The actua l exposure of such patient groups relative to the toxicity including CMR/ED property needs to be determined. However, even if the remaining risk is high, the benefit of the treatment should be considered as well. It might be useful to evaluate the patient subgroups separately:  Paediatric Population (see subgroups)  Peripubertal males  Pregnant women  Breast -feeding women  any other patient group considered particularly vulnerable or exposed to high levels of phthalates. For purposes of this Guideline, the following ranges of paediatric subpopulations are proposed to be used as a guide for manufacturers in medical devices (ref. SCCS Notes of Guidance – SCCS/1602/18, section 3 -6.9.1, page 7818) 18 https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs _o_224.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 59 Definition of Paediatric Population Subgroups Paediatri c Subgroup Approximate Age Range Full-term neonate <1 week Newborn 1 week–2 months Early infant 2–6 months Crawlers/toddler 6 months –2 years Preadolescent 2–12 years Adolescent 12–18 years In view of ED activity, a dditional (paediatric ) subpopulations may need to be considered includ ing:  very low birth weight describes newborns less than 1.5 Kg  low birth weight describes newborns less than 2.5 Kg  preadolescent age group typically ranges from 11 to 13 years.  peripubertal males or females It should be realised that the benefit of medical devices including the use of phthalates must also be considered: The survival of prematurely born infants often depends on the availability of the same medical devices that result in a relative ly high phthalate content exposure due to treatment. Whenever possible, material with low release potential should be used (see SCENIHR opinion 201 5). Besides the direct patient benefits of the treatment with a medical device containing phthalates, other functionalities may also need to be considered. For example, DEHP has a stabilising effect on red blood cells (RBCs). RBCs have increased survival rates when stored in DEHP containing blood bags. DEHP is incorporated into the cell walls of RBCs and stabil ises the membrane integrity of the RBCs. This results in a prolonged shelf life and thus patient availability of blood stored in DEHP containing blood bags (SCENIHR 2015). A maximum limit of extractable DEHP of 15 mg/100 mL for flexible PVC containing DEHP is indicated in EN ISO 3826 -1 on containers for the collection of human blood and blood components. The plasticiser industry has been investing and developing alternatives to DEHP in medical devices. Today, other plasticisers such as Di -isononyl cyclohe xanoate (DINCH, CAS 166412 -78-8), Tri -2-ethylhexyl trimellitate (TEHTM, CAS 3319 -31-1), butyryl tri -n- hexyl citrate (BTHC, CAS 102818 -95-1) and Dioctyl Terephthalate (DOTP, CAS ‎6422-86- 2) are being proposed in medical applications such as medical tubing and blood bags. https://www.plasticisers.org/applications/medical -applications/ Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 60 In conclusion, for any BRA on the use of phthalates and the development of alternatives in me dical devices, careful consideration should be used to appropriate patient subgroup analysis regarding medical device use and the resulting potential exposure. Reference Huntley P, Editor . The classified phthalates should be phased out of medical devices. Program Meeting on Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark. https://pvc.dk/wp -content/uploads/2016/02/pvc -alternativer -til-klassificerede -ftalater - program.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 61 Annex 7: Approaches for Benefit -Risk Assessment Several approaches for BRA have been proposed especially in the context of medicinal products. The Innovative Medicines Initiative PROTECT Project (www.imiprotect.eu), presented a detailed review of approaches used for BRA (Mt -Isa et al. 2014). In this review, a large number of approaches were identified and classified as descriptive (qualitative or semi -qualitative) or quantitative frameworks (relying on quantitative methods of trading risks and benefits following mathematical principles), metrics (measure s for benefits and risks that are usually endpoint specific), estimation techniques (i.e., simulation techniques and meta -analysis) , and utility survey techniques (to elicit stakeholders’ preferences). Concerning quantitative frameworks, according to the European Medicines Agency (EMA) Project Report (EMA/227124/2011), there is no agreement on any one approach to be used in regulatory submission on the benefits and risks of medicines. However, EMA has encouraged the use of quantitative frameworks in regulatory submissions of applications for marketing authorisation of medicinal products. Although there is little experience with quantitative frameworks in the area of medical devices, some of the BRA appro aches used for pharmaceuticals may also be relevant for medical devices and particularly regarding the use of CMR/ED phthalates. In particular, approaches based on multicriteria decision analysis ( MCDA) have attracted much attention during the past years in the field of medical decisions. For an introduction to MCDA see Dodgson et al. (2009). In brief, MCDA is based on decision theory and belongs to the general class of multi - criteria analysis mode ls that accommodate decision making with multiple objectives. The main purpose of MCDA is to bring together evaluations of options on different criteria into one overall evaluation. The starting point for MCDA approaches include s identification of the alte rnatives and the criteria against which the alternatives are appraised. MCDA includes weighting, which ensures that the units of value on all the criteria are comparable so that benefits and risks can be compared by using a common unit of value. In this wa y, the added value of benefits can be compared to the loss of value from the risks. A number of different weighting methods can be used, ranging from precise elicitation of weights, to weights based on qualitative judgements or including uncertainty. A generic framework for conducting an MCDA can be based on the steps of the PROACT - URL framework (Hammond et al. , 1999), as presented below. A detailed description of the different implementations of MCDA techniques is beyond the scope of this guideline. The c hosen techniques and analyses should be presented and justified among others on the basis of internal consistency, logical soundness and transparency. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 62 STEP Description and relation to framework for Benefit -Risk Assessment described in section A of the Guidelines Problem Describe the medical device, its intended use, and the therapeutic context; frame the decision problem in terms of potential alternatives to CMR/ED phthalate. See Step 1: Description and characterisation of the composition of the medic al device; and Step 2: Use and function of the phthalates in the medical device. Objectives Identify the full set of criteria to evaluate different alternatives. See Step 2: Use and function of the phthalates in the medical device; and Step 3: Assessment of the risks of the CMR/ED phthalate. See 7 Benefit assessment . Alternatives Identify alternatives that are being evaluated against each other. See Step 4: Inventory of possible alternatives; and Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates . Consequences Describe how the alternatives perform for each of the criteria, i.e., the magnitudes of all effects in terms of the different benefits and risks. See Step 2: Use and function of the phthalates in the medical device; Step 3: Assessment of the risks of the C MR/ED phthalate; Step 6: Description of identified relevant potential alternative(s); Step 7: Assessment of the risk of identified potential relevant alternatives. For a summary table see Table 1. Example for a comparison of CMR/ED phthalate with potential alternative(s). Trade -offs Assess the balance between benefits and risks using judgements of weights associated with the criteria and the value associated with the benefits and risks of every alternative. MCDA techniques commonly achieve this through num erical analysis. A number of different weighting methods can be used. Conduct sensitivity analyses to explore uncertainties using different scenarios, and assess how different weights affect the overall ordering of the alternatives. See also Step 8: Compar ison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternatives; Step 9: Comparison of risk(s) of original CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives; and Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Uncertainty Report the uncertainty associated with the benefits and Risks. Consider how the balance between benefits and risks is affected by uncertainty. A quantitative model will Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 63 explore in sensitivity analyses and scenario analyses (or by explicitly incorporating probability distributions in the model) the effects on the overall benefit -risk balance of all sources of uncertainty. See 1.9 Uncertainty analysis. Risk tolerance Describe any considerations that could or should affect the decision maker’s attitude toward risks (e.g., special population, unmet medical need). Linked -decisions Discuss how the value judgements and data are consistent with similar decisions on medical devices. References  Dodgson J, Spackman M, Pearman A, Phillips LD. Multi -criteria analysis: A manual. London: Department for Communities and Local Government, First published in 2000 by the Department for Environment, Transport and the Regions; 2009.  ECHA 2011 Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  Hammond JS, Keeney RL, Raiffa H, Smart Choices: A Practical Guide to making Better Decisions, Boston, MA: Harvard Business School Press; 1999.  Mt-Isa S, Hallgreen C.E., Wang N., Callréus T., Genov G., Hirsch I., Hobbiger S., Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki I., Micaleff A., Ashby D. - Balancing benefit and risk of medicines a systematic review and classification of available methodologies, Pharmacoepidemiology and Drug Safety, May 2014 .

md_transitional-provisions-art-3-and-4_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 rev. 1 Class I Transitional provisions under Article 120 (3 and 4) – (MDR) March 2020 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 revision 1 changes MDR postponement dates : from 2020 to 2021 How can a ffected manufacturers of some class I devices1 make efficient use of the transitional provisions in A rticle 120 (3 ) and (4) of Regulation (EU) 2017/745 – Medical Devices Regulation ( MDR )? Background: The corrected MDR2 Article 120 (3) allows under certain condition s, some class I devices pursuant to Directive 93/42/EEC – Medical Devices Directive (MDD) , for which the Declaration of C onformity was drawn up prior to 26 May 2021 and for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body, to be placed on the market3 until 2 6 May 20244. In order to make use of this article , the following conditions must be met: 1. The device continues to comply with Directive 93/42/EEC, 2. A notified body will need to be involved under the MDR (e.g. re -usable surgical instruments or up -classified devices) 3. A valid Declaration of C onformity , according to Annex VII of the MDD , must be drawn up befor e 26 May 2021, 4. No significant changes to the design or intended purpose of the device after 26 May 202 15, 5. The requirements of the MDR relating to post -market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in Directive 93/42/EEC .6 This shall be in place on the 26 May 2021. Scope The scope of this document is to provide guidance related to the information to be provided in the form of a Declaration of Conformity by manufacturers of Class I devices (devices which are non - 1 Class I devices for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body. 2 Corrigendum to Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/E EC and 93/42/EEC (OJ L 117, 5.5.2017), of 27.12.2019. 3 Devices which are not placed on the market but put into service may also make use of the transitional provisions . 4 Article 120(4) ‘and may continue to be made available on the market …until 26 May 2025’ . 5 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD . 6 Upcoming guidance on harmonised practices and technical solutions to facilitate exchange of information in absence of EUDAMED . Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 sterile or do not have a measuring function) that are required to have certificates after 26 May 2024 according to the MDR. Content of a val id Declaration of Conformity The manufacturer or his authorised representative established in the European Union is obliged to issue a Declaration of Conformity that the product has undergone a conformity assessment procedure required by the MDD before being placed on the market. With the Declaration of Conformity, the manufacturer declares that the products concerned meet the relevant provisions of the MDD. MDD Annex II, Annex V, Annex VI set out that a Declaration of Conformity must cover one or more medical devices manufactured 7 clearly identified by means of product name, product code or other unambiguous reference for class IIa, IIb and III devices, and also class Im and class Is devices. This is however not necessary for other Class I devices, as it is not required by the MD D (Annex VII) and as there is no certificate from a notified body to which the issued Declaration of Conformity is related. Guidance on the content of the Declaration of C onformity can be found, inter alia, in the “The ‘Blue Guide’ on the implementa tion of EU products rules 2016 (2016/C272/01) ”8 and the standard EN ISO/IEC 17050 -1.9 According to this standard , the declaration may take the form of a document or any other suitable medium , and should contain sufficient information to enable all products covered to be traced back to it. The model declaration in Annex III of Decision No 768/2008/EC and the ‘Blue Guide’ on the implementation of EU products rules 2016 (2016/C272/0 1) describe the content of the Declaration of C onformity to be as follows: 1. A number identifying the product. This number does not need to be unique to each product. It could refer to a product, batch, type or a serial number .10 This is left to the discretion of the manufacturer .11 2. The name and address of the manufacturer or the authorised representative issuing the declaration. 3. A statement that the declaration is issued under the sole responsibility of the manufacturer. 7 MDD Annex II, paragraph 2 ‘This declaration must cover one or more medical devices manufactured, clearly identified by means of product name, product code or other unambiguous reference and must be kept by the manufacturer.’ 8 https://eur -lex.europa.eu/legal -content/GA/TXT/?uri=CELEX:52016XC0726(02) . 9 EN ISO/IEC 17050 -1 : 2004 Conf ormity assessment – Supplier’s D eclaration of Conformity – Part 1: General requirements /EN ISO/IEC 17050 -2 : 200 4 Conformity assessment – Supplier’s Declaration of C onformity – Part 2: Supporting documentation . 10 The ‘number’ may be an alpha -numerical code or could also refer to a software version . 11 In addition, whether this is expressly envisaged or not by the Union harmonisation legislation, manufacturers are free to add a number identifying the Declaration of Conformity itself in line with EN ISO/IEC 17050 -2. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 4. The identification of the product allowing traceability. This is any relevant information suppleme ntary to point 1 describing the product and allowing for its traceability . Where relevant for the identification of the product , it may contain an image, but unless specified as a requirement in the Union harmonisation legislation this is left to the discr etion of the manufacturer. 5. All relevant Union harmonisation legislation complied with; the referenced standards or other technical specifications (such as national technical standards and specifications) in a precise, complete and clearly defined way; this implies that the version and/or date of the relevant standard is specified.12 6. If applicable, t he name and identification number of the notified body ,13 when it has been involved in the conformity assessment procedure ,14 15 and the reference to the relevant certificate. 7. If applicable, a ll supplementary information that may be required (for example category) . 8. The date of issue of the declaration; signature and title or an equivalent marking of the authorised person16 17  This could be any date after the complet ion of the conformity assessment , but must be before 26 May 202 1 if the manufacturer wants to make use of the transitional period in Article 120(3) and (4) of the MDR . Every Declaration of C onformity must be based on proper technical documentation according to Annex VII para graph 3 of the MDD. The technical documentation and the D eclaration of Conformity should be subject to appropriate measures of document and record control. The Declaration of Conformity is to be kept by the manufacturer and shall be at the disposal of the competent authorities for a period ending at least five years after the last product has been manufactured. Necessary amendm ents/updates to the t echnical documentation should be done in a transparent manner. Both t he changes and the dates of when the changes were made should be recorded. On the basis of the Declaration of Conformity and the corresponding technical documentation, the manufacturer should be able to demonstrate that the Declaration of Conformity was lawfully18 issued before 26 May 202 1 and that, subsequently, there are no significant changes in the design or intended 12 According to the MDD , referencing st andards or technical specifications complied with is voluntary . 13 For class I devices in scope of this guidance document, the involvement of a notified body is not required. 14 Not all Union harmonisation legislation requires the intervention of a notified body (e.g. the Low Voltage Directive and the Toys D irective . 15 The name and address of the person who keeps the technical documentation may also be required by some pieces of Union harmonisation legislation since according to those, not only the manufactu rer shall keep the technical documentation. 16 This could be the m anaging director of the company or another representative of the company to whom this responsibility has been delegated. 17 It is not necessary for the signatory to be domiciled in the Europea n Union. A manufacturer established outside the Union is entitled to carry out all the conformity assessment procedures at his premises and, to sign the Declaration of Conformity . 18 Lawfully according to the Directive and to any relevant national provisions which apply. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 purpose19 in the meaning of Article 120(3) MDR. Taking into account Article 123(3) and 123 (3)(d), and a s EUDAMED will not be fully functional in May 202 1, it is required that the manufacturer keep the Declaration of Conformity together with the technical documentation available to the Competent Authorities . This would also include details o f all device registrations and economic operator registrations completed pursuant to national provisions implementing the requirements of Articles 14 (1) and (2) of Directive 93/42/EEC. 19 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD .

09 MDCG 2020-9 Regulatory Requirements for Ventilators and Reated Accessories.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-9 MDCG 2020-9 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES Options for supporting production and/or placing on the market of ventilators in the context of COVID-19 pandemic 1. INTRODUCTION AND SCOPE The World Health Organization (WHO) declared the COVID-19 outbreak a pandemic on March the 12th 2020. Patients infected by SARS-CoV-2 virus and developing the COVID-19 disease with acute and severe respiratory symptoms have to be treated with mechanical ventilators to assure possibilities of survival. This guidance document focuses on ventilators and related accessories that are currently regulated under the Council Directive 93/42/EEC (MDD)1. According to the MDD, devices may be placed on the market and/or put into service only if they comply with the requirements laid down in this Directive when duly supplied and properly installed, maintained and used in accordance with their intended purpose2. The devices must meet the essential requirements set out in Annex I of the MDD, which apply to them, taking account of the intended purpose of the devices concerned. In addition, devices may be placed and circulate on the European single market if they have been subject to a conformity assessment in accordance with the provisions of Article 11 of the MDD. Under the current COVID-19 context, the demand for ventilators and related accessories has rapidly increased. Therefore, this document intends to outline the different regulatory options for placing these devices on the EU market indicating their feasibility to allow short-term supply. 2. TYPES OF MEDICAL DEVICES AND THEIR PARTS /COMPONENTS 2.1. Ventilators Ventilators are breathing support devices and can fall into different types according to their intended use and characteristics3: 1 However, placing on the market of devices which comply with MDD is limited to 27 May 2024. After this date every device placed on the market has to comply with the requirements of Regulation (EU) 2017/745 (MDR). According to the Article 120 section 5 and 6 of the MDR devices which comply with MDR may be placed on the market before its application and notified bodies which are designated and notified in accordance with MDR may carry out the conformity assessment procedures laid down in MDR and issue certificates in accordance with MDR. 2 According to Article 1(g) of the MDD, intended purpose is the use for which the device is intended according to the data supplied by the manufacturer on the labelling, in the instructions and/or in promotional materials. 3 This list of ventilators includes some standards applicable to the specific ventilator. However, it should be noted that this is not an exhaustive list and other standards also apply to these devices and should be taken into account (e.g. EN 60601-1-2, EN 60601-1-6, EN 60601-1-8, EN 60601-1-11, EN 62304, EN 62366). In addition, the current state of the art should be considered. This applies also to accessories. 3 - Ventilator for critical care: automatic equipment that is intended to augment or provide ventilation of the lungs of the patient when connected to the airway of the patient: o intended for use in an environment that provides specialized care for patients whose conditions can be life threatening and who can require comprehensive care and constant monitoring in a professional healthcare facility; o intended to be operated by a healthcare professional operator; and o intended for those patients who need differing levels of support from artificial ventilation including for ventilator-dependent patients. (See e.g. EN ISO/IEC 80601-2-12:2011 + Cor.:2011). - Home healthcare environment ventilators for ventilator-dependent patients: intended for use in the home healthcare environment; intended for use by a lay operator; intended for use with patients who are dependent on mechanical ventilation for their life support. Depending on the intended purpose can be also used in the clinical setting (See e.g. EN ISO 80601-2-72:2015). - Ventilators for emergency and transport : these ventilators are used in Emergency Medical Service environment, e.g. in ambulances, transport of patients to the hospital, patient transport from hospital to hospital or transport within the hospital. The alarm and safety concept of emergency and transport ventilators in general is designed for a permanent presence of the user. This facilitates fast recognition and response in the event of an alarm or in the event of any malfunction (See e.g. EN 794-3:1998+A2:2009). - Anaesthetic ventilator: are designed for use during anaesthesia with an anaesthetic breathing system (See e.g. EN ISO 80601-2-13:2012). Ventilators for critical care are usually invasive, which enables the ventilator machine to provide lung support for inspiration and expiration through tracheal intubation. However, most critical care ventilators allow non-invasive ventilation modes for critical care patients as well. Ventilators for non-critical care are usually non-invasive and therefore provide air pressure support to natural breathing through e.g. a facemask. Ventilators may offer different types of additional complementary functions that include:  High flow oxygen supply (nasal high flow therapy);  Monitoring systems;  Nebulisation systems. 2.2. Accessories Ventilators need to be “connected” to the patients through dedicated accessories4 to the ventilator that allow the machine to support the patient’s breathing; therefore, it is important to proof compatibility with the ventilator(s). These accessories can be placed on the market individually and usually fall into one of the following categories: 4 See MEDDEV 2.1/1 Definitions of 'medical devices', 'accessory' and 'manufacturer' (https://ec.europa.eu/docsroom/documents/10278/attachments/1/translations ). 4  Breathing systems and circuits, such as: o Circuits; o Connections/Adapters; o Tubes; o Nasal cannulas for O 2; o Masks or helmets for non-invasive ventilation; o Air compressors;  Nebulizers;  Humidifiers and filters;  Monitoring accessories, including alarms, in-built safety features. Accessories are provided either disposable or reusable and are treated as medical devices in their own right5. 2.3. Parts or components Parts or components of medical devices that do not qualify as accessories are generally not considered medical devices and thus not requiring themselves to be CE marked according to the MDD (e.g. expiratory valves or flow sensors). 3. CLASSIFICATION 3.1. Ventilators There are different types of ventilators depending on the degree of invasiveness and the setting in which they are used in (e.g. Intensive Care Unit - ICU). Ventilators fall under two different classes in accordance with rule 11 (or rule 9) of Annex IX6,7 to the MDD: - Class IIa: only applicable to non-invasive devices, e.g. continuous positive airway pressure – CPAP non-intended for critical care, or devices that only support spontaneous breathing. - Class IIb: applicable to most ventilators. The classification depends on the intended purpose of the ventilator and has important implications in the selection of appropriate conformity assessment procedure(s) for the device including timing and complexity (see section 4 for details). 3.2. Accessories Accessories are classified in their own right usually in accordance with rule 2 or 5 of Annex IX to the MDD, under Class I, IIa or IIb. 5 Art. 1(1) of the MDD 6 See MEDDEV 2.4/1 rev.9 Classification of Medical Devices - (https://ec.europa.eu/docsroom/documents/10337/attachments/1/translations). 7 Please note that if a conformity assessment under the MDR is followed, the rules of classification specified in Annex VIII to the MDR apply. Breathing support devices may be classified to class IIa or IIb (rule 12) or class III (rule 22) if they integrate or incorporate diagnostic functions which significantly determine the patient management by the device, such as closed loop systems. 5 3.3. Impact of classification on conformity assessment Given that ventilators are classified as Class IIa or Class IIb, and accessories (except for Class I non-sterile and without measuring function), will in principle need the involvement of a notified body prior to their placing on the market. Other options for the placing on the market are provided in section 4 for both ventilators and accessories. 4. REGULATORY OPTIONS FOR PLACING VENTILATORS ON THE MARKET In the context of the COVID-19 outbreak, several industries have expressed their willingness to support and scale up the production of ventilators8. There are different regulatory options9 available for supporting production or placing on the market of ventilators. These options are presented below, ordered by feasibility, to allow a swift supply in the current context. 4.1. Supplying parts, components or the finished devices to medical devices manufacturers currently placing on the market ventilators When the legal manufacturer10 has already undergone a conformity assessment for the ventilator, has obtained a certificate and is lawfully placing ventilators on the market under its own name, other producers (e.g. not currently working in the medical devices field) can support its production. Such producers can provide parts or components, or the finished device, therefore becoming suppliers or subcontractors of this manufacturer. Given that the medical devices sector is highly regulated and complex, leveraging the knowledge and responsibilities of an already established manufacturer of ventilators could be the least burdensome and fastest option to scale up the production of ventilators. 4.1.1. Producers supplying parts or components to medical devices manufacturers currently placing on the market ventilators Manufacturers of medical devices can have many suppliers, which in case of quality system certification are qualified, approved and controlled by the manufacturer. These suppliers may need to be assessed by a notified body as part of the conformity assessment procedure on the basis of their criticality and the manufacturer’s process in place to control suppliers and the verification of purchased products11. When the manufacturer wishes to use an additional supplier, this might need to be communicated in advance to the notified body. 8 Scaling up of production might also be needed for accessories. These medical devices can follow the same options explained in section 4 but small differences can be applicable in case they have a different classification (e.g. class Is). 9 This document mainly focuses on regulatory options provided by the MDD. If a conformity assessment under the MDR is followed, similar procedures will apply under Annex IX, X or XI of the MDR depending on the classification of the product. 10 Legal manufacturer refers to the definition of manufacturer established in Art. 1(f) of the MDD. 11 See Guidance for Notified Bodies auditing suppliers to medical device manufacturers – (http://www.doks.nbog.eu/Doks/NBOG_BPG_2010_1.pdf) 6 4.1.2. Producers manufacturing the ventilator itself for the medical device manufacturer currently placing on the market ventilators Manufacturers of medical devices producing ventilators may provide the specifications of a ventilator (e.g. current or older/simpler design) including parts of the technical documentation to a producer that becomes its subcontractor. The producer will manufacture the ventilator but the medical device manufacturer will keep its role of legal manufacturer according to the MDD. The legal manufacturer of the ventilator, which holds a quality system certification, qualifies, approves and controls the subcontractor that will need to be assessed by a notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on-site12) audit. Alternatively, the manufacturer of medical devices could also follow other conformity assessment routes such as the EC type-examination, as established in Annex III to the MDD, and/or EC verification, as established in Annex IV to the MDD (these routes are elaborated in 4.3.2). 4.2. Derogation procedure – placing on the market authorised by the relevant authorities of one Member State in the interest of public health The relevant authority of one Member State may decide to authorise the placing on the market of devices in the interest of protection of health, even if the applicable conformity assessment procedures have not been finalised or initiated ('national derogation'). In view of the epidemiological context as well as the exponential growth in demand for medical devices, the Commission has published a Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the Covid-19 context. Question 5 of this guidance provides information on the derogation procedures for medical devices which is established in Article 11(13) of the MDD. In particular, the guidance specifies that the Covid-19 context warrants the application of such derogations. By amendment of 23 April 202013, Article 59(1) of Medical Devices Regulation (EU) 2017/745 (MDR) empowers Member States to adopt national derogations under both the MDD and the MDR from the date of entry into force of that amendment. The relevant competent authority of the Member State in this case authorises the placing on the market within its territory and can also organise the purchase. 12 See MDCG 2020-4 Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID-19 quarantine orders and travel restrictions (https://ec.europa.eu/docsroom/documents/40705). 13 Regulation 2020/561 amending Regulation (EU) 2017/745 on medical devices as regards the dates of application of certain of its provisions. 7 In practice, this implies that each competent authority would need to assess whether the products produced by the manufacture provides an adequate level of safety in respect to the applicable legal requirements. The assessment procedures can vary among Member States and in some cases will involve the support of third parties (e.g. testing laboratories). In the exceptional COVID-19 context, the assessment procedures will ensure a short- term supply while guaranteeing patient safety14. The Member State will evaluate the available technical documentation to find evidence that essential performance and safety requirements are guaranteed in the context of use. In particular, the role of healthcare teams and health facilities is essential to allow a rational use and a continuous assessment of these crisis solutions. Once this assessment is performed, the authority has to take a decision, whether or not the respective device produced by the manufacturer may enter the national territory of the Member State. Competent authorities should inform the Commission and their counterparts in other Member States of any temporary agreement they have granted to specific devices. In addition, Article 59(3) of the MDR empowers the Commission to extend, in exceptional cases relating to public health or patient safety or health, by means of implementing acts, for a limited period of time the validity of a national derogation, granted by a Member State under the MDD or the MDR, to the territory of the Union and set the conditions under which a device may be placed on the market or put into service. This allows the Commission and the Member States to address potential shortages Union wide of vitally important medical devices in an effective manner. Timing to obtain a national derogation by a competent authority will greatly depend on the quality and adequacy of the evidence provided by the manufacturer. When technical documentation and evidence of safety of performance is adequate, this can be a feasible option to ensure short-term supply. 4.3. Manufacturing of the finished device by a producer that was not previously placing on the market ventilators If the ventilator is entirely manufactured by a producer that decides to place it on the market under its name, such producer will become the legal manufacturer in its own right. This means that the manufacturer will need to fulfil all requirements of the MDD (e.g. including the need to draw up the technical documentation and clinical evaluation related to the ventilator, and to establish and keep up to date a systematic procedure to review experience gained from devices in the post-production phase). The manufacturer who places the finished CE marked ventilator on the market under its own name needs to ensure that the device complies with the essential requirements (established in Annex I of the MDD) and provide relevant evidence. A notified body will be involved in the conformity assessment in all cases. 14 Some Member States have published guidance on their respective websites to support this assessment e.g. in case of implementation of innovative manufacturing processes such as 3D printing. 8 Given that the medical devices sector is highly regulated and complex, the scenarios presented below will be the most burdensome and therefore only applicable to increase supply in the medium-long term. 4.3.1. Medical devices manufacturers’ not currently producing ventilators request an extension of their product range. This option is available for medical devices manufacturers currently certified. It includes, for instance, medical devices manufacturers already holding a full quality management system certificate under Annex II to the MDD for other devices and wishing to add ventilators to their certification. They could seek the support from (non-medical devices) producers to act as subcontractors and extend the scope of their certificate. From a procedural point of view, the medical devices manufacturer may produce the ventilator itself or may utilise a subcontractor (i.e. producer linked or not to the medical devices field). In the latter case, the manufacturer will qualify, approve and control the subcontractor that will be assessed by the notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on- site12) audit. Most importantly, the manufacturer will need to request an extension of the product range from its notified body. The notified body will assess the available information in relation to the new product (that include an assessment of the technical documentation and clinical evaluation) and update the certificate. The manufacturer of medical devices could also use other conformity assessment routes such as the EC Type-Examination and EC Verification and testing of every product under Annex III and IV respectively (these routes are elaborated in section 4.3.2). 4.3.2. Ventilator manufactured entirely by a producer that is not currently a legal manufacturer under the MDD Producers that do not currently qualify as legal manufacturers under the MDD and decide to place ventilators on the market under their own name need to be aware of all the legal requirements for manufactures under the MDD. It is important to mention that in the field of medical devices some Member States could have additional requirements, for instance, the need to authorise the facility of the medical device manufacturer prior to starting production. In addition to this, the involvement of a notified body will depend on the classification. In particular: 1. Class IIa ventilators can follow the following routes established in the relevant Annexes of the MDD: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and 9 regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the product to be certified prior to certification on a sampling basis15. b. Declaration of conformity (Annex VII) combined with either an assessment of the quality assurance of the production or of the product (Annex V or VI) or a EC verification (set out in Annex IV):  The assessment of the quality system performed by the notified body will be similar to the one outlined in section 1.a above.  The verification by testing of products by the notified body will be performed by examination and testing of every product. 2. Class IIb ventilators can follow the following routes: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the products to be certified prior to certification on a sampling basis15. b. EC type-examination (Annex III) combined with either an assessment of the quality assurance either of the production or of the product (Annex V or VI) or EC verification by testing of products (set out in Annex IV). EC Type-examination consists in the assessment of the technical documentation and testing of a number of features of the device type to ensure it conforms to the requirements. The additional procedures (Annex IV, V or VI) are the same as the ones described in 1.b above. The assessment of the quality management system of the manufacturer (Annex II, V and VI) can be partly fulfilled by compliance with a harmonised standard (EN ISO 13485) but this route will unlikely be fast enough to ensure short-term supply. This is due to the timelines and experience required to get a certificate under these annexes of the MDD and taking into account the current circumstances where auditing capacity is restricted by the Covid19 situation. A faster route but also time-consuming route will probably be the performance of tests on the products that might be combined with the assessment of the technical documentation, namely: - declaration of conformity (Annex VII) + verification of products (Annex IV) for Class IIa; or - EC type-examination (Annex III) + verification of products (Annex IV) for Class IIb. Through this route, the device type or device samples are tested and there is no obligation to have a certified quality management system in place and subject to regular surveillance audits. However, quality management processes are important and critical to the production of safe and functional medical devices. The conformity assessment will be 15 See Annex II, section 3.3 to the MDD 10 based on the manufacturers testing strategy that must ensure compliance with the safety and performance requirements. It should be noted that this option is burdensome and will take several months, especially to draw up an adequate technical documentation. In addition, there is only a limited number of notified bodies designated to perform EC type-examination and/or EC verification in ventilators (according to NANDO16 18 notified bodies out of 56 are authorised to perform these tests at the moment). 16 This information can be found in NANDO, by searching notified bodies under the MDD that are designated under Annex III and IV for code MD 1102 - Respiratory devices, devices including hyperbaric chambers for oxygen therapy, inhalation anaesthesia - https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13

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L_2017117EN.01000101.xml 5.5.2017    EN Official Journal of the European Union L 117/1 REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Text with EEA relevance) THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, Having regard to the Treaty on the Functioning of the European Union, and in particular Article 114 and Article 168(4)(c) thereof, Having regard to the proposal from the European Commission, After transmission of the draft legislative act to the national parliaments, Having regard to the opinion of the European Economic and Social Committee (1), After consulting the Committee of the Regions, Acting in accordance with the ordinary legislative procedure (2), Whereas: (1) Council Directive 90/385/EEC (3) and Council Directive 93/42/EEC (4) constitute the Union regulatory framework for medical devices, other than in vitro diagnostic medical devices. However, a fundamental revision of those Directives is needed to establish a robust, transparent, predictable and sustainable regulatory framework for medical devices which ensures a high level of safety and health whilst supporting innovation. (2) This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users, and taking into account the small- and medium-sized enterprises that are active in this sector. At the same time, this Regulation sets high standards of quality and safety for medical devices in order to meet common safety concerns as regards such products. Both objectives are being pursued simultaneously and are inseparably linked whilst one not being secondary to the other. As regards Article 114 of the Treaty on the Functioning of the European Union (TFEU), this Regulation harmonises the rules for the placing on the market and putting into service of medical devices and their accessories on the Union market thus allowing them to benefit from the principle of free movement of goods. As regards Article 168(4)(c) TFEU, this Regulation sets high standards of quality and safety for medical devices by ensuring, among other things, that data generated in clinical investigations are reliable and robust and that the safety of the subjects participating in a clinical investigation is protected. (3) This Regulation does not seek to harmonise rules relating to the further making available on the market of medical devices after they have already been put into service such as in the context of second-hand sales. (4) Key elements of the existing regulatory approach, such as the supervision of notified bodies, conformity assessment procedures, clinical investigations and clinical evaluation, vigilance and market surveillance should be significantly reinforced, whilst provisions ensuring transparency and traceability regarding medical devices should be introduced, to improve health and safety. (5) To the extent possible, guidance developed for medical devices at international level, in particular in the context of the Global Harmonization Task Force (GHTF) and its follow-up initiative, the International Medical Devices Regulators Forum (IMDRF), should be taken into account to promote the global convergence of regulations which contributes to a high level of safety protection worldwide, and to facilitate trade, in particular in the provisions on Unique Device Identification, general safety and performance requirements, technical documentation, classification rules, conformity assessment procedures and clinical investigations. (6) For historical reasons, active implantable medical devices, covered by Directive 90/385/EEC, and other medical devices, covered by Directive 93/42/EEC, were regulated in two separate legal instruments. In the interest of simplification, both directives, which have been amended several times, should be replaced by a single legislative act applicable to all medical devices other than in vitro diagnostic medical devices. (7) The scope of application of this Regulation should be clearly delimited from other Union harmonisation legislation concerning products, such as in vitro diagnostic medical devices, medicinal products, cosmetics and food. Therefore, Regulation (EC) No 178/2002 of the European Parliament and of the Council (5) should be amended to exclude medical devices from its scope. (8) It should be the responsibility of the Member States to decide on a case-by-case basis whether or not a product falls within the scope of this Regulation. In order to ensure consistent qualification decisions in that regard across all Member States, particularly with regard to borderline cases, the Commission should be allowed to, on its own initiative or at the duly substantiated request of a Member State, having consulted the Medical Device Coordination Group (‘MDCG’), decide on a case-by-case basis whether or not a specific product, category or group of products falls within the scope of this Regulation. When deliberating on the regulatory status of products in borderline cases involving medicinal products, human tissues and cells, biocidal products or food products, the Commission should ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency and the European Food Safety Authority, as relevant. (9) Since in some cases it is difficult to distinguish between medical devices and cosmetic products, the possibility of taking a Union-wide decision regarding the regulatory status of a product should also be introduced in Regulation (EC) No 1223/2009 of the European Parliament and of the Council (6). (10) Products which combine a medicinal product or substance and a medical device are regulated either under this Regulation or under Directive 2001/83/EC of the European Parliament and of the Council. (7) The two legislative acts should ensure appropriate interaction in terms of consultations during pre-market assessment, and of exchange of information in the context of vigilance activities involving such combination products. For medicinal products that integrate a medical device part, compliance with the general safety and performance requirements laid down in this Regulation for the device part should be adequately assessed in the context of the marketing authorisation for such medicinal products. Directive 2001/83/EC should therefore be amended. (11) Union legislation, in particular Regulation (EC) No 1394/2007 of the European Parliament and of the Council (8) and Directive 2004/23/EC of the European Parliament and of the Council (9), is incomplete in respect of certain products manufactured utilising derivatives of tissues or cells of human origin that are non-viable or are rendered non-viable. Such products should come under the scope of this Regulation, provided they comply with the definition of a medical device or are covered by this Regulation. (12) Certain groups of products for which a manufacturer claims only an aesthetic or another non-medical purpose but which are similar to medical devices in terms of functioning and risks profile should be covered by this Regulation. In order for manufacturers to be able to demonstrate the conformity of such products, the Commission should adopt common specifications at least with regard to application of risk management and, where necessary, clinical evaluation regarding safety. Such common specifications should be developed specifically for a group of products without an intended medical purpose and should not be used for conformity assessment of the analogous devices with a medical purpose. Devices with both a medical and a non-medical intended purpose should fulfil both the requirements applicable to devices with, and to devices without, an intended medical purpose. (13) As is the case for products that contain viable tissues or cells of human or animal origin, that are explicitly excluded from Directives 90/385/EEC and 93/42/EEC and hence from this Regulation, it should be clarified that products that contain or consist of viable biological materials or viable organisms of another origin in order to achieve or support the intended purpose of those products are not covered by this Regulation either. (14) The requirements laid down in Directive 2002/98/EC of the European Parliament and of the Council (10) should continue to apply. (15) There is scientific uncertainty about the risks and benefits of nanomaterials used for devices. In order to ensure a high level of health protection, free movement of goods and legal certainty for manufacturers, it is necessary to introduce a uniform definition for nanomaterials based on Commission Recommendation 2011/696/EU (11), with the necessary flexibility to adapt that definition to scientific and technical progress and subsequent regulatory development at Union and international level. In the design and manufacture of devices, manufacturers should take special care when using nanoparticles for which there is a high or medium potential for internal exposure. Such devices should be subject to the most stringent conformity assessment procedures. In preparation of implementing acts regulating the practical and uniform application of the corresponding requirements laid down in this Regulation, the relevant scientific opinions of the relevant scientific committees should be taken into account. (16) Safety aspects addressed by Directive 2014/30/EU of the European Parliament and of the Council (12) are an integral part of the general safety and performance requirements laid down in this Regulation for devices. Consequently, this Regulation should be considered a lex specialis in relation to that Directive. (17) This Regulation should include requirements regarding the design and manufacture of devices emitting ionizing radiation without affecting the application of Council Directive 2013/59/Euratom (13) which pursues other objectives. (18) This Regulation should include requirements for devices' design, safety and performance characteristics which are developed in such a way as to prevent occupational injuries, including protection from radiation. (19) It is necessary to clarify that software in its own right, when specifically intended by the manufacturer to be used for one or more of the medical purposes set out in the definition of a medical device, qualifies as a medical device, while software for general purposes, even when used in a healthcare setting, or software intended for life-style and well-being purposes is not a medical device. The qualification of software, either as a device or an accessory, is independent of the software's location or the type of interconnection between the software and a device. (20) The definitions in this Regulation, regarding devices themselves, the making available of devices, economic operators, users and specific processes, the conformity assessment, clinical investigations and clinical evaluations, post-market surveillance, vigilance and market surveillance, standards and other technical specifications, should be aligned with well-established practice in the field at Union and international level in order to enhance legal certainty. (21) It should be made clear that it is essential that devices offered to persons in the Union by means of information society services within the meaning of Directive (EU) 2015/1535 of the European Parliament and of the Council (14) and devices used in the context of a commercial activity to provide a diagnostic or therapeutic service to persons within the Union comply with the requirements of this Regulation, where the product in question is placed on the market or the service is provided in the Union. (22) To recognise the important role of standardisation in the field of medical devices, compliance with harmonised standards as defined in Regulation (EU) No 1025/2012 of the European Parliament and of the Council (15) should be a means for manufacturers to demonstrate conformity with the general safety and performance requirements and other legal requirements, such as those relating to quality and risk management, laid down in this Regulation. (23) Directive 98/79/EC of the European Parliament and of the Council (16) allows the Commission to adopt common technical specifications for specific categories of in vitro diagnostic medical devices. In areas where no harmonised standards exist or where they are insufficient, the Commission should be empowered to lay down common specifications which provide a means of complying with the general safety and performance requirements, and the requirements for clinical investigations and clinical evaluation and/or post-market clinical follow-up, laid down in this Regulation. (24) Common specifications (‘CS’) should be developed after consulting the relevant stakeholders and taking account of European and international standards. (25) The rules applicable to devices should be aligned, where appropriate, with the New Legislative Framework for the Marketing of Products, which consists of Regulation (EC) No 765/2008 of the European Parliament and of the Council (17) and Decision No 768/2008/EC of the European Parliament and of the Council (18). (26) The rules on Union market surveillance and control of products entering the Union market laid down in Regulation (EC) No 765/2008 apply to devices covered by this Regulation which does not prevent Member States from choosing the competent authorities to carry out those tasks. (27) It is appropriate to set out clearly the general obligations of the different economic operators, including importers and distributors, building on the New Legislative Framework for the Marketing of Products, without prejudice to the specific obligations laid down in the various parts of this Regulation, to enhance understanding of the requirements laid down in this Regulation and thus to improve regulatory compliance by the relevant operators. (28) For the purpose of this Regulation, the activities of distributors should be deemed to include acquisition, holding and supplying of devices. (29) Several of the obligations on manufacturers, such as clinical evaluation or vigilance reporting, that were set out only in the Annexes to Directives 90/385/EEC and 93/42/EEC, should be incorporated into the enacting provisions of this Regulation to facilitate its application. (30) Health institutions should have the possibility of manufacturing, modifying and using devices in-house and thereby address, on a non-industrial scale, the specific needs of target patient groups which cannot be met at the appropriate level of performance by an equivalent device available on the market. In that context, it is appropriate to provide that certain rules of this Regulation, as regards medical devices manufactured and used only within health institutions, including hospitals as well as institutions, such as laboratories and public health institutes that support the healthcare system and/or address patient needs, but which do not treat or care for patients directly, should not apply, since the aims of this Regulation would still be met in a proportionate manner. It should be noted that the concept of ‘health institution’ does not cover establishments primarily claiming to pursue health interests or healthy lifestyles, such as gyms, spas, wellness and fitness centres. As a result, the exemption applicable to health institutions does not apply to such establishments. (31) In view of the fact that natural or legal persons can claim compensation for damage caused by a defective device in accordance with applicable Union and national law, it is appropriate to require manufacturers to have measures in place to provide sufficient financial coverage in respect of their potential liability under Council Directive 85/374/EEC (19). Such measures should be proportionate to the risk class, type of device and the size of the enterprise. In this context, it is also appropriate to lay down rules concerning the facilitation, by a competent authority, of the provision of information to persons who may have been injured by a defective device. (32) To ensure that devices manufactured in series production continue to be in conformity with the requirements of this Regulation and that experience from the use of the devices they manufacture is taken into account for the production process, all manufacturers should have a quality management system and a post-market surveillance system in place which should be proportionate to the risk class and the type of the device in question. In addition, in order to minimize risks or prevent incidents related to devices, manufacturers should establish a system for risk management and a system for reporting of incidents and field safety corrective actions. (33) The risk management system should be carefully aligned with and reflected in the clinical evaluation for the device, including the clinical risks to be addressed as part of clinical investigations, clinical evaluation and post-market clinical follow up. The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated. (34) It should be ensured that supervision and control of the manufacture of devices, and the post-market surveillance and vigilance activities concerning them, are carried out within the manufacturer's organisation by a person responsible for regulatory compliance who fulfils minimum conditions of qualification. (35) For manufacturers who are not established in the Union, the authorised representative plays a pivotal role in ensuring the compliance of the devices produced by those manufacturers and in serving as their contact person established in the Union. Given that pivotal role, for the purposes of enforcement it is appropriate to make the authorised representative legally liable for defective devices in the event that a manufacturer established outside the Union has not complied with its general obligations. The liability of the authorised representative provided for in this Regulation is without prejudice to the provisions of Directive 85/374/EEC, and accordingly the authorised representative should be jointly and severally liable with the importer and the manufacturer. The tasks of an authorised representative should be defined in a written mandate. Considering the role of authorised representatives, the minimum requirements they should meet should be clearly defined, including the requirement of having available a person who fulfils minimum conditions of qualification which should be similar to those for a manufacturer's person responsible for regulatory compliance. (36) To ensure legal certainty in respect of the obligations incumbent on economic operators, it is necessary to clarify when a distributor, importer or other person is to be considered the manufacturer of a device. (37) Parallel trade in products already placed on the market is a lawful form of trade within the internal market on the basis of Article 34 TFEU subject to the limitations arising from the need for protection of health and safety and from the need for protection of intellectual property rights provided for under Article 36 TFEU. Application of the principle of parallel trade is, however, subject to different interpretations in the Member States. The conditions, in particular the requirements for relabelling and repackaging, should therefore be specified in this Regulation, taking into account the case-law of the Court of Justice (20) in other relevant sectors and existing good practice in the field of medical devices. (38) The reprocessing and further use of single-use devices should only take place where permitted by national law and while complying with the requirements laid down in this Regulation. The reprocessor of a single-use device should be considered to be the manufacturer of the reprocessed device and should assume the obligations incumbent on manufacturers under this Regulation. Nevertheless, Member States should have the possibility of deciding that the obligations relating to reprocessing and re-use of single-use devices within a health institution or by an external reprocessor acting on its behalf may differ from the obligations on a manufacturer described in this Regulation. In principle, such divergence should only be permitted where reprocessing and reuse of single-use devices within a health institution or by an external reprocessor are compliant with CS that have been adopted, or, in the absence of such CS, with relevant harmonised standards and national provisions. The reprocessing of such devices should ensure an equivalent level of safety and performance to that of the corresponding initial single-use device. (39) Patients who are implanted with a device should be given clear and easily accessible essential information allowing the implanted device to be identified and other relevant information about the device, including any necessary health risk warnings or precautions to be taken, for example indications as to whether or not it is compatible with certain diagnostic devices or with scanners used for security controls. (40) Devices should, as a general rule, bear the CE marking to indicate their conformity with this Regulation so that they can move freely within the Union and be put into service in accordance with their intended purpose. Member States should not create obstacles to the placing on the market or putting into service of devices that comply with the requirements laid down in this Regulation. However, Member States should be allowed to decide whether to restrict the use of any specific type of device in relation to aspects that are not covered by this Regulation. (41) The traceability of devices by means of a Unique Device Identification system (UDI system) based on international guidance should significantly enhance the effectiveness of the post-market safety-related activities for devices, which is owing to improved incident reporting, targeted field safety corrective actions and better monitoring by competent authorities. It should also help to reduce medical errors and to fight against falsified devices. Use of the UDI system should also improve purchasing and waste disposal policies and stock-management by health institutions and other economic operators and, where possible, be compatible with other authentication systems already in place in those settings. (42) The UDI system should apply to all devices placed on the market except custom-made devices, and be based on internationally recognised principles including definitions that are compatible with those used by major trade partners. In order for the UDI system to become functional in time for the application of this Regulation, detailed rules should be laid down in this Regulation. (43) Transparency and adequate access to information, appropriately presented for the intended user, are essential in the public interest, to protect public health, to empower patients and healthcare professionals and to enable them to make informed decisions, to provide a sound basis for regulatory decision-making and to build confidence in the regulatory system. (44) One key aspect in fulfilling the objectives of this Regulation is the creation of a European database on medical devices (Eudamed) that should integrate different electronic systems to collate and process information regarding devices on the market and the relevant economic operators, certain aspects of conformity assessment, notified bodies, certificates, clinical investigations, vigilance and market surveillance. The objectives of the database are to enhance overall transparency, including through better access to information for the public and healthcare professionals, to avoid multiple reporting requirements, to enhance coordination between Member States and to streamline and facilitate the flow of information between economic operators, notified bodies or sponsors and Member States as well as between Member States among themselves and with the Commission. Within the internal market, this can be ensured effectively only at Union level and the Commission should therefore further develop and manage the European databank on medical devices set up by Commission Decision 2010/227/EU (21). (45) To facilitate the functioning of Eudamed, an internationally recognised medical device nomenclature should be available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. Furthermore, that nomenclature should be available, where reasonably practicable, free of charge also to other stakeholders. (46) Eudamed's electronic systems regarding devices on the market, the relevant economic operators and certificates should enable the public to be adequately informed about devices on the Union market. The electronic system on clinical investigations should serve as a tool for the cooperation between Member States and for enabling sponsors to submit, on a voluntary basis, a single application for several Member States and to report serious adverse events, device deficiencies and related updates. The electronic system on vigilance should enable manufacturers to report serious incidents and other reportable events and to support the coordination of the evaluation of such incidents and events by competent authorities. The electronic system regarding market surveillance should be a tool for the exchange of information between competent authorities. (47) In respect of data collated and processed through the electronic systems of Eudamed, Directive 95/46/EC of the European Parliament and of the Council (22) applies to the processing of personal data carried out in the Member States, under the supervision of the Member States' competent authorities, in particular the public independent authorities designated by the Member States. Regulation (EC) No 45/2001 of the European Parliament and of the Council (23) applies to the processing of personal data carried out by the Commission within the framework of this Regulation, under the supervision of the European Data Protection Supervisor. In accordance with Regulation (EC) No 45/2001, the Commission should be designated as the controller of Eudamed and its electronic systems. (48) For implantable devices and for class III devices, manufacturers should summarise the main safety and performance aspects of the device and the outcome of the clinical evaluation in a document that should be publicly available. (49) The summary of safety and clinical performance for a device should include in particular the place of the device in the context of diagnostic or therapeutic options taking into account the clinical evaluation of that device when compared to the diagnostic or therapeutic alternatives and the specific conditions under which that device and its alternatives can be considered. (50) The proper functioning of notified bodies is crucial for ensuring a high level of health and safety protection and citizens' confidence in the system. Designation and monitoring of notified bodies by the Member States, in accordance with detailed and strict criteria, should therefore be subject to controls at Union level. (51) Notified bodies' assessments of manufacturers' technical documentation, in particular documentation on clinical evaluation, should be critically evaluated by the authority responsible for notified bodies. That evaluation should be part of the risk-based approach to the oversight and monitoring activities of notified bodies and should be based on sampling of the relevant documentation. (52) The position of notified bodies vis-à-vis manufacturers should be strengthened, including with regard to their right and duty to carry out unannounced on-site audits and to conduct physical or laboratory tests on devices to ensure continuous compliance by manufacturers after receipt of the original certification. (53) To increase transparency with regard to the oversight of notified bodies by national authorities, the authorities responsible for notified bodies should publish information on the national measures governing the assessment, designation and monitoring of notified bodies. In accordance with good administrative practice, this information should be kept up to date by those authorities in particular to reflect relevant, significant or substantive changes to the procedures in question. (54) The Member State in which a notified body is established should be responsible for enforcing the requirements of this Regulation with regard to that notified body. (55) In view, in particular, of the responsibility of Member States for the organisation and delivery of health services and medical care, they should be allowed to lay down additional requirements on notified bodies designated for the conformity assessment of devices and established on their territory as far as issues that are not regulated in this Regulation are concerned. Any such additional requirements laid down should not affect more specific horizontal Union legislation on notified bodies and equal treatment of notified bodies. (56) For class III implantable devices and class IIb active devices intended to administer and/or remove a medicinal product, notified bodies should, except in certain cases, be obliged to request expert panels to scrutinise their clinical evaluation assessment report. Competent authorities should be informed about devices that have been granted a certificate following a conformity assessment procedure involving an expert panel. The consultation of expert panels in relation to the clinical evaluation should lead to a harmonised evaluation of high-risk medical devices by sharing expertise on clinical aspects and developing CS on categories of devices that have undergone that consultation process. (57) For class III devices and for certain class IIb devices, a manufacturer should be able to consult voluntarily an expert panel, prior to that manufacturer's clinical evaluation and/or investigation, on its clinical development strategy and on proposals for clinical investigations. (58) It is necessary, in particular for the purpose of the conformity assessment procedures, to maintain the division of devices into four product classes in line with international practice. The classification rules, which are based on the vulnerability of the human body, should take into account the potential risks associated with the technical design and manufacture of the devices. To maintain the same level of safety as provided by Directive 90/385/EEC, active implantable devices should be in the highest risk class. (59) Rules under the old regime applied to invasive devices do not sufficiently take account of the level of invasiveness and potential toxicity of certain devices which are introduced into the human body. In order to obtain a suitable risk-based classification of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body, it is necessary to introduce specific classification rules for such devices. The classification rules should take into account the place where the device performs its action in or on the human body, where it is introduced or applied, and whether a systemic absorption of the substances of which the device is composed, or of the products of metabolism in the human body of those substances occurs. (60) The conformity assessment procedure for class I devices should be carried out, as a general rule, under the sole responsibility of manufacturers in view of the low level of vulnerability associated with such devices. For class IIa, class IIb and class III devices, an appropriate level of involvement of a notified body should be compulsory. (61) The conformity assessment procedures for devices should be further strengthened and streamlined whilst the requirements for notified bodies as regards the performance of their assessments should be clearly specified to ensure a level playing field. (62) It is appropriate that certificates of free sale contain information that makes it possible to use Eudamed in order to obtain information on the device, in particular with regard to whether it is on the market, withdrawn from the market or recalled, and on any certificate on its conformity. (63) To ensure a high level of safety and performance, demonstration of compliance with the general safety and performance requirements laid down in this Regulation should be based on clinical data that, for class III devices and implantable devices should, as a general rule, be sourced from clinical investigations that have been carried out under the responsibility of a sponsor. It should be possible both for the manufacturer and for another natural or legal person to be the sponsor taking responsibility for the clinical investigation. (64) The rules on clinical investigations should be in line with well-established international guidance in this field, such as the international standard ISO 14155:2011 on good clinical practice for clinical investigations of medical devices for human subjects, so as to make it easier for the results of clinical investigations conducted in the Union to be accepted as documentation outside the Union and to make it easier for the results of clinical investigations conducted outside the Union in accordance with international guidelines to be accepted within the Union. In addition, the rules should be in line with the most recent version of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. (65) It should be left to the Member State where a clinical investigation is to be conducted to determine the appropriate authority to be involved in the assessment of the application to conduct a clinical investigation and to organise the involvement of ethics committees within the timelines for the authorisation of that clinical investigation as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. In that context, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. (66) Where, in the course of a clinical investigation, harm caused to a subject leads to the civil or criminal liability of the investigator or the sponsor being invoked, the conditions for liability in such cases, including issues of causality and the level of damages and sanctions, should remain governed by national law. (67) An electronic system should be set up at Union level to ensure that every clinical investigation is recorded and reported in a publicly accessible database. To protect the right to the protection of personal data, recognised by Article 8 of the Charter of Fundamental Rights of the European Union (‘the Charter’), no personal data of subjects participating in a clinical investigation should be recorded in the electronic system. To ensure synergies with the area of clinical trials on medicinal products, the electronic system on clinical investigations should be interoperable with the EU database to be set up for clinical trials on medicinal products for human use. (68) Where a clinical investigation is to be conducted in more than one Member State, the sponsor should have the possibility of submitting a single application in order to reduce administrative burden. In order to allow for resource-sharing and to ensure consistency regarding the assessment of the health and safety-related aspects of the investigational device and of the scientific design of that clinical investigation, the procedure for the assessment of such single application should be coordinated between the Member States under the direction of a coordinating Member State. Such coordinated assessment should not include the assessment of intrinsically national, local and ethical aspects of a clinical investigation, including informed consent. For an initial period of seven years from the date of application of this Regulation, Member States should be able to participate on a voluntary basis in the coordinated assessment. After that period, all Member States should be obliged to participate in the coordinated assessment. The Commission, based on the experience gained from the voluntary coordination between Member States, should draw up a report on the application of the relevant provisions regarding the coordinated assessment procedure. In the event that the findings of the report are negative, the Commission should submit a proposal to extend the period of participation on a voluntary basis in the coordinated assessment procedure. (69) Sponsors should report certain adverse events and device deficiencies that occur during clinical investigations to the Member States in which those clinical investigations are being conducted. Member States should have the possibility of terminating or suspending the investigations or revoking the authorisation for those investigations, if considered necessary to ensure a high level of protection of the subjects participating in a clinical investigation. Such information should be communicated to the other Member States. (70) The sponsor of a clinical investigation should submit a summary of results of the clinical investigation that is easily understandable for the intended user together with the clinical investigation report, where applicable, within the timelines laid down in this Regulation. Where it is not possible to submit the summary of the results within the defined timelines for scientific reasons, the sponsor should justify this and specify when the results will be submitted. (71) This Regulation should cover clinical investigations intended to gather clinical evidence for the purpose of demonstrating conformity of devices and should also lay down basic requirements regarding ethical and scientific assessments for other types of clinical investigations of medical devices. (72) Incapacitated subjects, minors, pregnant women and breastfeeding women require specific protection measures. However, it should be left to Member States to determine the legally designated representatives of incapacitated subjects and minors. (73) The principles of replacement, reduction and refinement in the area of animal experimentation laid down in the Directive 2010/63/EU of the European Parliament and of the Council (24) should be observed. In particular, the unnecessary duplication of tests and studies should be avoided. (74) Manufacturers should play an active role during the post-market phase by systematically and actively gathering information from post-market experience with their devices in order to update their technical documentation and cooperate with the national competent authorities in charge of vigilance and market surveillance activities. To this end, manufacturers should establish a comprehensive post-market surveillance system, set up under their quality management system and based on a post-market surveillance plan. Relevant data and information gathered through post-market surveillance, as well as lessons learned from any implemented preventive and/or corrective actions, should be used to update any relevant part of technical documentation, such as those relating to risk assessment and clinical evaluation, and should also serve the purpose of transparency. (75) In order to better protect health and safety regarding devices on the market, the electronic system on vigilance for devices should be made more effective by creating a central portal at Union level for reporting serious incidents and field safety corrective actions. (76) Member States should take appropriate measures to raise awareness among healthcare professionals, users and patients about the importance of reporting incidents. Healthcare professionals, users and patients should be encouraged and enabled to report suspected serious incidents at national level using harmonised formats. The national competent authorities should inform manufacturers of any suspected serious incidents and, where a manufacturer confirms that such an incident has occurred, the authorities concerned should ensure that appropriate follow-up action is taken in order to minimise recurrence of such incidents. (77) The evaluation of reported serious incidents and field safety corrective actions should be conducted at national level but coordination should be ensured where similar incidents have occurred or field safety corrective actions have to be carried out in more than one Member State, with the objective of sharing resources and ensuring consistency regarding the corrective action. (78) In the context of the investigation of incidents, the competent authorities should take into account, where appropriate, the information provided by and views of relevant stakeholders, including patient and healthcare professionals' organisations and manufacturers' associations. (79) The reporting of serious adverse events or device deficiencies during clinical investigations and the reporting of serious incidents occurring after a device has been placed on the market should be clearly distinguished to avoid double reporting. (80) Rules on market surveillance should be included in this Regulation to reinforce the rights and obligations of the national competent authorities, to ensure effective coordination of their market surveillance activities and to clarify the applicable procedures. (81) Any statistically significant increase in the number or severity of incidents that are not serious or in expected side-effects that could have a significant impact on the benefit-risk analysis and which could lead to unacceptable risks should be reported to the competent authorities in order to permit their assessment and the adoption of appropriate measures. (82) An expert committee, the Medical Device Coordination Group (MDCG), composed of persons designated by the Member States based on their role and expertise in the field of medical devices including in vitro diagnostic medical devices, should be established to fulfil the tasks conferred on it by this Regulation and by Regulation (EU) 2017/746 of the European Parliament and of the Council (25), to provide advice to the Commission and to assist the Commission and the Member States in ensuring a harmonised implementation of this Regulation. The MDCG should be able to establish subgroups in order to have access to necessary in-depth technical expertise in the field of medical devices including in vitro diagnostic medical devices. When establishing subgroups, appropriate consideration should be given to the possibility of involving existing groups at Union level in the field of medical devices. (83) Expert panels and expert laboratories should be designated by the Commission on the basis of their up-to-date clinical, scientific or technical expertise, with the aim of providing scientific, technical and clinical assistance to the Commission, the MDCG, manufacturers and notified bodies in relation to the implementation of this Regulation. Moreover, expert panels should fulfil the tasks of providing an opinion on clinical evaluation assessment reports of notified bodies in the case of certain high-risk devices. (84) Closer coordination between national competent authorities through information exchange and coordinated assessments under the direction of a coordinating authority is essential for ensuring a consistently high level of health and safety protection within the internal market, in particular in the areas of clinical investigations and vigilance. The principle of coordinated exchange and assessment should also apply across other authority activities described in this Regulation, such as the designation of notified bodies and should be encouraged in the area of market surveillance of devices. Joint working, coordination and communication of activities should also lead to more efficient use of resources and expertise at national level. (85) The Commission should provide scientific, technical and corresponding logistical support to coordinating national authorities and ensure that the regulatory system for devices is effectively and uniformly implemented at Union level based on sound scientific evidence. (86) The Union and, where appropriate, the Member States should actively participate in international regulatory cooperation in the field of medical devices to facilitate the exchange of safety-related information regarding medical devices and to foster the further development of international regulatory guidelines that promote the adoption in other jurisdictions of regulations that lead to a level of health and safety protection equivalent to that set by this Regulation. (87) Member States should take all necessary measures to ensure that the provisions of this Regulation are implemented, including by laying down effective, proportionate and dissuasive penalties for their infringement. (88) Whilst this Regulation should not affect the right of Member States to levy fees for activities at national level, Member States should, in order to ensure transparency, inform the Commission and the other Member States before they decide on the level and structure of such fees. In order to further ensure transparency, the structure and level of the fees should be publicly available on request. (89) This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter and in particular human dignity, the integrity of the person, the protection of personal data, the freedom of art and science, the freedom to conduct business and the right to property. This Regulation should be applied by the Member States in accordance with those rights and principles. (90) The power to adopt delegated acts in accordance with Article 290 TFEU should be delegated to the Commission in order to amend certain non-essential provisions of this Regulation. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making (26). In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States' experts, and their experts systematically have access to meetings of Commission expert groups dealing with preparation of delegated acts. (91) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council (27). (92) The advisory procedure should be used for implementing acts that set out the form and presentation of the data elements of manufacturers' summaries of safety and clinical performance, and that establish the model for certificates of free sale, given that such implementing acts are of a procedural nature and do not directly have an impact on health and safety at Union level. (93) The Commission should adopt immediately applicable implementing acts where, in duly justified cases relating to the extension to the territory of the Union of a national derogation from the applicable conformity assessment procedures, imperative grounds of urgency so require. (94) In order to enable it to designate issuing entities, expert panels and expert laboratories, implementing powers should be conferred on the Commission. (95) To allow economic operators, especially SMEs, notified bodies, Member States and the Commission to adapt to the changes introduced by this Regulation and to ensure its proper application, it is appropriate to provide for a sufficient transitional period for that adaptation and for the organisational arrangements that are to be made. However, certain parts of the Regulation that directly affect Member States and the Commission should be implemented as soon as possible. It is also particularly important that, by the date of application of this Regulation, a sufficient number of notified bodies be designated in accordance with the new requirements so as to avoid any shortage of medical devices on the market. Nonetheless, it is necessary that any designation of a notified body in accordance with the requirements of this Regulation prior to the date of its application be without prejudice to the validity of the designation of those notified bodies under Directives 90/385/EEC and 93/42/EEC and to their capacity to continue issuing valid certificates under those two Directives until the date of application of this Regulation. (96) In order to ensure a smooth transition to the new rules for registration of devices and of certificates, the obligation to submit the relevant information to the electronic systems set up at Union level pursuant to this Regulation should, in the event that the corresponding IT systems are developed according to plan, only become fully effective from 18 months after the date of application of this Regulation. During this transitional period, certain provisions of Directives 90/385/EEC and 93/42/EEC should remain in force. However, in order to avoid multiple registrations, economic operators and notified bodies who register in the relevant electronic systems set up at Union level pursuant to this Regulation should be considered to be in compliance with the registration requirements adopted by the Member States pursuant to those provisions. (97) In order to provide for a smooth introduction of the UDI system, the moment of application of the obligation to place the UDI carrier on the label of the device should vary from one to five years after the date of application of this Regulation depending upon the class of the device concerned. (98) Directives 90/385/EEC and 93/42/EEC should be repealed to ensure that only one set of rules applies to the placing of medical devices on the market and the related aspects covered by this Regulation. Manufacturers' obligations as regards the making available of documentation regarding devices they placed on the market and manufacturers' and Member States' obligations as regards vigilance activities for devices placed on the market pursuant to those Directives should however continue to apply. While it should be left to Member States to decide how to organise vigilance activities, it is desirable for them to have the possibility of reporting incidents related to devices placed on the market pursuant to the Directives using the same tools as those for reporting on devices placed on the market pursuant to this Regulation. It is furthermore appropriate, in order to ensure a smooth transition from the old regime to the new regime, to provide that Commission Regulation (EU) No 207/2012 (28) and Commission Regulation (EU) No 722/2012 (29) should remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. Decision 2010/227/EU adopted in implementation of those Directives and Directive 98/79/EC should also remain in force and continue to apply until the date when Eudamed becomes fully functional. Conversely, no such maintenance in force is required for Commission Directives 2003/12/EC (30) and 2005/50/EC (31) and Commission Implementing Regulation (EU) No 920/2013 (32). (99) The requirements of this Regulation should be applicable to all devices placed on the market or put into service from the date of application of this Regulation. However, in order to provide for a smooth transition it should be possible, for a limited period of time from that date, for devices to be placed on the market or put into service by virtue of a valid certificate issued pursuant to Directive 90/385/EEC or pursuant to Directive 93/42/EEC. (100) The European Data Protection Supervisor has given an opinion (33) pursuant to Article 28(2) of Regulation (EC) No 45/2001. (101) Since the objectives of this Regulation, namely to ensure the smooth functioning of the internal market as regards medical devices and to ensure high standards of quality and safety for medical devices, thus ensuring a high level of protection of health and safety of patients, users and other persons, cannot be sufficiently achieved by the Member States but can rather, by reason of its scale and effects, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve those objectives, HAVE ADOPTED THIS REGULATION: CHAPTER I SCOPE AND DEFINITIONS Article 1 Subject matter and scope 1.   This Regulation lays down rules concerning the placing on the market, making available on the market or putting into service of medical devices for human use and accessories for such devices in the Union. This Regulation also applies to clinical investigations concerning such medical devices and accessories conducted in the Union. 2.   This Regulation shall also apply, as from the date of application of common specifications adopted pursuant to Article 9, to the groups of products without an intended medical purpose that are listed in Annex XVI, taking into account the state of the art, and in particular existing harmonised standards for analogous devices with a medical purpose, based on similar technology. The common specifications for each of the groups of products listed in Annex XVI shall address, at least, application of risk management as set out in Annex I for the group of products in question and, where necessary, clinical evaluation regarding safety. The necessary common specifications shall be adopted by 26 May 2020. They shall apply as from six months after the date of their entry into force or from 26 May 2020, whichever is the latest. Notwithstanding Article 122, Member States' measures regarding the qualification of the products covered by Annex XVI as medical devices pursuant to Directive 93/42/EEC shall remain valid until the date of application, as referred to in the first subparagraph, of the relevant common specifications for that group of products. This Regulation also applies to clinical investigations conducted in the Union concerning the products referred to in the first subparagraph. 3.   Devices with both a medical and a non-medical intended purpose shall fulfil cumulatively the requirements applicable to devices with an intended medical purpose and those applicable to devices without an intended medical purpose. 4.   For the purposes of this Regulation, medical devices, accessories for medical devices, and products listed in Annex XVI to which this Regulation applies pursuant to paragraph 2 shall hereinafter be referred to as ‘devices’. 5.   Where justified on account of the similarity between a device with an intended medical purpose placed on the market and a product without an intended medical purpose in respect of their characteristics and risks, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list in Annex XVI, by adding new groups of products, in order to protect the health and safety of users or other persons or other aspects of public health. 6.   This Regulation does not apply to: (a) in vitro diagnostic medical devices covered by Regulation (EU) 2017/746; (b) medicinal products as defined in point 2 of Article 1 of Directive 2001/83/EC. In deciding whether a product falls under Directive 2001/83/EC or under this Regulation, particular account shall be taken of the principal mode of action of the product; (c) advanced therapy medicinal products covered by Regulation (EC) No 1394/2007; (d) human blood, blood products, plasma or blood cells of human origin or devices which incorporate, when placed on the market or put into service, such blood products, plasma or cells, except for devices referred to in paragraph 8 of this Article; (e) cosmetic products covered by Regulation (EC) No 1223/2009; (f) transplants, tissues or cells of animal origin, or their derivatives, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or are rendered non-viable; (g) transplants, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable; (h) products, other than those referred to in points (d), (f) and (g), that contain or consist of viable biological material or viable organisms, including living micro-organisms, bacteria, fungi or viruses in order to achieve or support the intended purpose of the product; (i) food covered by Regulation (EC) No 178/2002. 7.   Any device which, when placed on the market or put into service, incorporates as an integral part an in vitro diagnostic medical device as defined in point 2 of Article 2 of Regulation (EU) 2017/746, shall be governed by this Regulation. The requirements of Regulation (EU) 2017/746 shall apply to the in vitro diagnostic medical device part of the device. 8.   Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation. However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council (34), as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 9.   Any device which is intended to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal product. However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned. 10.   Any device which, when placed on the market or put into service, incorporates, as an integral part, non-viable tissues or cells of human origin or their derivatives that have an action ancillary to that of the device shall be assessed and authorised in accordance with this Regulation. In that case, the provisions for donation, procurement and testing laid down in Directive 2004/23/EC shall apply. However, if the action of those tissues or cells or their derivatives is principal and not ancillary to that of the device and the product is not governed by Regulation (EC) No 1394/2007, the product shall be governed by Directive 2004/23/EC. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 11.   This Regulation is specific Union legislation within the meaning of Article 2(3) of Directive 2014/30/EU. 12.   Devices that are also machinery within the meaning of point (a) of the second paragraph of Article 2 of Directive 2006/42/EC of the European Parliament and of the Council (35) shall, where a hazard relevant under that Directive exists, also meet the essential health and safety requirements set out in Annex I to that Directive to the extent to which those requirements are more specific than the general safety and performance requirements set out in Chapter II of Annex I to this Regulation. 13.   This Regulation shall not affect the application of Directive 2013/59/Euratom. 14.   This Regulation shall not affect the right of a Member State to restrict the use of any specific type of device in relation to aspects not covered by this Regulation. 15.   This Regulation shall not affect national law concerning the organisation, delivery or financing of health services and medical care, such as the requirement that certain devices may only be supplied on a medical prescription, the requirement that only certain health professionals or healthcare institutions may dispense or use certain devices or that their use be accompanied by specific professional counselling. 16.   Nothing in this Regulation shall restrict the freedom of the press or the freedom of expression in the media in so far as those freedoms are guaranteed in the Union and in the Member States, in particular under Article 11 of the Charter of Fundamental Rights of the European Union. Article 2 Definitions For the purposes of this Regulation, the following definitions apply: (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conception; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (2) ‘accessory for a medical device’ means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); (3) ‘custom-made device’ means any device specifically made in accordance with a written prescription of any person authorised by national law by virtue of that person's professional qualifications which gives, under that person's responsibility, specific design characteristics, and is intended for the sole use of a particular patient exclusively to meet their individual conditions and needs. However, mass-produced devices which need to be adapted to meet the specific requirements of any professional user and devices which are mass-produced by means of industrial manufacturing processes in accordance with the written prescriptions of any authorised person shall not be considered to be custom-made devices; (4) ‘active device’ means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; (5) ‘implantable device’ means any device, including those that are partially or wholly absorbed, which is intended: — to be totally introduced into the human body, or — to replace an epithelial surface or the surface of the eye, by clinical intervention and which is intended to remain in place after the procedure. Any device intended to be partially introduced into the human body by clinical intervention and intended to remain in place after the procedure for at least 30 days shall also be deemed to be an implantable device; (6) ‘invasive device’ means any device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body; (7) ‘generic device group’ means a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics; (8) ‘single-use device’ means a device that is intended to be used on one individual during a single procedure; (9) ‘falsified device’ means any device with a false presentation of its identity and/or of its source and/or its CE marking certificates or documents relating to CE marking procedures. This definition does not include unintentional non-compliance and is without prejudice to infringements of intellectual property rights; (10) ‘procedure pack’ means a combination of products packaged together and placed on the market with the purpose of being used for a specific medical purpose; (11) ‘system’ means a combination of products, either packaged together or not, which are intended to be inter-connected or combined to achieve a specific medical purpose; (12) ‘intended purpose’ means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation; (13) ‘label’ means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices; (14) ‘instructions for use’ means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use and of any precautions to be taken; (15) ‘Unique Device Identifier’ (‘UDI’) means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market; (16) ‘non-viable’ means having no potential for metabolism or multiplication; (17) ‘derivative’ means a ‘non-cellular substance’ extracted from human or animal tissue or cells through a manufacturing process. The final substance used for manufacturing of the device in this case does not contain any cells or tissues; (18) ‘nanomaterial’ means a natural, incidental or manufactured material containing particles in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1-100 nm; Fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1 nm shall also be deemed to be nanomaterials; (19) ‘particle’, for the purposes of the definition of nanomaterial in point (18), means a minute piece of matter with defined physical boundaries; (20) ‘agglomerate’, for the purposes of the definition of nanomaterial in point (18), means a collection of weakly bound particles or aggregates where the resulting external surface area is similar to the sum of the surface areas of the individual components; (21) ‘aggregate’, for the purposes of the definition of nanomaterial in point (18), means a particle comprising of strongly bound or fused particles; (22) ‘performance’ means the ability of a device to achieve its intended purpose as stated by the manufacturer; (23) ‘risk’ means the combination of the probability of occurrence of harm and the severity of that harm; (24) ‘benefit-risk determination’ means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer; (25) ‘compatibility’ is the ability of a device, including software, when used together with one or more other devices in accordance with its intended purpose, to: (a) perform without losing or compromising the ability to perform as intended, and/or (b) integrate and/or operate without the need for modification or adaption of any part of the combined devices, and/or (c) be used together without conflict/interference or adverse reaction. (26) ‘interoperability’ is the ability of two or more devices, including software, from the same manufacturer or from different manufacturers, to: (a) exchange information and use the information that has been exchanged for the correct execution of a specified function without changing the content of the data, and/or (b) communicate with each other, and/or (c) work together as intended. (27) ‘making available on the market’ means any supply of a device, other than an investigational device, for distribution, consumption or use on the Union market in the course of a commercial activity, whether in return for payment or free of charge; (28) ‘placing on the market’ means the first making available of a device, other than an investigational device, on the Union market; (29) ‘putting into service’ means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; (30) ‘manufacturer’ means a natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark; (31) ‘fully refurbishing’, for the purposes of the definition of manufacturer, means the complete rebuilding of a device already placed on the market or put into service, or the making of a new device from used devices, to bring it into conformity with this Regulation, combined with the assignment of a new lifetime to the refurbished device; (32) ‘authorised representative’ means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under this Regulation; (33) ‘importer’ means any natural or legal person established within the Union that places a device from a third country on the Union market; (34) ‘distributor’ means any natural or legal person in the supply chain, other than the manufacturer or the importer, that makes a device available on the market, up until the point of putting into service; (35) ‘economic operator’ means a manufacturer, an authorised representative, an importer, a distributor or the person referred to in Article 22(1) and 22(3); (36) ‘health institution’ means an organisation the primary purpose of which is the care or treatment of patients or the promotion of public health; (37) ‘user’ means any healthcare professional or lay person who uses a device; (38) ‘lay person’ means an individual who does not have formal education in a relevant field of healthcare or medical discipline; (39) ‘reprocessing’ means a process carried out on a used device in order to allow its safe reuse including cleaning, disinfection, sterilisation and related procedures, as well as testing and restoring the technical and functional safety of the used device; (40) ‘conformity assessment’ means the process demonstrating whether the requirements of this Regulation relating to a device have been fulfilled; (41) ‘conformity assessment body’ means a body that performs third-party conformity assessment activities including calibration, testing, certification and inspection; (42) ‘notified body’ means a conformity assessment body designated in accordance with this Regulation; (43) ‘CE marking of conformity’ or ‘CE marking’ means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in this Regulation and other applicable Union harmonisation legislation providing for its affixing; (44) ‘clinical evaluation’ means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer; (45) ‘clinical investigation’ means any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device; (46) ‘investigational device’ means a device that is assessed in a clinical investigation; (47) ‘clinical investigation plan’ means a document that describes the rationale, objectives, design, methodology, monitoring, statistical considerations, organisation and conduct of a clinical investigation; (48) ‘clinical data’ means information concerning safety or performance that is generated from the use of a device and is sourced from the following: — clinical investigation(s) of the device concerned, — clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated, — reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated, — clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up; (49) ‘sponsor’ means any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation; (50) ‘subject’ means an individual who participates in a clinical investigation; (51) ‘clinical evidence’ means clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer; (52) ‘clinical performance’ means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; (53) ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health; (54) ‘investigator’ means an individual responsible for the conduct of a clinical investigation at a clinical investigation site; (55) ‘informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in a particular clinical investigation, after having been informed of all aspects of the clinical investigation that are relevant to the subject's decision to participate or, in the case of minors and of incapacitated subjects, an authorisation or agreement from their legally designated representative to include them in the clinical investigation; (56) ‘ethics committee’ means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations; (57) ‘adverse event’ means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device; (58) ‘serious adverse event’ means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitalisation or prolongation of patient hospitalisation, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect; (59) ‘device deficiency’ means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer; (60) ‘post-market surveillance’ means all activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions; (61) ‘market surveillance’ means the activities carried out and measures taken by competent authorities to check and ensure that devices comply with the requirements set out in the relevant Union harmonisation legislation and do not endanger health, safety or any other aspect of public interest protection; (62) ‘recall’ means any measure aimed at achieving the return of a device that has already been made available to the end user; (63) ‘withdrawal’ means any measure aimed at preventing a device in the supply chain from being further made available on the market; (64) ‘incident’ means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; (65) ‘serious incident’ means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; (66) ‘serious public health threat’ means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time; (67) ‘corrective action’ means action taken to eliminate the cause of a potential or actual non-conformity or other undesirable situation; (68) ‘field safety corrective action’ means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market; (69) ‘field safety notice’ means a communication sent by a manufacturer to users or customers in relation to a field safety corrective action; (70) ‘harmonised standard’ means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) No 1025/2012; (71) ‘common specifications’ (CS) means a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system. Article 3 Amendment of certain definitions The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend the definition of nanomaterial set out in point (18) and the related definitions in points (19), (20) and (21) of Article 2 in the light of technical and scientific progress and taking into account definitions agreed at Union and international level. Article 4 Regulatory status of products 1.   Without prejudice to Article 2(2) of Directive 2001/83/EC, upon a duly substantiated request of a Member State, the Commission shall, after consulting the Medical Device Coordination Group established under Article 103 of this Regulation (‘MDCG’), by means of implementing acts, determine whether or not a specific product, or category or group of products, falls within the definitions of ‘medical device’ or ‘accessory for a medical device’. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3) of this Regulation. 2.   The Commission may also, on its own initiative, after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 3.   The Commission shall ensure that Member States share expertise in the fields of medical devices, in vitro diagnostic medical devices, medicinal products, human tissues and cells, cosmetics, biocides, food and, if necessary, other products, in order to determine the appropriate regulatory status of a product, or category or group of products. 4.   When deliberating on the possible regulatory status as a device of products involving medicinal products, human tissues and cells, biocides or food products, the Commission shall ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA), as relevant. CHAPTER II MAKING AVAILABLE ON THE MARKET AND PUTTING INTO SERVICE OF DEVICES, OBLIGATIONS OF ECONOMIC OPERATORS, REPROCESSING, CE MARKING, FREE MOVEMENT Article 5 Placing on the market and putting into service 1.   A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose. 2.   A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose. 3.   Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61. 4.   Devices that are manufactured and used within health institutions shall be considered as having been put into service. 5.   With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices, manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met: (a) the devices are not transferred to another legal entity, (b) manufacture and use of the devices occur under appropriate quality management systems, (c) the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market, (d) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use; (e) the health institution draws up a declaration which it shall make publicly available, including: (i) the name and address of the manufacturing health institution; (ii) the details necessary to identify the devices; (iii) a declaration that the devices meet the general safety and performance requirements set out in Annex I to this Regulation and, where applicable, information on which requirements are not fully met with a reasoned justification therefor, (f) the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met; (g) the health institution takes all necessary measures to ensure that all devices are manufactured in accordance with the documentation referred to in point (f), and (h) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions. Member States may require that such health institutions submit to the competent authority any further relevant information about such devices which have been manufactured and used on their territory. Member States shall retain the right to restrict the manufacture and the use of any specific type of such devices and shall be permitted access to inspect the activities of the health institutions. This paragraph shall not apply to devices that are manufactured on an industrial scale. 6.   In order to ensure the uniform application of Annex I, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 6 Distance sales 1.   A device offered by means of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to a natural or legal person established in the Union shall comply with this Regulation. 2.   Without prejudice to national law regarding the exercise of the medical profession, a device that is not placed on the market but used in the context of a commercial activity, whether in return for payment or free of charge, for the provision of a diagnostic or therapeutic service offered by means of information society services as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535 or by other means of communication, directly or through intermediaries, to a natural or legal person established in the Union shall comply with this Regulation. 3.   Upon request by a competent authority, any natural or legal person offering a device in accordance with paragraph 1 or providing a service in accordance with paragraph 2 shall make available a copy of the EU declaration of conformity of the device concerned. 4.   A Member State may, on grounds of protection of public health, require a provider of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to cease its activity. Article 7 Claims In the labelling, instructions for use, making available, putting into service and advertising of devices, it shall be prohibited to use text, names, trademarks, pictures and figurative or other signs that may mislead the user or the patient with regard to the device's intended purpose, safety and performance by: (a) ascribing functions and properties to the device which the device does not have; (b) creating a false impression regarding treatment or diagnosis, functions or properties which the device does not have; (c) failing to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; (d) suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. Article 8 Use of harmonised standards 1.   Devices that are in conformity with the relevant harmonised standards, or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union, shall be presumed to be in conformity with the requirements of this Regulation covered by those standards or parts thereof. The first subparagraph shall also apply to system or process requirements to be fulfilled in accordance with this Regulation by economic operators or sponsors, including those relating to quality management systems, risk management, post-market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-up (‘PMCF’). References in this Regulation to harmonised standards shall be understood as meaning harmonised standards the references of which have been published in the Official Journal of the European Union. 2.   References in this Regulation to harmonised standards shall also include the monographs of the European Pharmacopoeia adopted in accordance with the Convention on the Elaboration of a European Pharmacopoeia, in particular on surgical sutures and on interaction between medicinal products and materials used in devices containing such medicinal products, provided that references to those monographs have been published in the Official Journal of the European Union. Article 9 Common specifications 1.   Without prejudice to Article 1(2) and 17(5) and the deadline laid down in those provisions, where no harmonised standards exist or where relevant harmonised standards are not sufficient, or where there is a need to address public health concerns, the Commission, after having consulted the MDCG, may, by means of implementing acts, adopt common specifications (CS) in respect of the general safety and performance requirements set out in Annex I, the technical documentation set out in Annexes II and III, the clinical evaluation and post-market clinical follow-up set out in Annex XIV or the requirements regarding clinical investigation set out in Annex XV. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Devices that are in conformity with the CS referred to in paragraph 1 shall be presumed to be in conformity with the requirements of this Regulation covered by those CS or the relevant parts of those CS. 3.   Manufacturers shall comply with the CS referred to in paragraph 1 unless they can duly justify that they have adopted solutions that ensure a level of safety and performance that is at least equivalent thereto. 4.   Notwithstanding paragraph 3, manufacturers of products listed in Annex XVI shall comply with the relevant CS for those products. Article 10 General obligations of manufacturers 1.   When placing their devices on the market or putting them into service, manufacturers shall ensure that they have been designed and manufactured in accordance with the requirements of this Regulation. 2.   Manufacturers shall establish, document, implement and maintain a system for risk management as described in Section 3 of Annex I. 3.   Manufacturers shall conduct a clinical evaluation in accordance with the requirements set out in Article 61 and Annex XIV, including a PMCF. 4.   Manufacturers of devices other than custom-made devices shall draw up and keep up to date technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III. The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress, the Annexes II and III. 5.   Manufacturers of custom-made devices shall draw up, keep up to date and keep available for competent authorities documentation in accordance with Section 2 of Annex XIII. 6.   Where compliance with the applicable requirements has been demonstrated following the applicable conformity assessment procedure, manufacturers of devices, other than custom-made or investigational devices, shall draw up an EU declaration of conformity in accordance with Article 19, and affix the CE marking of conformity in accordance with Article 20. 7.   Manufacturers shall comply with the obligations relating to the UDI system referred to in Article 27 and with the registration obligations referred to in Articles 29 and 31. 8.   Manufacturers shall keep the technical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market. In the case of implantable devices, the period shall be at least 15 years after the last device has been placed on the market. Upon request by a competent authority, the manufacturer shall, as indicated therein, provide that technical documentation in its entirety or a summary thereof. A manufacturer with a registered place of business outside the Union shall, in order to allow its authorised representative to fulfil the tasks mentioned in Article 11(3), ensure that the authorised representative has the necessary documentation permanently available. 9.   Manufacturers shall ensure that procedures are in place to keep series production in conformity with the requirements of this Regulation. Changes in device design or characteristics and changes in the harmonised standards or CS by reference to which the conformity of a device is declared shall be adequately taken into account in a timely manner. Manufacturers of devices, other than investigational devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device. The quality management system shall cover all parts and elements of a manufacturer's organisation dealing with the quality of processes, procedures and devices. It shall govern the structure, responsibilities, procedures, processes and management resources required to implement the principles and actions necessary to achieve compliance with the provisions of this Regulation. The quality management system shall address at least the following aspects: (a) a strategy for regulatory compliance, including compliance with conformity assessment procedures and procedures for management of modifications to the devices covered by the system; (b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; (c) responsibility of the management; (d) resource management, including selection and control of suppliers and sub-contractors; (e) risk management as set out in in Section 3 of Annex I; (f) clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF; (g) product realisation, including planning, design, development, production and service provision; (h) verification of the UDI assignments made in accordance with Article 27(3) to all relevant devices and ensuring consistency and validity of information provided in accordance with Article 29; (i) setting-up, implementation and maintenance of a post-market surveillance system, in accordance with Article 83; (j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; (k) processes for reporting of serious incidents and field safety corrective actions in the context of vigilance; (l) management of corrective and preventive actions and verification of their effectiveness; (m) processes for monitoring and measurement of output, data analysis and product improvement. 10.   Manufacturers of devices shall implement and keep up to date the post-market surveillance system in accordance with Article 83. 11.   Manufacturers shall ensure that the device is accompanied by the information set out in Section 23 of Annex I in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label shall be indelible, easily legible and clearly comprehensible to the intended user or patient. 12.   Manufacturers who consider or have reason to believe that a device which they have placed on the market or put into service is not in conformity with this Regulation shall immediately take the necessary corrective action to bring that device into conformity, to withdraw it or to recall it, as appropriate. They shall inform the distributors of the device in question and, where applicable, the authorised representative and importers accordingly. Where the device presents a serious risk, manufacturers shall immediately inform the competent authorities of the Member States in which they made the device available and, where applicable, the notified body that issued a certificate for the device in accordance with Article 56, in particular, of the non-compliance and of any corrective action taken. 13.   Manufacturers shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88. 14.   Manufacturers shall, upon request by a competent authority, provide it with all the information and documentation necessary to demonstrate the conformity of the device, in an official Union language determined by the Member State concerned. The competent authority of the Member State in which the manufacturer has its registered place of business may require that the manufacturer provide samples of the device free of charge or, where that is impracticable, grant access to the device. Manufacturers shall cooperate with a competent authority, at its request, on any corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market or put into service. If the manufacturer fails to cooperate or the information and documentation provided is incomplete or incorrect, the competent authority may, in order to ensure the protection of public health and patient safety, take all appropriate measures to prohibit or restrict the device's being made available on its national market, to withdraw the device from that market or to recall it until the manufacturer cooperates or provides complete and correct information. If a competent authority considers or has reason to believe that a device has caused damage, it shall, upon request, facilitate the provision of the information and documentation referred to in the first subparagraph to the potentially injured patient or user and, as appropriate, the patient's or user's successor in title, the patient's or user's health insurance company or other third parties affected by the damage caused to the patient or user, without prejudice to data protection rules and, unless there is an overriding public interest in disclosure, without prejudice to the protection of intellectual property rights. The competent authority need not comply with the obligation laid down in the third subparagraph where disclosure of the information and documentation referred to in the first subparagraph is ordinarily dealt with in the context of legal proceedings. 15.   Where manufacturers have their devices designed or manufactured by another legal or natural person the information on the identity of that person shall be part of the information to be submitted in accordance with Article 30(1). 16.   Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Manufacturers shall, in a manner that is proportionate to the risk class, type of device and the size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to more protective measures under national law. Article 11 Authorised representative 1.   Where the manufacturer of a device is not established in a Member State, the device may only be placed on the Union market if the manufacturer designates a sole authorised representative. 2.   The designation shall constitute the authorised representative's mandate, it shall be valid only when accepted in writing by the authorised representative and shall be effective at least for all devices of the same generic device group. 3.   The authorised representative shall perform the tasks specified in the mandate agreed between it and the manufacturer. The authorised representative shall provide a copy of the mandate to the competent authority, upon request. The mandate shall require, and the manufacturer shall enable, the authorised representative to perform at least the following tasks in relation to the devices that it covers: (a) verify that the EU declaration of conformity and technical documentation have been drawn up and, where applicable, that an appropriate conformity assessment procedure has been carried out by the manufacturer; (b) keep available a copy of the technical documentation, the EU declaration of conformity and, if applicable, a copy of the relevant certificate, including any amendments and supplements, issued in accordance with Article 56, at the disposal of competent authorities for the period referred to in Article 10(8); (c) comply with the registration obligations laid down in Article 31 and verify that the manufacturer has complied with the registration obligations laid down in Articles 27 and 29; (d) in response to a request from a competent authority, provide that competent authority with all the information and documentation necessary to demonstrate the conformity of a device, in an official Union language determined by the Member State concerned; (e) forward to the manufacturer any request by a competent authority of the Member State in which the authorised representative has its registered place of business for samples, or access to a device and verify that the competent authority receives the samples or is given access to the device; (f) cooperate with the competent authorities on any preventive or corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices; (g) immediately inform the manufacturer about complaints and reports from healthcare professionals, patients and users about suspected incidents related to a device for which they have been designated; (h) terminate the mandate if the manufacturer acts contrary to its obligations under this Regulation. 4.   The mandate referred to in paragraph 3 of this Article shall not delegate the manufacturer's obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). 5.   Without prejudice to paragraph 4 of this Article, where the manufacturer is not established in a Member State and has not complied with the obligations laid down in Article 10, the authorised representative shall be legally liable for defective devices on the same basis as, and jointly and severally with, the manufacturer. 6.   An authorised representative who terminates its mandate on the ground referred to in point (h) of paragraph 3 shall immediately inform the competent authority of the Member State in which it is established and, where applicable, the notified body that was involved in the conformity assessment for the device of the termination of the mandate and the reasons therefor. 7.   Any reference in this Regulation to the competent authority of the Member State in which the manufacturer has its registered place of business shall be understood as a reference to the competent authority of the Member State in which the authorised representative, designated by a manufacturer referred to in paragraph 1, has its registered place of business. Article 12 Change of authorised representative The detailed arrangements for a change of authorised representative shall be clearly defined in an agreement between the manufacturer, where practicable the outgoing authorised representative, and the incoming authorised representative. That agreement shall address at least the following aspects: (a) the date of termination of the mandate of the outgoing authorised representative and date of beginning of the mandate of the incoming authorised representative; (b) the date until which the outgoing authorised representative may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the obligation of the outgoing authorised representative after the end of the mandate to forward to the manufacturer or incoming authorised representative any complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device for which it had been designated as authorised representative. Article 13 General obligations of importers 1.   Importers shall place on the Union market only devices that are in conformity with this Regulation. 2.   In order to place a device on the market, importers shall verify that: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) a manufacturer is identified and that an authorised representative in accordance with Article 11 has been designated by the manufacturer; (c) the device is labelled in accordance with this Regulation and accompanied by the required instructions for use; (d) where applicable, a UDI has been assigned by the manufacturer in accordance with Article 27. Where an importer considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not place the device on the market until it has been brought into conformity and shall inform the manufacturer and the manufacturer's authorised representative. Where the importer considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which the importer is established. 3.   Importers shall indicate on the device or on its packaging or in a document accompanying the device their name, registered trade name or registered trade mark, their registered place of business and the address at which they can be contacted, so that their location can be established. They shall ensure that any additional label does not obscure any information on the label provided by the manufacturer. 4.   Importers shall verify that the device is registered in the electronic system in accordance with Article 29. Importers shall add their details to the registration in accordance with Article 31. 5.   Importers shall ensure that, while a device is under their responsibility, storage or transport conditions do not jeopardise its compliance with the general safety and performance requirements set out in Annex I and shall comply with the conditions set by the manufacturer, where available. 6.   Importers shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and provide the manufacturer, authorised representative and distributors with any information requested by them, in order to allow them to investigate complaints. 7.   Importers who consider or have reason to believe that a device which they have placed on the market is not in conformity with this Regulation shall immediately inform the manufacturer and its authorised representative. Importers shall co-operate with the manufacturer, the manufacturer's authorised representative and the competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or recall it is taken. Where the device presents a serious risk, they shall also immediately inform the competent authorities of the Member States in which they made the device available and, if applicable, the notified body that issued a certificate in accordance with Article 56 for the device in question, giving details, in particular, of the non-compliance and of any corrective action taken. 8.   Importers who have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device which they have placed on the market shall immediately forward this information to the manufacturer and its authorised representative. 9.   Importers shall, for the period referred to in Article 10(8), keep a copy of the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56. 10.   Importers shall cooperate with competent authorities, at the latters' request, on any action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market. Importers, upon request by a competent authority of the Member State in which the importer has its registered place of business, shall provide samples of the device free of charge or, where that is impracticable, grant access to the device. Article 14 General obligations of distributors 1.   When making a device available on the market, distributors shall, in the context of their activities, act with due care in relation to the requirements applicable. 2.   Before making a device available on the market, distributors shall verify that all of the following requirements are met: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) the device is accompanied by the information to be supplied by the manufacturer in accordance with Article 10(11); (c) for imported devices, the importer has complied with the requirements set out in Article 13(3); (d) that, where applicable, a UDI has been assigned by the manufacturer. In order to meet the requirements referred to in points (a), (b) and (d) of the first subparagraph the distributor may apply a sampling method that is representative of the devices supplied by that distributor. Where a distributor considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not make the device available on the market until it has been brought into conformity, and shall inform the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. Where the distributor considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which it is established. 3.   Distributors shall ensure that, while the device is under their responsibility, storage or transport conditions comply with the conditions set by the manufacturer. 4.   Distributors that consider or have reason to believe that a device which they have made available on the market is not in conformity with this Regulation shall immediately inform the manufacturer and, where applicable, the manufacturer's authorised representative and the importer. Distributors shall co-operate with the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer, and with competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or to recall it, as appropriate, is taken. Where the distributor considers or has reason to believe that the device presents a serious risk, it shall also immediately inform the competent authorities of the Member States in which it made the device available, giving details, in particular, of the non-compliance and of any corrective action taken. 5.   Distributors that have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device they have made available, shall immediately forward this information to the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. They shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and keep the manufacturer and, where available, the authorised representative and the importer informed of such monitoring and provide them with any information upon their request. 6.   Distributors shall, upon request by a competent authority, provide it with all the information and documentation that is at their disposal and is necessary to demonstrate the conformity of a device. Distributors shall be considered to have fulfilled the obligation referred to in the first subparagraph when the manufacturer or, where applicable, the authorised representative for the device in question provides the required information. Distributors shall cooperate with competent authorities, at their request, on any action taken to eliminate the risks posed by devices which they have made available on the market. Distributors, upon request by a competent authority, shall provide free samples of the device or, where that is impracticable, grant access to the device. Article 15 Person responsible for regulatory compliance 1.   Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom-made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. 2.   Micro and small enterprises within the meaning of Commission Recommendation 2003/361/EC (36) shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal. 3.   The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; (b) the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date; (c) the post-market surveillance obligations are complied with in accordance with Article 10(10); (d) the reporting obligations referred to in Articles 87 to 91 are fulfilled; (e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV is issued. 4.   If a number of persons are jointly responsible for regulatory compliance in accordance with paragraphs 1, 2 and 3, their respective areas of responsibility shall be stipulated in writing. 5.   The person responsible for regulatory compliance shall suffer no disadvantage within the manufacturer's organisation in relation to the proper fulfilment of his or her duties, regardless of whether or not they are employees of the organisation. 6.   Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Article 16 Cases in which obligations of manufacturers apply to importers, distributors or other persons 1.   A distributor, importer or other natural or legal person shall assume the obligations incumbent on manufacturers if it does any of the following: (a) makes available on the market a device under its name, registered trade name or registered trade mark, except in cases where a distributor or importer enters into an agreement with a manufacturer whereby the manufacturer is identified as such on the label and is responsible for meeting the requirements placed on manufacturers in this Regulation; (b) changes the intended purpose of a device already placed on the market or put into service; (c) modifies a device already placed on the market or put into service in such a way that compliance with the applicable requirements may be affected. The first subparagraph shall not apply to any person who, while not considered a manufacturer as defined in point (30) of Article 2, assembles or adapts for an individual patient a device already on the market without changing its intended purpose. 2.   For the purposes of point (c) of paragraph 1, the following shall not be considered to be a modification of a device that could affect its compliance with the applicable requirements: (a) provision, including translation, of the information supplied by the manufacturer, in accordance with Section 23 of Annex I, relating to a device already placed on the market and of further information which is necessary in order to market the device in the relevant Member State; (b) changes to the outer packaging of a device already placed on the market, including a change of pack size, if the repackaging is necessary in order to market the device in the relevant Member State and if it is carried out in such conditions that the original condition of the device cannot be affected by it. In the case of devices placed on the market in sterile condition, it shall be presumed that the original condition of the device is adversely affected if the packaging that is necessary for maintaining the sterile condition is opened, damaged or otherwise negatively affected by the repackaging. 3.   A distributor or importer that carries out any of the activities mentioned in points (a) and (b) of paragraph 2 shall indicate on the device or, where that is impracticable, on its packaging or in a document accompanying the device, the activity carried out together with its name, registered trade name or registered trade mark, registered place of business and the address at which it can be contacted, so that its location can be established. Distributors and importers shall ensure that they have in place a quality management system that includes procedures which ensure that the translation of information is accurate and up-to-date, and that the activities mentioned in points (a) and (b) of paragraph 2 are performed by a means and under conditions that preserve the original condition of the device and that the packaging of the repackaged device is not defective, of poor quality or untidy. The quality management system shall cover, inter alia, procedures ensuring that the distributor or importer is informed of any corrective action taken by the manufacturer in relation to the device in question in order to respond to safety issues or to bring it into conformity with this Regulation. 4.   At least 28 days prior to making the relabelled or repackaged device available on the market, distributors or importers carrying out any of the activities mentioned in points (a) and (b) of paragraph 2 shall inform the manufacturer and the competent authority of the Member State in which they plan to make the device available of the intention to make the relabelled or repackaged device available and, upon request, shall provide the manufacturer and the competent authority with a sample or mock-up of the relabelled or repackaged device, including any translated label and instructions for use. Within the same period of 28 days, the distributor or importer shall submit to the competent authority a certificate, issued by a notified body designated for the type of devices that are subject to activities mentioned in points (a) and (b) of paragraph 2, attesting that the quality management system of the distributer or importer complies with the requirements laid down in paragraph 3. Article 17 Single-use devices and their reprocessing 1.   Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 2.   Any natural or legal person who reprocesses a single-use device to make it suitable for further use within the Union shall be considered to be the manufacturer of the reprocessed device and shall assume the obligations incumbent on manufacturers laid down in this Regulation, which include obligations relating to the traceability of the reprocessed device in accordance with Chapter III of this Regulation. The reprocessor of the device shall be considered to be a producer for the purpose of Article 3(1) of Directive 85/374/EEC. 3.   By way of derogation from paragraph 2, as regards single-use devices that are reprocessed and used within a health institution, Member States may decide not to apply all of the rules relating to manufacturers' obligations laid down in this Regulation provided that they ensure that: (a) the safety and performance of the reprocessed device is equivalent to that of the original device and the requirements in points (a), (b), (d), (e), (f), (g) and (h) of Article 5(5) are complied with; (b) the reprocessing is performed in accordance with CS detailing the requirements concerning: — risk management, including the analysis of the construction and material, related properties of the device (reverse engineering) and procedures to detect changes in the design of the original device as well as of its planned application after reprocessing, — the validation of procedures for the entire process, including cleaning steps, — the product release and performance testing, — the quality management system, — the reporting of incidents involving devices that have been reprocessed, and — the traceability of reprocessed devices. Member States shall encourage, and may require, health institutions to provide information to patients on the use of reprocessed devices within the health institution and, where appropriate, any other relevant information on the reprocessed devices that patients are treated with. Member States shall notify the Commission and the other Member States of the national provisions introduced pursuant to this paragraph and the grounds for introducing them. The Commission shall keep the information publicly available. 4.   Member States may choose to apply the provisions referred to in paragraph 3 also as regards single-use devices that are reprocessed by an external reprocessor at the request of a health institution, provided that the reprocessed device in its entirety is returned to that health institution and the external reprocessor complies with the requirements referred to in points (a) and (b) of paragraph 3. 5.   The Commission shall adopt, in accordance with Article 9(1), the necessary CS referred to in point (b) of paragraph 3 by 26 May 2020. Those CS shall be consistent with the latest scientific evidence and shall address the application of the general requirements on safety and performance laid down in in this Regulation. In the event that those CS are not adopted by 26 May 2020, reprocessing shall be performed in accordance with any relevant harmonised standards and national provisions that cover the aspects outlined in point (b) of paragraph 3. Compliance with CS or, in the absence of CS, with any relevant harmonised standards and national provisions, shall be certified by a notified body. 6.   Only single-use devices that have been placed on the market in accordance with this Regulation, or prior to 26 May 2020 in accordance with Directive 93/42/EEC, may be reprocessed. 7.   Only reprocessing of single-use devices that is considered safe according to the latest scientific evidence may be carried out. 8.   The name and address of the legal or natural person referred to in paragraph 2 and the other relevant information referred to in Section 23 of Annex I shall be indicated on the label and, where applicable, in the instructions for use of the reprocessed device. The name and address of the manufacturer of the original single-use device shall no longer appear on the label, but shall be mentioned in the instructions for use of the reprocessed device. 9.   A Member State that permits reprocessing of single-use devices may maintain or introduce national provisions that are stricter than those laid down in this Regulation and which restrict or prohibit, within its territory, the following: (a) the reprocessing of single-use devices and the transfer of single-use devices to another Member State or to a third country with a view to their reprocessing; (b) the making available or further use of reprocessed single-use devices. Member States shall notify the Commission and the other Member States of those national provisions. The Commission shall make such information publicly available. 10.   The Commission shall by 27 May 2024 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. On the basis of that report, the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 18 Implant card and information to be supplied to the patient with an implanted device 1.   The manufacturer of an implantable device shall provide together with the device the following: (a) information allowing the identification of the device, including the device name, serial number, lot number, the UDI, the device model, as well as the name, address and the website of the manufacturer; (b) any warnings, precautions or measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions; (c) any information about the expected lifetime of the device and any necessary follow-up; (d) any other information to ensure safe use of the device by the patient, including the information in point (u) of Section 23.4 of Annex I. The information referred to in the first subparagraph shall be provided, for the purpose of making it available to the particular patient who has been implanted with the device, by any means that allow rapid access to that information and shall be stated in the language(s) determined by the concerned Member State. The information shall be written in a way that is readily understood by a lay person and shall be updated where appropriate. Updates of the information shall be made available to the patient via the website mentioned in point (a) of the first subparagraph. In addition, the manufacturer shall provide the information referred to in point (a) of the first subparagraph on an implant card delivered with the device. 2.   Member States shall require health institutions to make the information referred to in paragraph 1 available, by any means that allow rapid access to that information, to any patients who have been implanted with the device, together with the implant card, which shall bear their identity. 3.   The following implants shall be exempted from the obligations laid down in this Article: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors. The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend this list by adding other types of implants to it or by removing implants therefrom. Article 19 EU declaration of conformity 1.   The EU declaration of conformity shall state that the requirements specified in this Regulation have been fulfilled in relation to the device that is covered. The manufacturer shall continuously update the EU declaration of conformity. The EU declaration of conformity shall, as a minimum, contain the information set out in Annex IV and shall be translated into an official Union language or languages required by the Member State(s) in which the device is made available. 2.   Where, concerning aspects not covered by this Regulation, devices are subject to other Union legislation which also requires an EU declaration of conformity by the manufacturer that fulfilment of the requirements of that legislation has been demonstrated, a single EU declaration of conformity shall be drawn up in respect of all Union acts applicable to the device. The declaration shall contain all the information required for identification of the Union legislation to which the declaration relates. 3.   By drawing up the EU declaration of conformity, the manufacturer shall assume responsibility for compliance with the requirements of this Regulation and all other Union legislation applicable to the device. 4.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the EU declaration of conformity set out in Annex IV in the light of technical progress. Article 20 CE marking of conformity 1.   Devices, other than custom-made or investigational devices, considered to be in conformity with the requirements of this Regulation shall bear the CE marking of conformity, as presented in Annex V. 2.   The CE marking shall be subject to the general principles set out in Article 30 of Regulation (EC) No 765/2008. 3.   The CE marking shall be affixed visibly, legibly and indelibly to the device or its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE marking shall be affixed to the packaging. The CE marking shall also appear in any instructions for use and on any sales packaging. 4.   The CE marking shall be affixed before the device is placed on the market. It may be followed by a pictogram or any other mark indicating a special risk or use. 5.   Where applicable, the CE marking shall be followed by the identification number of the notified body responsible for the conformity assessment procedures set out in Article 52. The identification number shall also be indicated in any promotional material which mentions that a device fulfils the requirements for CE marking. 6.   Where devices are subject to other Union legislation which also provides for the affixing of the CE marking, the CE marking shall indicate that the devices also fulfil the requirements of that other legislation. Article 21 Devices for special purposes 1.   Member States shall not create obstacles to: (a) investigational devices being supplied to an investigator for the purpose of a clinical investigation if they meet the conditions laid down in Articles 62 to 80 and Article 82, in the implementing acts adopted pursuant to Article 81 and in Annex XV; (b) custom-made devices being made available on the market if Article 52(8) and Annex XIII have been complied with. The devices referred to in the first subparagraph shall not bear the CE marking, with the exception of the devices referred to in Article 74. 2.   Custom-made devices shall be accompanied by the statement referred to in Section 1 of Annex XIII, which shall be made available to the particular patient or user identified by name, an acronym or a numerical code. Member States may require that the manufacturer of a custom-made device submit to the competent authority a list of such devices which have been made available in their territory. 3.   At trade fairs, exhibitions, demonstrations or similar events, Member States shall not create obstacles to the showing of devices which do not comply with this Regulation, provided a visible sign clearly indicates that such devices are intended for presentation or demonstration purposes only and cannot be made available until they have been brought into compliance with this Regulation. Article 22 Systems and procedure packs 1.   Natural or legal persons shall draw up a statement if they combine devices bearing a CE marking with the following other devices or products, in a manner that is compatible with the intended purpose of the devices or other products and within the limits of use specified by their manufacturers, in order to place them on the market as a system or procedure pack: (a) other devices bearing the CE marking; (b) in vitro diagnostic medical devices bearing the CE marking in conformity with Regulation (EU) 2017/746; (c) other products which are in conformity with legislation that applies to those products only where they are used within a medical procedure or their presence in the system or procedure pack is otherwise justified. 2.   In the statement made pursuant to paragraph 1, the natural or legal person concerned shall declare that: (a) they verified the mutual compatibility of the devices and, if applicable other products, in accordance with the manufacturers' instructions and have carried out their activities in accordance with those instructions; (b) they packaged the system or procedure pack and supplied relevant information to users incorporating the information to be supplied by the manufacturers of the devices or other products which have been put together; (c) the activity of combining devices and, if applicable, other products as a system or procedure pack was subject to appropriate methods of internal monitoring, verification and validation. 3.   Any natural or legal person who sterilises systems or procedure packs referred to in paragraph 1 for the purpose of placing them on the market shall, at their choice, apply one of the procedures set out in Annex IX or the procedure set out in Part A of Annex XI. The application of those procedures and the involvement of the notified body shall be limited to the aspects of the procedure relating to ensuring sterility until the sterile packaging is opened or damaged. The natural or legal person shall draw up a statement declaring that sterilisation has been carried out in accordance with the manufacturer's instructions. 4.   Where the system or procedure pack incorporates devices which do not bear the CE marking or where the chosen combination of devices is not compatible in view of their original intended purpose, or where the sterilisation has not been carried out in accordance with the manufacturer's instructions, the system or procedure pack shall be treated as a device in its own right and shall be subject to the relevant conformity assessment procedure pursuant to Article 52. The natural or legal person shall assume the obligations incumbent on manufacturers. 5.   The systems or procedure packs referred to in paragraph 1 of this Article shall not themselves bear an additional CE marking but they shall bear the name, registered trade name or registered trade mark of the person referred to in paragraphs 1 and 3 of this Article as well as the address at which that person can be contacted, so that the person's location can be established. Systems or procedure packs shall be accompanied by the information referred to in Section 23 of Annex I. The statement referred to in paragraph 2 of this Article shall be kept at the disposal of the competent authorities, after the system or procedure pack has been put together, for the period that is applicable under Article 10(8) to the devices that have been combined. Where those periods differ, the longest period shall apply. Article 23 Parts and components 1.   Any natural or legal person who makes available on the market an item specifically intended to replace an identical or similar integral part or component of a device that is defective or worn in order to maintain or restore the function of the device without changing its performance or safety characteristics or its intended purpose, shall ensure that the item does not adversely affect the safety and performance of the device. Supporting evidence shall be kept available for the competent authorities of the Member States. 2.   An item that is intended specifically to replace a part or component of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation. Article 24 Free movement Except where otherwise provided for in this Regulation, Member States shall not refuse, prohibit or restrict the making available on the market or putting into service within their territory of devices which comply with the requirements of this Regulation. CHAPTER III IDENTIFICATION AND TRACEABILITY OF DEVICES, REGISTRATION OF DEVICES AND OF ECONOMIC OPERATORS, SUMMARY OF SAFETY AND CLINICAL PERFORMANCE, EUROPEAN DATABASE ON MEDICAL DEVICES Article 25 Identification within the supply chain 1.   Distributors and importers shall co-operate with manufacturers or authorised representatives to achieve an appropriate level of traceability of devices. 2.   Economic operators shall be able to identify the following to the competent authority, for the period referred to in Article 10(8): (a) any economic operator to whom they have directly supplied a device; (b) any economic operator who has directly supplied them with a device; (c) any health institution or healthcare professional to which they have directly supplied a device. Article 26 Medical devices nomenclature To facilitate the functioning of the European database on medical devices (‘Eudamed’) as referred to in Article 33, the Commission shall ensure that an internationally recognised medical devices nomenclature is available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. The Commission shall also endeavour to ensure that that nomenclature is available to other stakeholders free of charge, where reasonably practicable. Article 27 Unique Device Identification system 1.   The Unique Device Identification system (‘UDI system’) described in Part C of Annex VI shall allow the identification and facilitate the traceability of devices, other than custom-made and investigational devices, and shall consist of the following: (a) production of a UDI that comprises the following: (i) a UDI device identifier (‘UDI-DI’) specific to a manufacturer and a device, providing access to the information laid down in Part B of Annex VI; (ii) a UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI; (b) placing of the UDI on the label of the device or on its packaging; (c) storage of the UDI by economic operators, health institutions and healthcare professionals, in accordance with the conditions laid down in paragraphs 8 and 9 of this Article respectively; (d) establishment of an electronic system for Unique Device Identification (‘UDI database’) in accordance with Article 28. 2.   The Commission shall, by means of implementing acts, designate one or several entities to operate a system for assignment of UDIs pursuant to this Regulation (‘issuing entity’). That entity or those entities shall satisfy all of the following criteria: (a) the entity is an organisation with legal personality; (b) its system for the assignment of UDIs is adequate to identify a device throughout its distribution and use in accordance with the requirements of this Regulation; (c) its system for the assignment of UDIs conforms to the relevant international standards; (d) the entity gives access to its system for the assignment of UDIs to all interested users in accordance with a set of predetermined and transparent terms and conditions; (e) the entity undertakes to do the following: (i) operate its system for the assignment of UDIs for at least 10 years after its designation; (ii) make available to the Commission and to the Member States, upon request, information concerning its system for the assignment of UDIs; (iii) remain in compliance with the criteria for designation and the terms of designation. When designating issuing entities, the Commission shall endeavour to ensure that UDI carriers, as defined in Part C of Annex VI, are universally readable regardless of the system used by the issuing entity, with a view to minimising financial and administrative burdens for economic operators and health institutions. 3.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall assign to the device and, if applicable, to all higher levels of packaging, a UDI created in compliance with the rules of the issuing entity designated by the Commission in accordance with paragraph 2. Before a device, other than a custom-made or investigational device, is placed on the market the manufacturer shall ensure that the information referred to in Part B of Annex VI of the device in question are correctly submitted and transferred to the UDI database referred to in Article 28. 4.   UDI carriers shall be placed on the label of the device and on all higher levels of packaging. Higher levels of packaging shall not be understood to include shipping containers. 5.   The UDI shall be used for reporting serious incidents and field safety corrective actions in accordance with Article 87. 6.   The Basic UDI-DI, as defined in Part C of Annex VI, of the device shall appear on the EU declaration of conformity referred to in Article 19. 7.   As part of the technical documentation referred to in Annex II, the manufacturer shall keep up-to-date a list of all UDIs that it has assigned. 8.   Economic operators shall store and keep, preferably by electronic means, the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to: — class III implantable devices; — the devices, categories or groups of devices determined by a measure referred to in point (a) of paragraph 11. 9.   Health institutions shall store and keep preferably by electronic means the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to class III implantable devices. For devices other than class III implantable devices, Member States shall encourage, and may require, health institutions to store and keep, preferably by electronic means, the UDI of the devices with which they have been supplied. Member States shall encourage, and may require, healthcare professionals to store and keep preferably by electronic means, the UDI of the devices with which they have been supplied with. 10.   The Commission is empowered to adopt delegated acts in accordance with Article 115: (a) amending the list of information set out in Part B of Annex VI in the light of technical progress; and (b) amending Annex VI in the light of international developments and technical progress in the field of Unique Device Identification. 11.   The Commission may, by means of implementing acts, specify the detailed arrangements and the procedural aspects for the UDI system with a view to ensuring its harmonised application in relation to any of the following: (a) determining the devices, categories or groups of devices to which the obligation laid down in paragraph 8 is to apply; (b) specifying the data to be included in the UDI-PI of specific devices or device groups; The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). 12.   When adopting the measures referred to in paragraph 11, the Commission shall take into account all of the following: (a) confidentiality and data protection as referred to in Articles 109 and 110 respectively; (b) the risk-based approach; (c) the cost-effectiveness of the measures; (d) the convergence of UDI systems developed at international level; (e) the need to avoid duplications in the UDI system; (f) the needs of the healthcare systems of the Member States, and where possible, compatibility with other medical device identification systems that are used by stakeholders. Article 28 UDI database 1.   The Commission, after consulting the MDCG shall set up and manage a UDI database to validate, collate, process and make available to the public the information mentioned in Part B of Annex VI. 2.   When designing the UDI database, the Commission shall take into account the general principles set out in Section 5 of Part C of Annex VI. The UDI database shall be designed in particular such that no UDI-PIs and no commercially confidential product information can be included therein. 3.   The core data elements to be provided to the UDI database, referred to in Part B of Annex VI, shall be accessible to the public free of charge. 4.   The technical design of the UDI database shall ensure maximum accessibility to information stored therein, including multi-user access and automatic uploads and downloads of that information. The Commission shall provide for technical and administrative support to manufacturers and other users of the UDI database. Article 29 Registration of devices 1.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall, in accordance with the rules of the issuing entity referred to in Article 27(2), assign a Basic UDI-DI as defined in Part C of Annex VI to the device and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 2.   Before placing on the market a system or procedure pack pursuant to Article 22(1) and (3), that is not a custom-made device, the natural or legal person responsible shall assign to the system or procedure pack, in compliance with the rules of the issuing entity, a Basic UDI-DI and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that system or procedure pack. 3.   For devices that are the subject of a conformity assessment as referred to in Article 52(3) and in the second and third subparagraphs of Article 52(4), the assignment of a Basic UDI-DI referred to in paragraph 1 of this Article shall be done before the manufacturer applies to a notified body for that assessment. For the devices referred to in the first subparagraph, the notified body shall include a reference to the Basic UDI-DI on the certificate issued in accordance with point (a) of Section 4 of Chapter I of Annex XII and confirm in Eudamed that the information referred to in Section 2.2 of Part A of Annex VI is correct. After the issuing of the relevant certificate and before placing the device on the market, the manufacturer shall provide the Basic UDI-DI to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 4.   Before placing a device on the market, other than a custom-made device, the manufacturer shall enter or if, already provided, verify in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and shall thereafter keep the information updated. Article 30 Electronic system for registration of economic operators 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to create the single registration number referred to in Article 31(2) and to collate and process information that is necessary and proportionate to identify the manufacturer and, where applicable, the authorised representative and the importer. The details regarding the information to be provided to that electronic system by the economic operators are laid down in Section 1 of Part A of Annex VI. 2.   Member States may maintain or introduce national provisions on registration of distributors of devices which have been made available on their territory. 3.   Within two weeks of placing a device, other than a custom-made device, on the market, importers shall verify that the manufacturer or authorised representative has provided to the electronic system the information referred to in paragraph 1. Where applicable, importers shall inform the relevant authorised representative or manufacturer if the information referred to in paragraph 1 is not included or is incorrect. Importers shall add their details to the relevant entry/entries. Article 31 Registration of manufacturers, authorised representatives and importers 1.   Before placing a device, other than a custom-made device, on the market, manufacturers, authorised representatives and importers shall, in order to register, submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already registered in accordance with this Article. In cases where the conformity assessment procedure requires the involvement of a notified body pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI shall be provided to that electronic system before applying to the notified body. 2.   After having verified the data entered pursuant to paragraph 1, the competent authority shall obtain a single registration number (‘SRN’) from the electronic system referred to in Article 30 and issue it to the manufacturer, the authorised representative or the importer. 3.   The manufacturer shall use the SRN when applying to a notified body for conformity assessment and for accessing Eudamed in order to fulfil its obligations under Article 29. 4.   Within one week of any change occurring in relation to the information referred to in paragraph 1 of this Article, the economic operator shall update the data in the electronic system referred to in Article 30. 5.   Not later than one year after submission of the information in accordance with paragraph 1, and every second year thereafter, the economic operator shall confirm the accuracy of the data. In the event of a failure to do so within six months of those deadlines, any Member State may take appropriate corrective measures within its territory until that economic operator complies with that obligation. 6.   Without prejudice to the economic operator's responsibility for the data, the competent authority shall verify the confirmed data referred to in Section 1 of Part A of Annex VI. 7.   The data entered pursuant to paragraph 1 of this Article in the electronic system referred to in Article 30 shall be accessible to the public. 8.   The competent authority may use the data to charge the manufacturer, the authorised representative or the importer a fee pursuant to Article 111. Article 32 Summary of safety and clinical performance 1.   For implantable devices and for class III devices, other than custom-made or investigational devices, the manufacturer shall draw up a summary of safety and clinical performance. The summary of safety and clinical performance shall be written in a way that is clear to the intended user and, if relevant, to the patient and shall be made available to the public via Eudamed. The draft of the summary of safety and clinical performance shall be part of the documentation to be submitted to the notified body involved in the conformity assessment pursuant to Article 52 and shall be validated by that body. After its validation, the notified body shall upload the summary to Eudamed. The manufacturer shall mention on the label or instructions for use where the summary is available. 2.   The summary of safety and clinical performance shall include at least the following aspects: (a) the identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN; (b) the intended purpose of the device and any indications, contraindications and target populations; (c) a description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intended to be used in combination with the device; (d) possible diagnostic or therapeutic alternatives; (e) reference to any harmonised standards and CS applied; (f) the summary of clinical evaluation as referred to in Annex XIV, and relevant information on post-market clinical follow-up; (g) suggested profile and training for users; (h) information on any residual risks and any undesirable effects, warnings and precautions. 3.   The Commission may, by means of implementing acts, set out the form and the presentation of the data elements to be included in the summary of safety and clinical performance. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). Article 33 European database on medical devices 1.   The Commission, after consulting the MDCG, shall set up, maintain and manage the European database on medical devices (‘Eudamed’) for the following purposes: (a) to enable the public to be adequately informed about devices placed on the market, the corresponding certificates issued by notified bodies and about the relevant economic operators; (b) to enable unique identification of devices within the internal market and to facilitate their traceability; (c) to enable the public to be adequately informed about clinical investigations and to enable sponsors of clinical investigations to comply with obligations under Articles 62 to 80, Article 82, and any acts adopted pursuant to Article 81; (d) to enable manufacturers to comply with the information obligations laid down in Articles 87 to 90 or in any acts adopted pursuant to Article 91; (e) to enable the competent authorities of the Member States and the Commission to carry out their tasks relating to this Regulation on a well-informed basis and to enhance the cooperation between them. 2.   Eudamed shall include the following electronic systems: (a) the electronic system for registration of devices referred to in Article 29(4); (b) the UDI-database referred to in Article 28; (c) the electronic system on registration of economic operators referred to in Article 30; (d) the electronic system on notified bodies and on certificates referred to in Article 57; (e) the electronic system on clinical investigations referred to in Article 73; (f) the electronic system on vigilance and post-market surveillance referred to in Article 92; (g) the electronic system on market surveillance referred to in Article 100. 3.   When designing Eudamed the Commission shall give due consideration to compatibility with national databases and national web-interfaces to allow for import and export of data. 4.   The data shall be entered into Eudamed by the Member States, notified bodies, economic operators and sponsors as specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall provide for technical and administrative support to users of Eudamed. 5.   All the information collated and processed by Eudamed shall be accessible to the Member States and to the Commission. The information shall be accessible to notified bodies, economic operators, sponsors and the public to the extent specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall ensure that public parts of Eudamed are presented in a user-friendly and easily-searchable format. 6.   Eudamed shall contain personal data only insofar as necessary for the electronic systems referred to in paragraph 2 of this Article to collate and process information in accordance with this Regulation. Personal data shall be kept in a form which permits identification of data subjects for periods no longer than those referred to in Article 10(8). 7.   The Commission and the Member States shall ensure that data subjects may effectively exercise their rights to information, of access, to rectification and to object in accordance with Regulation (EC) No 45/2001 and Directive 95/46/EC, respectively. They shall also ensure that data subjects may effectively exercise the right of access to data relating to them, and the right to have inaccurate or incomplete data corrected and erased. Within their respective responsibilities, the Commission and the Member States shall ensure that inaccurate and unlawfully processed data are deleted, in accordance with the applicable legislation. Corrections and deletions shall be carried out as soon as possible, but no later than 60 days after a request is made by a data subject. 8.   The Commission shall, by means of implementing acts, lay down the detailed arrangements necessary for the setting up and maintenance of Eudamed. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). When adopting those implementing acts, the Commission shall ensure that, as far as possible, the system is developed in such a way as to avoid having to enter the same information twice within the same module or in different modules of the system. 9.   In relation to its responsibilities under this Article and the processing of personal data involved therein, the Commission shall be considered to be the controller of Eudamed and its electronic systems. Article 34 Functionality of Eudamed 1.   The Commission shall, in collaboration with the MDCG, draw up the functional specifications for Eudamed. The Commission shall draw up a plan for the implementation of those specifications by 26 May 2018. That plan shall seek to ensure that Eudamed is fully functional at a date that allows the Commission to publish the notice referred to in paragraph 3 of this Article by 25 March 2020 and that all other relevant deadlines laid down in Article 123 of this Regulation and in Article 113 of Regulation (EU) 2017/746 are met. 2.   The Commission shall, on the basis of an independent audit report, inform the MDCG when it has verified that Eudamed has achieved full functionality and Eudamed meets the functional specifications drawn up pursuant to paragraph 1. 3.   The Commission shall, after consultation with the MDCG and when it is satisfied that the conditions referred to in paragraph 2 have been fulfilled, publish a notice to that effect in the Official Journal of the European Union. CHAPTER IV NOTIFIED BODIES Article 35 Authorities responsible for notified bodies 1.   Any Member State that intends to designate a conformity assessment body as a notified body, or has designated a notified body, to carry out conformity assessment activities under this Regulation shall appoint an authority (‘authority responsible for notified bodies’), which may consist of separate constituent entities under national law and shall be responsible for setting up and carrying out the necessary procedures for the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, including subcontractors and subsidiaries of those bodies. 2.   The authority responsible for notified bodies shall be established, organised and operated so as to safeguard the objectivity and impartiality of its activities and to avoid any conflicts of interests with conformity assessment bodies. 3.   The authority responsible for notified bodies shall be organised in a manner such that each decision relating to designation or notification is taken by personnel different from those who carried out the assessment. 4.   The authority responsible for notified bodies shall not perform any activities that notified bodies perform on a commercial or competitive basis. 5.   The authority responsible for notified bodies shall safeguard the confidential aspects of the information it obtains. However, it shall exchange information on notified bodies with other Member States, the Commission and, when required, with other regulatory authorities. 6.   The authority responsible for notified bodies shall have a sufficient number of competent personnel permanently available for the proper performance of its tasks. Where the authority responsible for notified bodies is a different authority from the national competent authority for medical devices, it shall ensure that the national authority responsible for medical devices is consulted on relevant matters. 7.   Member States shall make publicly available general information on their measures governing the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, and on changes which have a significant impact on such tasks. 8.   The authority responsible for notified bodies shall participate in the peer-review activities provided for in Article 48. Article 36 Requirements relating to notified bodies 1.   Notified bodies shall fulfil the tasks for which they are designated in accordance with this Regulation. They shall satisfy the organisational and general requirements and the quality management, resource and process requirements that are necessary to fulfil those tasks. In particular, notified bodies shall comply with Annex VII. In order to meet the requirements referred to in the first subparagraph, notified bodies shall have permanent availability of sufficient administrative, technical and scientific personnel in accordance with Section 3.1.1 of Annex VII and personnel with relevant clinical expertise in accordance with Section 3.2.4 of Annex VII, where possible employed by the notified body itself. The personnel referred to in Sections 3.2.3 and 3.2.7 of Annex VII shall be employed by the notified body itself and shall not be external experts or subcontractors. 2.   Notified bodies shall make available and submit upon request all relevant documentation, including the manufacturer's documentation, to the authority responsible for notified bodies to allow it to conduct its assessment, designation, notification, monitoring and surveillance activities and to facilitate the assessment outlined in this Chapter. 3.   In order to ensure the uniform application of the requirements set out in Annex VII, the Commission may adopt implementing acts, to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 37 Subsidiaries and subcontracting 1.   Where a notified body subcontracts specific tasks connected with conformity assessment or has recourse to a subsidiary for specific tasks connected with conformity assessment, it shall verify that the subcontractor or the subsidiary meets the applicable requirements set out in Annex VII and shall inform the authority responsible for notified bodies accordingly. 2.   Notified bodies shall take full responsibility for the tasks performed on their behalf by subcontractors or subsidiaries. 3.   Notified bodies shall make publicly available a list of their subsidiaries. 4.   Conformity assessment activities may be subcontracted or carried out by a subsidiary provided that the legal or natural person that applied for conformity assessment has been informed accordingly. 5.   Notified bodies shall keep at the disposal of the authority responsible for notified bodies all relevant documents concerning the verification of the qualifications of the subcontractor or the subsidiary and the work carried out by them under this Regulation. Article 38 Application by conformity assessment bodies for designation 1.   Conformity assessment bodies shall submit an application for designation to the authority responsible for notified bodies. 2.   The application shall specify the conformity assessment activities as defined in this Regulation, and the types of devices for which the body is applying to be designated, and shall be supported by documentation demonstrating compliance with Annex VII. In respect of the organisational and general requirements and the quality management requirements set out in Sections 1 and 2 of Annex VII, a valid accreditation certificate and the corresponding evaluation report delivered by a national accreditation body in accordance with Regulation (EC) No 765/2008 may be submitted and shall be taken into consideration during the assessment described in Article 39. However, the applicant shall make available all the documentation referred to in the first subparagraph to demonstrate compliance with those requirements upon request. 3.   The notified body shall update the documentation referred to in paragraph 2 whenever relevant changes occur, in order to enable the authority responsible for notified bodies to monitor and verify continuous compliance with all the requirements set out in Annex VII. Article 39 Assessment of the application 1.   The authority responsible for notified bodies shall within 30 days check that the application referred to in Article 38 is complete and shall request the applicant to provide any missing information. Once the application is complete that authority shall send it to the Commission. The authority responsible for notified bodies shall review the application and supporting documentation in accordance with its own procedures and shall draw up a preliminary assessment report. 2.   The authority responsible for notified bodies shall submit the preliminary assessment report to the Commission which shall immediately transmit it to the MDCG. 3.   Within 14 days of the submission referred to in paragraph 2 of this Article, the Commission, in conjunction with the MDCG, shall appoint a joint assessment team made up of three experts, unless the specific circumstances require a different number of experts, chosen from the list referred to in Article 40(2). One of the experts shall be a representative of the Commission who shall coordinate the activities of the joint assessment team. The other two experts shall come from Member States other than the one in which the applicant conformity assessment body is established. The joint assessment team shall be comprised of experts who are competent to assess the conformity assessment activities and the types of devices which are the subject of the application or, in particular when the assessment procedure is initiated in accordance with Article 47(3), to ensure that the specific concern can be appropriately assessed. 4.   Within 90 days of its appointment, the joint assessment team shall review the documentation submitted with the application in accordance with Article 38. The joint assessment team may provide feedback to, or require clarification from, the authority responsible for notified bodies on the application and on the planned on-site assessment. The authority responsible for notified bodies together with the joint assessment team shall plan and conduct an on-site assessment of the applicant conformity assessment body and, where relevant, of any subsidiary or subcontractor, located inside or outside the Union, to be involved in the conformity assessment process. The on-site assessment of the applicant body shall be led by the authority responsible for notified bodies. 5.   Findings regarding non-compliance of an applicant conformity assessment body with the requirements set out in Annex VII shall be raised during the assessment process and discussed between the authority responsible for notified bodies and the joint assessment team with a view to reaching consensus and resolving any diverging opinions, with respect to the assessment of the application. At the end of the on-site assessment, the authority responsible for notified bodies shall list for the applicant conformity assessment body the non-compliances resulting from the assessment and summarise the assessment by the joint assessment team. Within a specified timeframe, the applicant conformity assessment body shall submit to the national authority a corrective and preventive action plan to address the non-compliances. 6.   The joint assessment team shall document any remaining diverging opinions with respect to the assessment within 30 days of completion of the on-site assessment and send them to the authority responsible for notified bodies. 7.   The authority responsible for notified bodies shall following receipt of a corrective and preventive action plan from the applicant body assess whether non-compliances identified during the assessment have been appropriately addressed. This plan shall indicate the root cause of the identified non-compliances and shall include a timeframe for implementation of the actions therein. The authority responsible for notified bodies shall having confirmed the corrective and preventive action plan forward it and its opinion thereon to the joint assessment team. The joint assessment team may request of the authority responsible for notified bodies further clarification and modifications. The authority responsible for notified bodies shall draw up its final assessment report which shall include: — the result of the assessment, — confirmation that the corrective and preventive actions have been appropriately addressed and, where required, implemented, — any remaining diverging opinion with the joint assessment team, and, where applicable, — the recommended scope of designation. 8.   The authority responsible for notified bodies shall submit its final assessment report and, if applicable, the draft designation to the Commission, the MDCG and the joint assessment team. 9.   The joint assessment team shall provide a final opinion regarding the assessment report prepared by the authority responsible for notified bodies and, if applicable, the draft designation within 21 days of receipt of those documents to the Commission, which shall immediately submit that final opinion to the MDCG. Within 42 days of receipt of the opinion of the joint assessment team, the MDCG shall issue a recommendation with regard to the draft designation, which the authority responsible for notified bodies shall duly take into consideration for its decision on the designation of the notified body. 10.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements specifying procedures and reports for the application for designation referred to in Article 38 and the assessment of the application set out in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 40 Nomination of experts for joint assessment of applications for notification 1.   The Member States and the Commission shall nominate experts qualified in the assessment of conformity assessment bodies in the field of medical devices to participate in the activities referred to in Articles 39 and 48. 2.   The Commission shall maintain a list of the experts nominated pursuant to paragraph 1 of this Article, together with information on their specific field of competence and expertise. That list shall be made available to Member States competent authorities through the electronic system referred to in Article 57. Article 41 Language requirements All documents required pursuant to Articles 38 and 39 shall be drawn up in a language or languages which shall be determined by the Member State concerned. Member States, in applying the first paragraph, shall consider accepting and using a commonly understood language in the medical field, for all or part of the documentation concerned. The Commission shall provide translations of the documentation pursuant to Articles 38 and 39, or parts thereof into an official Union language, such as is necessary for that documentation to be readily understood by the joint assessment team appointed in accordance with Article 39(3). Article 42 Designation and notification procedure 1.   Member States may only designate conformity assessment bodies for which the assessment pursuant to Article 39 was completed and which comply with Annex VII. 2.   Member States shall notify the Commission and the other Member States of the conformity assessment bodies they have designated, using the electronic notification tool within the database of notified bodies developed and managed by the Commission (NANDO). 3.   The notification shall clearly specify, using the codes referred to in paragraph 13 of this Article, the scope of the designation indicating the conformity assessment activities as defined in this Regulation and the types of devices which the notified body is authorised to assess and, without prejudice to Article 44, any conditions associated with the designation. 4.   The notification shall be accompanied by the final assessment report of the authority responsible for notified bodies, the final opinion of the joint assessment team referred to in Article 39(9) and the recommendation of the MDCG. Where the notifying Member State does not follow the recommendation of the MDCG, it shall provide a duly substantiated justification. 5.   The notifying Member State shall, without prejudice to Article 44, inform the Commission and the other Member States of any conditions associated with the designation and provide documentary evidence regarding the arrangements in place to ensure that the notified body will be monitored regularly and will continue to satisfy the requirements set out in Annex VII. 6.   Within 28 days of the notification referred to in paragraph 2, a Member State or the Commission may raise written objections, setting out its arguments, with regard either to the notified body or to its monitoring by the authority responsible for notified bodies. Where no objection is raised, the Commission shall publish in NANDO the notification within 42 days of its having been notified as referred to in paragraph 2. 7.   When a Member State or the Commission raises objections in accordance with paragraph 6, the Commission shall bring the matter before the MDCG within 10 days of the expiry of the period referred to in paragraph 6. After consulting the parties involved, the MDCG shall give its opinion at the latest within 40 days of the matter having been brought before it. Where the MDCG is of the opinion that the notification can be accepted, the Commission shall publish in NANDO the notification within 14 days. 8.   Where the MDCG, after having been consulted in accordance with paragraph 7, confirms the existing objection or raises another objection, the notifying Member State shall provide a written response to the MDCG opinion within 40 days of its receipt. The response shall address the objections raised in the opinion, and set out the reasons for the notifying Member State's decision to designate or not designate the conformity assessment body. 9.   Where the notifying Member State decides to uphold its decision to designate the conformity assessment body, having given its reasons in accordance with paragraph 8, the Commission shall publish in NANDO the notification within 14 days of being informed thereof. 10.   When publishing the notification in NANDO, the Commission shall also add to the electronic system referred to in Article 57 the information relating to the notification of the notified body along with the documents mentioned in paragraph 4 of this Article and the opinion and responses referred to in paragraphs 7 and 8 of this Article. 11.   The designation shall become valid the day after the notification is published in NANDO. The published notification shall state the scope of lawful conformity assessment activity of the notified body. 12.   The conformity assessment body concerned may perform the activities of a notified body only after the designation has become valid in accordance with paragraph 11. 13.   The Commission shall by 26 November 2017, by means of implementing acts, draw up a list of codes and corresponding types of devices for the purpose of specifying the scope of the designation of notified bodies. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). The Commission, after consulting the MDCG, may update this list based, inter alia, on information arising from the coordination activities described in Article 48. Article 43 Identification number and list of notified bodies 1.   The Commission shall assign an identification number to each notified body for which the notification becomes valid in accordance with Article 42(11). It shall assign a single identification number even when the body is notified under several Union acts. If they are successfully designated in accordance with this Regulation, bodies notified pursuant to Directives 90/385/EEC and 93/42/EEC shall retain the identification number assigned to them pursuant to those Directives. 2.   The Commission shall make the list of the bodies notified under this Regulation, including the identification numbers that have been assigned to them and the conformity assessment activities as defined in this Regulation and the types of devices for which they have been notified, accessible to the public in NANDO. It shall also make this list available on the electronic system referred to in Article 57. The Commission shall ensure that the list is kept up to date. Article 44 Monitoring and re-assessment of notified bodies 1.   Notified bodies shall, without delay, and at the latest within 15 days, inform the authority responsible for notified bodies of relevant changes which may affect their compliance with the requirements set out in Annex VII or their ability to conduct the conformity assessment activities relating to the devices for which they have been designated. 2.   The authorities responsible for notified bodies shall monitor the notified bodies established on their territory and their subsidiaries and subcontractors to ensure ongoing compliance with the requirements and the fulfilment of its obligations set out in this Regulation. Notified bodies shall, upon request by their authority responsible for notified bodies, supply all relevant information and documents, required to enable the authority, the Commission and other Member States to verify compliance. 3.   Where the Commission or the authority of a Member State submits a request to a notified body established on the territory of another Member State relating to a conformity assessment carried out by that notified body, it shall send a copy of that request to the authority responsible for notified bodies of that other Member State. The notified body concerned shall respond without delay and within 15 days at the latest to the request. The authority responsible for notified bodies of the Member State in which the body is established shall ensure that requests submitted by authorities of any other Member State or by the Commission are resolved by the notified body unless there is a legitimate reason for not doing so in which case the matter may be referred to the MDCG. 4.   At least once a year, the authorities responsible for notified bodies shall re-assess whether the notified bodies established on their respective territory and, where appropriate, the subsidiaries and subcontractors under the responsibility of those notified bodies still satisfy the requirements and fulfil their obligations set out in Annex VII. That review shall include an on-site audit of each notified body and, where necessary, of its subsidiaries and subcontractors. The authority responsible for notified bodies shall conduct its monitoring and assessment activities according to an annual assessment plan to ensure that it can effectively monitor the continued compliance of the notified body with the requirements of this Regulation. That plan shall provide a reasoned schedule for the frequency of assessment of the notified body and, in particular, associated subsidiaries and subcontractors. The authority shall submit its annual plan for monitoring or assessment for each notified body for which it is responsible to the MDCG and to the Commission. 5.   The monitoring of notified bodies by the authority responsible for notified bodies shall include observed audits of notified body personnel, including where necessary any personnel from subsidiaries and subcontractors, as that personnel is in the process of conducting quality management system assessments at a manufacturer's facility. 6.   The monitoring of notified bodies conducted by the authority responsible for notified bodies shall consider data arising from market surveillance, vigilance and post-market surveillance to help guide its activities. The authority responsible for notified bodies shall provide for a systematic follow-up of complaints and other information, including from other Member States, which may indicate non-fulfilment of the obligations by a notified body or its deviation from common or best practice. 7.   The authority responsible for notified bodies may in addition to regular monitoring or on-site assessments conduct short-notice, unannounced or ‘for-cause’ reviews if needed to address a particular issue or to verify compliance. 8.   The authority responsible for notified bodies shall review the assessments by notified bodies of manufacturers' technical documentation, in particular the clinical evaluation documentation as further outlined in Article 45. 9.   The authority responsible for notified bodies shall document and record any findings regarding non-compliance of the notified body with the requirements set out in Annex VII and shall monitor the timely implementation of corrective and preventive actions. 10.   Three years after notification of a notified body, and again every fourth year thereafter, a complete re-assessment to determine whether the notified body still satisfies the requirements set out in Annex VII shall be conducted by the authority responsible for notified bodies of the Member State in which the body is established and by a joint assessment team appointed for the purpose of the procedure described in Articles 38 and 39. 11.   The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend paragraph 10 to modify the frequency at which the complete re-assessment referred to in that paragraph is to be carried out. 12.   The Member States shall report to the Commission and to the MDCG, at least once a year, on their monitoring and on-site assessment activities regarding notified bodies and, where applicable, subsidiaries and subcontractors. The report shall provide details of the outcome of those activities, including activities pursuant to paragraph 7, and shall be treated as confidential by the MDCG and the Commission; however it shall contain a summary which shall be made publicly available. The summary of the report shall be uploaded to the electronic system referred to in Article 57. Article 45 Review of notified body assessment of technical documentation and clinical evaluation documentation 1.   The authority responsible for notified bodies, as part of its ongoing monitoring of notified bodies, shall review an appropriate number of notified body assessments of manufacturers' technical documentation, in particular the clinical evaluation documentation as referred to in points (c) and (d) of Section 6.1 of Annex II to verify the conclusions drawn by the notified body based on the information presented by the manufacturer. The reviews by the authority responsible for notified bodies shall be conducted both off-site and on-site. 2.   The sampling of files to be reviewed in accordance with paragraph 1 shall be planned and representative of the types and risk of devices certified by the notified body, in particular high-risk devices, and be appropriately justified and documented in a sampling plan, which shall be made available by the authority responsible for notified bodies to the MDCG upon request. 3.   The authority responsible for notified bodies shall review whether the assessment by the notified body was conducted appropriately and shall check the procedures used, associated documentation and the conclusions drawn by the notified body. Such checking shall include the technical documentation and clinical evaluation documentation of the manufacturer upon which the notified body has based its assessment. Such reviews shall be conducted utilising CS. 4.   Those reviews shall also form part of the re-assessment of notified bodies in accordance with Article 44(10) and the joint assessment activities referred to in Article 47(3). The reviews shall be conducted utilising appropriate expertise. 5.   Based on the reports of the reviews and assessments by the authority responsible for notified bodies or joint assessment teams, on input from the market surveillance, vigilance and post-market surveillance activities described in Chapter VII, on the continuous monitoring of technical progress, or on the identification of concerns and emerging issues concerning the safety and performance of devices, the MDCG may recommend that the sampling, carried out under this Article, cover a greater or lesser proportion of the technical documentation and clinical evaluation documentation assessed by a notified body. 6.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements, associated documents for, and coordination of, the review of assessments of technical documentation and clinical evaluation documentation, as referred to in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 46 Changes to designations and notifications 1.   The authority responsible for notified bodies shall notify the Commission and the other Member States of any relevant changes to the designation of a notified body. The procedures described in Article 39 and in Article 42 shall apply to extensions of the scope of the designation. For changes to the designation other than extensions of its scope, the procedures laid down in the following paragraphs shall apply. 2.   The Commission shall immediately publish the amended notification in NANDO. The Commission shall immediately enter information on the changes to the designation of the notified body in the electronic system referred to in Article 57. 3.   Where a notified body decides to cease its conformity assessment activities it shall inform the authority responsible for notified bodies and the manufacturers concerned as soon as possible and in the case of a planned cessation one year before ceasing its activities. The certificates may remain valid for a temporary period of nine months after cessation of the notified body's activities on condition that another notified body has confirmed in writing that it will assume responsibilities for the devices covered by those certificates. The new notified body shall complete a full assessment of the devices affected by the end of that period before issuing new certificates for those devices. Where the notified body has ceased its activity, the authority responsible for notified bodies shall withdraw the designation. 4.   Where a authority responsible for notified bodies has ascertained that a notified body no longer meets the requirements set out in Annex VII, or that it is failing to fulfil its obligations or has not implemented the necessary corrective measures, the authority shall suspend, restrict, or fully or partially withdraw the designation, depending on the seriousness of the failure to meet those requirements or fulfil those obligations. A suspension shall not exceed a period of one year, renewable once for the same period. The authority responsible for notified bodies shall immediately inform the Commission and the other Member States of any suspension, restriction or withdrawal of a designation. 5.   Where its designation has been suspended, restricted, or fully or partially withdrawn, the notified body shall inform the manufacturers concerned at the latest within 10 days. 6.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall take appropriate steps to ensure that the files of the notified body concerned are kept and make them available to authorities in other Member States responsible for notified bodies and to authorities responsible for market surveillance at their request. 7.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall: (a) assess the impact on the certificates issued by the notified body; (b) submit a report on its findings to the Commission and the other Member States within three months of having notified the changes to the designation; (c) require the notified body to suspend or withdraw, within a reasonable period of time determined by the authority, any certificates which were unduly issued to ensure the safety of devices on the market; (d) enter into the electronic system referred to in Article 57 information in relation to certificates of which it has required their suspension or withdrawal; (e) inform the competent authority for medical devices of the Member State in which the manufacturer has its registered place of business through the electronic system referred to in Article 57 of the certificates for which it has required suspension or withdrawal. That competent authority shall take the appropriate measures, where necessary to avoid a potential risk to the health or safety of patients, users or others. 8.   With the exception of certificates unduly issued, and where a designation has been suspended or restricted, the certificates shall remain valid in the following circumstances: (a) the authority responsible for notified bodies has confirmed, within one month of the suspension or restriction, that there is no safety issue in relation to certificates affected by the suspension or restriction, and the authority responsible for notified bodies has outlined a timeline and actions anticipated to remedy the suspension or restriction; or (b) the authority responsible for notified bodies has confirmed that no certificates relevant to the suspension will be issued, amended or re-issued during the course of the suspension or restriction, and states whether the notified body has the capability of continuing to monitor and remain responsible for existing certificates issued for the period of the suspension or restriction. In the event that the authority responsible for notified bodies determines that the notified body does not have the capability to support existing certificates issued, the manufacturer shall provide, to the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business, within three months of the suspension or restriction, a written confirmation that another qualified notified body is temporarily assuming the functions of the notified body to monitor and remain responsible for the certificates during the period of suspension or restriction. 9.   With the exception of certificates unduly issued, and where a designation has been withdrawn, the certificates shall remain valid for a period of nine months in the following circumstances: (a) where the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business has confirmed that there is no safety issue associated with the devices in question; and (b) another notified body has confirmed in writing that it will assume immediate responsibilities for those devices and will have completed assessment of them within twelve months of the withdrawal of the designation. In the circumstances referred to in the first subparagraph, the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its place of business may extend the provisional validity of the certificates for further periods of three months, which altogether shall not exceed twelve months. The authority or the notified body assuming the functions of the notified body affected by the change of designation shall immediately inform the Commission, the other Member States and the other notified bodies thereof. Article 47 Challenge to the competence of notified bodies 1.   The Commission, in conjunction with the MDCG, shall investigate all cases where concerns have been brought to its attention regarding the continued fulfilment by a notified body, or of one or more of its subsidiaries or subcontractors, of the requirements set out in Annex VII or the obligations to which they are subject. It shall ensure that the relevant authority responsible for notified bodies is informed and is given an opportunity to investigate those concerns. 2.   The notifying Member State shall provide the Commission, on request, with all information regarding the designation of the notified body concerned. 3.   The Commission, in conjunction with the MDCG, may initiate, as applicable, the assessment procedure described in Article 39(3) and (4), where there is reasonable concern about the ongoing compliance of a notified body or a subsidiary or subcontractor of the notified body with the requirements set out in Annex VII and where the investigation by the authority responsible for notified bodies is not deemed to have fully addressed the concerns or upon request of the authority responsible for notified bodies. The reporting and outcome of that assessment shall follow the principles of Article 39. Alternatively, depending on the severity of the issue, the Commission, in conjunction with the MDCG, may request that the authority responsible for notified bodies allow the participation of up to two experts from the list established pursuant to Article 40 in an on-site assessment as part of the planned monitoring and assessment activities in accordance with Article 44 and as outlined in the annual assessment plan described in Article 44(4). 4.   Where the Commission ascertains that a notified body no longer meets the requirements for its designation, it shall inform the notifying Member State accordingly and request it to take the necessary corrective measures, including the suspension, restriction or withdrawal of the designation if necessary. Where the Member State fails to take the necessary corrective measures, the Commission may, by means of implementing acts, suspend, restrict or withdraw the designation. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). It shall notify the Member State concerned of its decision and update NANDO and the electronic system referred to in Article 57. 5.   The Commission shall ensure that all confidential information obtained in the course of its investigations is treated accordingly. Article 48 Peer review and exchange of experience between authorities responsible for notified bodies 1.   The Commission shall provide for the organisation of exchange of experience and coordination of administrative practice between the authorities responsible for notified bodies. Such exchange shall cover elements including: (a) development of best practice documents relating to the activities of the authorities responsible for notified bodies; (b) development of guidance documents for notified bodies in relation to the implementation of this Regulation; (c) training and qualification of the experts referred to in Article 40; (d) monitoring of trends relating to changes to notified body designations and notifications and trends in certificate withdrawals and transfers between notified bodies; (e) monitoring of the application and applicability of scope codes referred to in Article 42(13); (f) development of a mechanism for peer reviews between authorities and the Commission; (g) methods of communication to the public on the monitoring and surveillance activities of authorities and the Commission on notified bodies. 2.   The authorities responsible for notified bodies shall participate in a peer review every third year through the mechanism developed pursuant to paragraph 1 of this Article. Such reviews shall normally be conducted in parallel with the on-site joint assessments described in Article 39. Alternatively, an authority may make the choice of having such reviews take place as part of its monitoring activities referred to in Article 44. 3.   The Commission shall participate in the organisation and provide support to the implementation of the peer review mechanism. 4.   The Commission shall compile an annual summary report of the peer review activities, which shall be made publicly available. 5.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements and related documents for the peer review mechanism and training and qualification as referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 49 Coordination of notified bodies The Commission shall ensure that appropriate coordination and cooperation between notified bodies is put in place and operated in the form of a coordination group of notified bodies in the field of medical devices, including in vitro diagnostic medical devices. This group shall meet on a regular basis and at least annually. The bodies notified under this Regulation shall participate in the work of that group. The Commission may establish the specific arrangements for the functioning of the coordination group of notified bodies. Article 50 List of standard fees Notified bodies shall establish lists of their standard fees for the conformity assessment activities that they carry out and shall make those lists publicly available. CHAPTER V CLASSIFICATION AND CONFORMITY ASSESSMENT SECTION 1 Classification Article 51 Classification of devices 1.   Devices shall be divided into classes I, IIa, IIb and III, taking into account the intended purpose of the devices and their inherent risks. Classification shall be carried out in accordance with Annex VIII. 2.   Any dispute between the manufacturer and the notified body concerned, arising from the application of Annex VIII, shall be referred for a decision to the competent authority of the Member State in which the manufacturer has its registered place of business. In cases where the manufacturer has no registered place of business in the Union and has not yet designated an authorised representative, the matter shall be referred to the competent authority of the Member State in which the authorised representative referred to in the last indent of point (b) of the second paragraph of Section 2.2 of Annex IX has its registered place of business. Where the notified body concerned is established in a Member State other than that of the manufacturer, the competent authority shall adopt its decision after consultation with the competent authority of the Member State that designated the notified body. The competent authority of the Member State in which the manufacturer has its registered place of business shall notify the MDCG and the Commission of its decision. The decision shall be made available upon request. 3.   At the request of a Member State the Commission shall after consulting the MDCG, decide, by means of implementing acts, on the following: (a) application of Annex VIII to a given device, or category or group of devices, with a view to determining the classification of such devices; (b) that a device, or category or group of devices, shall for reasons of public health based on new scientific evidence, or based on any information which becomes available in the course of the vigilance and market surveillance activities be reclassified, by way of derogation from Annex VIII. 4.   The Commission may also, on its own initiative and after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in points (a) and (b) of paragraph 3. 5.   In order to ensure the uniform application of Annex VIII, and taking account of the relevant scientific opinions of the relevant scientific committees, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. 6.   The implementing acts referred to in paragraphs 3, 4 and 5 of this Article shall be adopted in accordance with the examination procedure referred to in Article 114(3). SECTION 2 Conformity assessment Article 52 Conformity assessment procedures 1.   Prior to placing a device on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 2.   Prior to putting into service a device that is not placed on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 3.   Manufacturers of class III devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Annex X coupled with a conformity assessment as specified in Annex XI. 4.   Manufacturers of class IIb devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device per generic device group. However, for class IIb implantable devices, except sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors, the assessment of the technical documentation as specified in Section 4 of Annex IX shall apply for every device. Alternatively, the manufacturer may choose to apply a conformity assessment based on type examination as specified in Annex X coupled with a conformity assessment based on product conformity verification as specified in Annex XI. 5.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in the second subparagraph of paragraph 4 of this Article, being used in other class IIb implantable devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend that list by adding other types of class IIb implantable devices to that list or removing devices therefrom. 6.   Manufacturers of class IIa devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device for each category of devices. Alternatively, the manufacturer may choose to draw up the technical documentation set out in Annexes II and III coupled with a conformity assessment as specified in Section 10 or Section 18 of Annex XI. The assessment of the technical documentation shall apply for at least one representative device for each category of devices. 7.   Manufacturers of class I devices, other than custom-made or investigational devices, shall declare the conformity of their products by issuing the EU declaration of conformity referred to in Article 19 after drawing up the technical documentation set out in Annexes II and III. If those devices are placed on the market in sterile condition, have a measuring function or are reusable surgical instruments, the manufacturer shall apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI. However, the involvement of the notified body in those procedures shall be limited: (a) in the case of devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions; (b) in the case of devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements; (c) in the case of reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use. 8.   Manufacturers of custom-made devices shall follow the procedure set out in Annex XIII and draw up the statement set out in Section 1 of that Annex before placing such devices on the market. In addition to the procedure applicable pursuant to the first subparagraph, manufacturers of class III custom-made implantable devices shall be subject to the conformity assessment as specified in Chapter I of Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Part A of Annex XI. 9.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices referred to in the first subparagraph of Article 1(8), the procedure specified in Section 5.2 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 10.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices that are covered by this Regulation in accordance with point (f) or (g) of Article 1(6) and with the first subparagraph of Article 1(10), the procedure specified in Section 5.3 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 11.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7, in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the procedure specified in Section 5.4 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 12.   The Member State in which the notified body is established may require that all or certain documents, including the technical documentation, audit, assessment and inspection reports, relating to the procedures referred to in paragraphs 1 to 7 and 9 to 11 be made available in an official Union language(s) determined by that Member State. In the absence of such requirement, those documents shall be available in any official Union language acceptable to the notified body. 13.   Investigational devices shall be subject to the requirements set out in Articles 62 to 81. 14.   The Commission may, by means of implementing acts, specify detailed arrangements and procedural aspects with a view to ensuring the harmonised application of the conformity assessment procedures by the notified bodies for any of the following aspects: (a) the frequency and the sampling basis of the assessment of the technical documentation on a representative basis as set out in the third paragraph of Section 2.3 and in Section 3.5 of Annex IX in the case of class IIa and class IIb devices, and in Section 10.2 of Annex XI in the case of class IIa devices; (b) the minimum frequency of unannounced on-site audits and sample tests to be conducted by notified bodies in accordance with Section 3.4 of Annex IX, taking into account the risk-class and the type of device; (c) the physical, laboratory or other tests to be carried out by notified bodies in the context of sample tests, assessment of the technical documentation and type examination in accordance with Sections 3.4 and 4.3 of Annex IX, Section 3 of Annex X and Section 15 of Annex XI. The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 53 Involvement of notified bodies in conformity assessment procedures 1.   Where the conformity assessment procedure requires the involvement of a notified body, the manufacturer may apply to a notified body of its choice, provided that the chosen notified body is designated for conformity assessment activities related to the types of devices concerned. The manufacturer may not lodge an application in parallel with another notified body for the same conformity assessment procedure. 2.   The notified body concerned shall, by means of the electronic system referred to in Article 57, inform the other notified bodies of any manufacturer that withdraws its application prior to the notified body's decision regarding the conformity assessment. 3.   When applying to a notified body under paragraph 1, manufacturers shall declare whether they have withdrawn an application with another notified body prior to the decision of that notified body and provide information about any previous application for the same conformity assessment that has been refused by another notified body. 4.   The notified body may require any information or data from the manufacturer, which is necessary in order to properly conduct the chosen conformity assessment procedure. 5.   Notified bodies and the personnel of notified bodies shall carry out their conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific field and shall be free from all pressures and inducements, particularly financial, which might influence their judgement or the results of their conformity assessment activities, especially as regards persons or groups with an interest in the results of those activities. Article 54 Clinical evaluation consultation procedure for certain class III and class IIb devices 1.   In addition to the procedures applicable pursuant to Article 52, a notified body shall also follow the procedure regarding clinical evaluation consultation as specified in Section 5.1 of Annex IX or as referred to in Section 6 of Annex X, as applicable, when performing a conformity assessment of the following devices: (a) class III implantable devices, and (b) class IIb active devices intended to administer and/or remove a medicinal product, as referred to in Section 6.4 of Annex VIII (Rule 12). 2.   The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not adversely affect the benefit-risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device. 3.   The notified body shall notify the competent authorities, the authority responsible for notified bodies and the Commission through the electronic system referred to in Article 57 of whether or not the procedure referred to in paragraph 1 of this Article is to be applied. That notification shall be accompanied by the clinical evaluation assessment report. 4.   The Commission shall draw up an annual overview of devices which have been subject to the procedure specified in Section 5.1 of Annex IX and referred to in Section 6 of Annex X. The annual overview shall include the notifications in accordance with paragraph 3 of this Article and point (e) of Section 5.1 of Annex IX and a listing of the cases where the notified body did not follow the advice from the expert panel. The Commission shall submit this overview to the European Parliament, to the Council and to the MDCG. 5.   The Commission shall by 27 May 2025 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. The report shall take into account the annual overviews and any available relevant recommendations from the MDCG. On the basis of that report the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 55 Mechanism for scrutiny of conformity assessments of certain class III and class IIb devices 1.   A notified body shall notify the competent authorities of certificates it has granted to devices for which the conformity assessment has been performed pursuant to Article 54(1). Such notification shall take place through the electronic system referred to in Article 57 and shall include the summary of safety and clinical performance pursuant to Article 32, the assessment report by the notified body, the instructions for use referred to in Section 23.4 of Annex I, and, where applicable, the scientific opinion of the expert panels referred to in Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. In the case of divergent views between the notified body and the expert panels, a full justification shall also be included. 2.   A competent authority and, where applicable, the Commission may, based on reasonable concerns apply further procedures in accordance with Article 44, 45, 46, 47 or 94 and, where deemed necessary, take appropriate measures in accordance with Articles 95 and 97. 3.   The MDCG and, where applicable, the Commission, may, based on reasonable concerns, request scientific advice from the expert panels in relation to the safety and performance of any device. Article 56 Certificates of conformity 1.   The certificates issued by the notified bodies in accordance with Annexes IX, X and XI shall be in an official Union language determined by the Member State in which the notified body is established or otherwise in an official Union language acceptable to the notified body. The minimum content of the certificates shall be as set out in Annex XII. 2.   The certificates shall be valid for the period they indicate, which shall not exceed five years. On application by the manufacturer, the validity of the certificate may be extended for further periods, each not exceeding five years, based on a re-assessment in accordance with the applicable conformity assessment procedures. Any supplement to a certificate shall remain valid as long as the certificate which it supplements is valid. 3.   Notified bodies may impose restrictions to the intended purpose of a device to certain groups of patients or require manufacturers to undertake specific PMCF studies pursuant to Part B of Annex XIV. 4.   Where a notified body finds that the requirements of this Regulation are no longer met by the manufacturer, it shall, taking account of the principle of proportionality, suspend or withdraw the certificate issued or impose any restrictions on it unless compliance with such requirements is ensured by appropriate corrective action taken by the manufacturer within an appropriate deadline set by the notified body. The notified body shall give the reasons for its decision. 5.   The notified body shall enter in the electronic system referred to in Article 57 any information regarding certificates issued, including amendments and supplements thereto, and regarding suspended, reinstated, withdrawn or refused certificates and restrictions imposed on certificates. Such information shall be accessible to the public. 6.   In the light of technical progress, the Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the certificates set out in Annex XII. Article 57 Electronic system on notified bodies and on certificates of conformity 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to collate and process the following information: (a) the list of subsidiaries referred to in Article 37(3); (b) the list of experts referred to in Article 40(2); (c) the information relating to the notification referred to in Article 42(10) and the amended notifications referred to in Article 46(2); (d) the list of notified bodies referred to in Article 43(2); (e) the summary of the report referred to in Article 44(12); (f) the notifications for conformity assessments and certificates referred to in Articles 54(3) and 55(1); (g) withdrawal or refusals of applications for the certificates as referred to in Article 53(2) and Section 4.3 of Annex VII; (h) the information regarding certificates referred to in Article 56(5); (i) the summary of safety and clinical performance referred to in Article 32. 2.   The information collated and processed by the electronic system shall be accessible to the competent authorities of the Member States, to the Commission, where appropriate to the notified bodies and where provided elsewhere in this regulation or in Regulation (EU) 2017/746 to the public. Article 58 Voluntary change of notified body 1.   In cases where a manufacturer terminates its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device, the detailed arrangements for the change of notified body shall be clearly defined in an agreement between the manufacturer, the incoming notified body and, where practicable the outgoing notified body. That agreement shall cover at least the following aspects: (a) the date on which the certificates issued by the outgoing notified body become invalid; (b) the date until which the identification number of the outgoing notified body may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the date after which the conformity assessment tasks of the outgoing notified body is assigned to the incoming notified body; (e) the last serial number or lot number for which the outgoing notified body is responsible. 2.   The outgoing notified body shall withdraw the certificates it has issued for the device concerned on the date on which they become invalid. Article 59 Derogation from the conformity assessment procedures 1.   By way of derogation from Article 52, any competent authority may authorise, on a duly justified request, the placing on the market or putting into service within the territory of the Member State concerned, of a specific device for which the procedures referred to in that Article have not been carried out but use of which is in the interest of public health or patient safety or health. 2.   The Member State shall inform the Commission and the other Member States of any decision to authorise the placing on the market or putting into service of a device in accordance with paragraph 1 where such authorisation is granted for use other than for a single patient. 3.   Following a notification pursuant to paragraph 2 of this Article, the Commission, in exceptional cases relating to public health or patient safety or health, may, by means of implementing acts, extend for a limited period of time the validity of an authorisation granted by a Member State in accordance with paragraph 1 of this Article to the territory of the Union and set the conditions under which the device may be placed on the market or put into service. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). On duly justified imperative grounds of urgency relating to the health and safety of humans, the Commission shall adopt immediately applicable implementing acts in accordance with the procedure referred to in Article 114(4). Article 60 Certificate of free sale 1.   For the purpose of export and upon request by a manufacturer or an authorised representative, the Member State in which the manufacturer or the authorised representative has its registered place of business shall issue a certificate of free sale declaring that the manufacturer or the authorised representative, as applicable, has its registered place of business on its territory and that the device in question bearing the CE marking in accordance with this Regulation may be marketed in the Union. The certificate of free sale shall set out the Basic UDI-DI of the device as provided to the UDI database under Article 29. Where a notified body has issued a certificate pursuant to Article 56, the certificate of free sale shall set out the unique number identifying the certificate issued by the notified body, as referred to in Section 3 of Chapter II of Annex XII. 2.   The Commission may, by means of implementing acts, establish a model for certificates of free sale, taking into account international practice as regards the use of certificates of free sale. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). CHAPTER VI CLINICAL EVALUATION AND CLINICAL INVESTIGATIONS Article 61 Clinical evaluation 1.   Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III. The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV. 2.   For all class III devices and for the class IIb devices referred to in point (b) of Article 54(1), the manufacturer may, prior to its clinical evaluation and/or investigation, consult an expert panel as referred to in Article 106, with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation. The manufacturer shall give due consideration to the views expressed by the expert panel. Such consideration shall be documented in the clinical evaluation report referred to in paragraph 12 of this Article. The manufacturer may not invoke any rights to the views expressed by the expert panel with regard to any future conformity assessment procedure. 3.   A clinical evaluation shall follow a defined and methodologically sound procedure based on the following: (a) a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied: — it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate, in accordance with Section 3 of Annex XIV, and — the data adequately demonstrate compliance with the relevant general safety and performance requirements; (b) a critical evaluation of the results of all available clinical investigations, taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV; and (c) a consideration of currently available alternative treatment options for that purpose, if any. 4.   In the case of implantable devices and class III devices, clinical investigations shall be performed, except if: — the device has been designed by modifications of a device already marketed by the same manufacturer, — the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and — the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device. In addition, clinical investigations need not be performed in the cases referred to in paragraph 6. 5.   A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph: — the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and — the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body. 6.   The requirement to perform clinical investigations pursuant to paragraph 4 shall not apply to implantable devices and class III devices: (a) which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation: — is based on sufficient clinical data, and — is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available; or (b) that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific CS, where such a CS is available. 7.   Cases in which paragraph 4 is not applied by virtue of paragraph 6 shall be justified in the clinical evaluation report by the manufacturer and in the clinical evaluation assessment report by the notified body. 8.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in point (b) of paragraph 6 of this Article, being used in other devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list of exempted devices referred to in the second subparagraph of Article 52(4) and in point (b) of paragraph 6 of this Article, by adding other types of implantable or class III devices to that list or removing devices therefrom. 9.   In the case of the products without an intended medical purpose listed in Annex XVI, the requirement to demonstrate a clinical benefit in accordance with this Chapter and Annexes XIV and XV shall be understood as a requirement to demonstrate the performance of the device. Clinical evaluations of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified. 10.   Without prejudice to paragraph 4, where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation referred to in Annex II why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation, to be adequate. 11.   The clinical evaluation and its documentation shall be updated throughout the life cycle of the device concerned with clinical data obtained from the implementation of the manufacturer's PMCF plan in accordance with Part B of Annex XIV and the post-market surveillance plan referred to in Article 84. For class III devices and implantable devices, the PMCF evaluation report and, if indicated, the summary of safety and clinical performance referred to in Article 32 shall be updated at least annually with such data. 12.   The clinical evaluation, its results and the clinical evidence derived from it shall be documented in a clinical evaluation report as referred to in Section 4 of Annex XIV, which, except for custom-made devices, shall be part of the technical documentation referred to in Annex II relating to the device concerned. 13.   Where necessary to ensure the uniform application of Annex XIV, the Commission may, having due regard to technical and scientific progress, adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 62 General requirements regarding clinical investigations conducted to demonstrate conformity of devices 1.   Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and of Articles 63 to 80, the acts adopted pursuant to Article 81, and Annex XV, where carried out as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes: (a) to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer; (b) to establish and verify the clinical benefits of a device as specified by its manufacturer; (c) to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device. 2.   Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor. Member States may choose not to apply the first subparagraph to clinical investigations to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical investigation who shall be the addressee for all communications with the sponsor provided for in this Regulation. 3.   Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust. Clinical investigations shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by ethics committees are compatible with the procedures set out in this Regulation for the assessment of the application for authorisation of a clinical investigation. At least one lay person shall participate in the ethical review. 4.   A clinical investigation as referred to in paragraph 1 may be conducted only where all of the following conditions are met: (a) the clinical investigation is the subject of an authorisation by the Member State(s) in which the clinical investigation is to be conducted, in accordance with this Regulation, unless otherwise stated; (b) an ethics committee, set up in accordance with national law, has not issued a negative opinion in relation to the clinical investigation, which is valid for that entire Member State under its national law; (c) the sponsor, or its legal representative or a contact person pursuant to paragraph 2, is established in the Union; (d) vulnerable populations and subjects are appropriately protected in accordance with Articles 64 to 68; (e) the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored; (f) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has given informed consent in accordance with Article 63; (g) the subject or, where the subject is not able to give informed consent, his or her legally designated representative, has been provided with the contact details of an entity where further information can be received in case of need; (h) the rights of the subject to physical and mental integrity, to privacy and to the protection of the data concerning him or her in accordance with Directive 95/46/EC are safeguarded; (i) the clinical investigation has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are specifically defined in the clinical investigation plan and constantly monitored; (j) the medical care provided to the subjects is the responsibility of an appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner or any other person entitled by national law to provide the relevant patient care under clinical investigation conditions; (k) no undue influence, including that of a financial nature, is exerted on the subject, or, where applicable, on his or her legally designated representatives, to participate in the clinical investigation; (l) the investigational device(s) in question conform(s) to the applicable general safety and performance requirements set out in Annex I apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, technical and biological safety testing and pre-clinical evaluation, as well as provisions in the field of occupational safety and accident prevention, taking into consideration the state of the art; (m) the requirements of Annex XV are fulfilled. 5.   Any subject, or, where the subject is not able to give informed consent, his or her legally designated representative, may, without any resulting detriment and without having to provide any justification, withdraw from the clinical investigation at any time by revoking his or her informed consent. Without prejudice to Directive 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and the use of data obtained based on informed consent before its withdrawal. 6.   The investigator shall be a person exercising a profession which is recognised in the Member State concerned as qualifying for the role of investigator on account of having the necessary scientific knowledge and experience in patient care. Other personnel involved in conducting a clinical investigation shall be suitably qualified, by education, training or experience in the relevant medical field and in clinical research methodology, to perform their tasks. 7.   The facilities where the clinical investigation is to be conducted shall be suitable for the clinical investigation and shall be similar to the facilities where the device is intended to be used. Article 63 Informed consent 1.   Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document or the record, as appropriate, by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical investigation. 2.   Information given to the subject or, where the subject is not able to give informed consent, his or her legally designated representative for the purposes of obtaining his or her informed consent shall: (a) enable the subject or his or her legally designated representative to understand: (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical investigations; (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her right to refuse to participate in and the right to withdraw from the clinical investigation at any time without any resulting detriment and without having to provide any justification; (iii) the conditions under which the clinical investigations is to be conducted, including the expected duration of the subject's participation in the clinical investigation; and (iv) the possible treatment alternatives, including the follow-up measures if the participation of the subject in the clinical investigation is discontinued; (b) be kept comprehensive, concise, clear, relevant, and understandable to the subject or his or her legally designated representative; (c) be provided in a prior interview with a member of the investigating team who is appropriately qualified under national law; (d) include information about the applicable damage compensation system referred to in Article 69; and (e) include the Union-wide unique single identification number of the clinical investigation referred to in Article 70(1) and information about the availability of the clinical investigation results in accordance with paragraph 6 of this Article. 3.   The information referred to in paragraph 2 shall be prepared in writing and be available to the subject or, where the subject is not able to give informed consent, his or her legally designated representative. 4.   In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information. 5.   In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood the information. 6.   The subject shall be informed that a clinical investigation report and a summary presented in terms understandable to the intended user will be made available pursuant to Article 77(5) in the electronic system on clinical investigations referred to in Article 73 irrespective of the outcome of the clinical investigation, and shall be informed, to the extent possible, when they have become available. 7.   This Regulation is without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical investigation. Article 64 Clinical investigations on incapacitated subjects 1.   In the case of incapacitated subjects who have not given, or have not refused to give, informed consent before the onset of their incapacity, a clinical investigation may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the incapacitated subjects have received the information referred to in Article 63(2) in a way that is adequate in view of their capacity to understand it; (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to subjects or their legally designated representatives, except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical investigations on persons able to give informed consent, or by other research methods; (f) the clinical investigation relates directly to a medical condition from which the subject suffers; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the incapacitated subject outweighing the risks and burdens involved. 2.   The subject shall as far as possible take part in the informed consent procedure. Article 65 Clinical investigations on minors A clinical investigation on minors may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the minors have received the information referred to in Article 63(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children; (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is intended to investigate treatments for a medical condition that only occurs in minors or the clinical investigation is essential with respect to minors to validate data obtained in clinical investigations on persons able to give informed consent or by other research methods; (f) the clinical investigation either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the minor subject outweighing the risks and burdens involved; (h) the minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity; (i) if during a clinical investigation the minor reaches the age of legal competence to give informed consent as defined in national law, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical investigation. Article 66 Clinical investigations on pregnant or breastfeeding women A clinical investigation on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the clinical investigation has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; (b) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse impact on the health of the child; (c) no incentives or financial inducements are given to the subject except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation. Article 67 Additional national measures Member States may maintain additional measures regarding persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical investigations, or persons in residential care institutions. Article 68 Clinical investigations in emergency situations 1.   By way of derogation from point (f) of Article 62(4), from points (a) and (b) of Article 64(1) and from points (a) and (b) of Article 65, informed consent to participate in a clinical investigation may be obtained, and information on the clinical investigation may be given, after the decision to include the subject in the clinical investigation, provided that that decision is taken at the time of the first intervention on the subject, in accordance with the clinical investigation plan for that clinical investigation and that all of the following conditions are fulfilled: (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical investigation; (b) there are scientific grounds to expect that participation of the subject in the clinical investigation will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition; (c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative; (d) the investigator certifies that he or she is not aware of any objections to participate in the clinical investigation previously expressed by the subject; (e) the clinical investigation relates directly to the subject's medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical investigation is of such a nature that it may be conducted exclusively in emergency situations; (f) the clinical investigation poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition. 2.   Following an intervention pursuant to paragraph 1 of this Article, informed consent in accordance with Article 63 shall be sought to continue the participation of the subject in the clinical investigation, and information on the clinical investigation shall be given, in accordance with the following requirements: (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 63(2) shall be given as soon as possible to the subject and to his or her legally designated representative; (b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever can be done sooner, and the information referred to in Article 63(2) shall be given as soon as possible to the subject or his or her legally designated representative, as applicable. For the purposes of point (b) where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical investigation shall be obtained from the subject as soon as he or she is capable of giving informed consent. 3.   If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical investigation. Article 69 Damage compensation 1.   Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical investigation conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk. 2.   The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State in which the clinical investigation is conducted. Article 70 Application for clinical investigations 1.   The sponsor of a clinical investigation shall submit an application to the Member State(s) in which the clinical investigation is to be conducted (referred to for the purposes of this Article as ‘Member State concerned’) accompanied by the documentation referred to in Chapter II of Annex XV. The application shall be submitted by means of the electronic system referred to in Article 73, which shall generate a Union-wide unique single identification number for the clinical investigation, which shall be used for all relevant communication in relation to that clinical investigation. Within 10 days of it receiving the application, the Member State concerned shall notify the sponsor as to whether the clinical investigation falls within the scope of this Regulation and as to whether the application dossier is complete in accordance with Chapter II of Annex XV. 2.   Within one week of any change occurring in relation to the documentation referred to in Chapter II of Annex XV, the sponsor shall update the relevant data in the electronic system referred to in Article 73 and make that change to the documentation clearly identifiable. The Member State concerned shall be notified of the update by means of that electronic system. 3.   Where the Member State concerned finds that the clinical investigation applied for does not fall within the scope of this Regulation or that the application dossier is not complete, it shall inform the sponsor thereof and shall set a time limit of maximum 10 days for the sponsor to comment or to complete the application by means of the electronic system referred to in Article 73. The Member State concerned may extend this period by a maximum of 20 days where appropriate. Where the sponsor has not provided comments nor completed the application within the time limit referred to in the first subparagraph, the application shall be deemed to have lapsed. Where the sponsor considers the application does fall under the scope of this Regulation and/or is complete but the Member State concerned does not, the application shall be considered to have been rejected. The Member State concerned shall provide for an appeal procedure in respect of such refusal. The Member State concerned shall notify the sponsor within five days of receipt of the comments or of the requested additional information, whether the clinical investigation is considered as falling within the scope of this Regulation and the application is complete. 4.   The Member State concerned may also extend the period referred to in paragraph 1 and 3 each by a further five days. 5.   For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the periods referred to in paragraphs 1, 3 and 4 respectively. 6.   During the period when the application is being assessed, the Member State may request additional information from the sponsor. The expiry of the period laid down in point (b) of paragraph 7 shall be suspended from the date of the first request until such time as the additional information has been received. 7.   The sponsor may start the clinical investigation in the following circumstances: (a) in the case of investigational class I devices or in the case of non-invasive class IIa and class IIb devices, unless otherwise stated by national law, immediately after the validation date of the application pursuant to paragraph 5, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation; (b) in the case of investigational devices, other than those referred to in point (a), as soon as the Member State concerned has notified the sponsor of its authorisation, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation. The Member State shall notify the sponsor of the authorisation within 45 days of the validation date referred to in paragraph 5. The Member State may extend this period by a further 20 days for the purpose of consulting with experts. 8.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress and global regulatory developments, the requirements laid down in Chapter II of Annex XV. 9.   In order to ensure the uniform application of the requirements laid down in Chapter II of Annex XV, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 71 Assessment by Member States 1.   Member States shall ensure that the persons validating and assessing the application, or deciding on it, do not have conflicts of interest, are independent of the sponsor, the investigators involved and of natural or legal persons financing the clinical investigation, as well as free of any other undue influence. 2.   Member States shall ensure that the assessment is done jointly by an appropriate number of persons who collectively have the necessary qualifications and experience. 3.   Member States shall assess whether the clinical investigation is designed in such a way that potential remaining risks to subjects or third persons, after risk minimization, are justified, when weighed against the clinical benefits to be expected. They shall, while taking into account applicable CS or harmonised standards, examine in particular: (a) the demonstration of compliance of the investigational device(s) with the applicable general safety and performance requirements, apart from the aspects covered by the clinical investigation, and whether, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, assurance of technical and biological safety testing and pre-clinical evaluation; (b) whether the risk-minimisation solutions employed by the sponsor are described in harmonised standards and, in those cases where the sponsor does not use harmonised standards, whether the risk-minimisation solutions provide a level of protection that is equivalent to that provided by harmonised standards; (c) whether the measures planned for the safe installation, putting into service and maintenance of the investigational device are adequate; (d) the reliability and robustness of the data generated in the clinical investigation, taking account of statistical approaches, design of the investigation and methodological aspects, including sample size, comparator and endpoints; (e) whether the requirements of Annex XV are met; (f) in the case of devices for sterile use, evidence of the validation of the manufacturer's sterilisation procedures or information on the reconditioning and sterilisation procedures which have to be conducted by the investigation site; (g) the demonstration of the safety, quality and usefulness of any components of animal or human origin or of substances, which may be considered medicinal products in accordance with Directive 2001/83/EC. 4.   Member States shall refuse the authorisation of the clinical investigation if: (a) the application dossier submitted pursuant to Article 70(1) remains incomplete; (b) the device or the submitted documents, especially the investigation plan and the investigator's brochure, do not correspond to the state of scientific knowledge, and the clinical investigation, in particular, is not suitable for providing evidence for the safety, performance characteristics or benefit of the device on subjects or patients, (c) the requirements of Article 62 are not met, or (d) any assessment under paragraph 3 is negative. Member States shall provide for an appeal procedure in respect of a refusal pursuant to the first subparagraph. Article 72 Conduct of a clinical investigation 1.   The sponsor and the investigator shall ensure that the clinical investigation is conducted in accordance with the approved clinical investigation plan. 2.   In order to verify that the rights, safety and well-being of subjects are protected, that the reported data are reliable and robust, and that the conduct of the clinical investigation is in compliance with the requirements of this Regulation, the sponsor shall ensure adequate monitoring of the conduct of a clinical investigation. The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics of the clinical investigation including the following: (a) the objective and methodology of the clinical investigation; and (b) the degree of deviation of the intervention from normal clinical practice. 3.   All clinical investigation information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable law on personal data protection. 4.   Appropriate technical and organisational measures shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves transmission over a network. 5.   Member States shall inspect, at an appropriate level, investigation site(s) to check that clinical investigations are conducted in accordance with the requirements of this Regulation and with the approved investigation plan. 6.   The sponsor shall establish a procedure for emergency situations which enables the immediate identification and, where necessary, an immediate recall of the devices used in the investigation. Article 73 Electronic system on clinical investigations 1.   The Commission shall, in collaboration with the Member States, set up, manage and maintain an electronic system: (a) to create the single identification numbers for clinical investigations referred to in Article 70(1); (b) to be used as an entry point for the submission of all applications or notifications for clinical investigations referred to in Articles 70, 74, 75 and 78 and for all other submission of data, or processing of data in this context; (c) for the exchange of information relating to clinical investigations in accordance with this Regulation between the Member States and between them and the Commission including the exchange of information referred to in Articles 70 and 76; (d) for information to be provided by the sponsor in accordance with Article 77, including the clinical investigation report and its summary as required in paragraph 5 of that Article; (e) for reporting on serious adverse events and device deficiencies and related updates referred to in Article 80. 2.   When setting up the electronic system referred in paragraph 1 of this Article, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council (37) as concerns combined clinical investigations of devices with a clinical trial under that Regulation. 3.   The information referred to in point (c) of paragraph 1 shall only be accessible to the Member States and the Commission. The information referred to in the other points of that paragraph shall be accessible to the public, unless, for all or parts of that information, confidentiality of the information is justified on any of the following grounds: (a) protection of personal data in accordance with Regulation (EC) No 45/2001; (b) protection of commercially confidential information, especially in the investigators brochure, in particular through taking into account the status of the conformity assessment for the device, unless there is an overriding public interest in disclosure; (c) effective supervision of the conduct of the clinical investigation by the Member State(s) concerned. 4.   No personal data of subjects shall be publicly available. 5.   The user interface of the electronic system referred to in paragraph 1 shall be available in all official languages of the Union. Article 74 Clinical investigations regarding devices bearing the CE marking 1.   Where a clinical investigation is to be conducted to further assess, within the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), (‘PMCF investigation’), and where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned at least 30 days prior to its commencement by means of the electronic system referred to in Article 73. The sponsor shall include the documentation referred to in Chapter II of Annex XV as part of the notification. Points (b) to (k) and (m) of Article 62(4), Article 75, Article 76, Article 77, Article 80(5) and the relevant provisions of Annex XV shall apply to PMCF investigations. 2.   Where a clinical investigation is to be conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), Articles 62 to 81 shall apply. Article 75 Substantial modifications to clinical investigations 1.   If a sponsor intends to introduce modifications to a clinical investigation that are likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation, it shall notify, within one week, by means of the electronic system referred to in Article 73 the Member State(s) in which the clinical investigation is being or is to be conducted of the reasons for and the nature of those modifications. The sponsor shall include an updated version of the relevant documentation referred to in Chapter II of Annex XV as part of the notification. Changes to the relevant documentation shall be clearly identifiable. 2.   The Member State shall assess any substantial modification to the clinical investigation in accordance with the procedure laid down in Article 71. 3.   The sponsor may implement the modifications referred to in paragraph 1 at the earliest 38 days after the notification referred to in that paragraph, unless: (a) the Member State in which the clinical investigation is being or is to be conducted has notified the sponsor of its refusal based on the grounds referred to in Article 71(4) or on considerations of public health, subject and user safety or health, of public policy, or (b) an ethics committee in that Member State has issued a negative opinion in relation to the substantial modification to the clinical investigation, which, in accordance with national law, is valid for that entire Member State. 4.   The Member State(s) concerned may extend the period referred to in paragraph 3 by a further seven days, for the purpose of consulting with experts. Article 76 Corrective measures to be taken by Member States and information exchange between Member States 1.   Where a Member State in which a clinical investigation is being or is to be conducted has grounds for considering that the requirements set out in this Regulation are not met, it may take at least any of the following measures on its territory: (a) revoke the authorisation for the clinical investigation; (b) suspend or terminate the clinical investigation; (c) require the sponsor to modify any aspect of the clinical investigation. 2.   Before the Member State concerned takes any of the measures referred to in paragraph 1 it shall, except where immediate action is required, ask the sponsor or the investigator or both for their opinion. That opinion shall be delivered within seven days. 3.   Where a Member State has taken a measure referred to in paragraph 1 of this Article or has refused a clinical investigation, or has been notified by the sponsor of the early termination of a clinical investigation on safety grounds, that Member State shall communicate the corresponding decision and the grounds therefor to all Member States and the Commission by means of the electronic system referred to in Article 73. 4.   Where an application is withdrawn by the sponsor prior to a decision by a Member State, that information shall be made available through the electronic system referred to in Article 73 to all Member States and the Commission. Article 77 Information from the sponsor at the end of a clinical investigation or in the event of a temporary halt or early termination 1.   If the sponsor has temporarily halted a clinical investigation or has terminated a clinical investigation early, it shall inform within 15 days the Member State in which that clinical investigation has been temporarily halted or terminated early, through the electronic system referred to in Article 73, of the temporary halt or early termination, providing a justification. In the event that the sponsor has temporarily halted or terminated early the clinical investigation on safety grounds, it shall inform all Member States in which that clinical investigation is being conducted thereof within 24 hours. 2.   The end of a clinical investigation shall be deemed to coincide with the last visit of the last subject unless another point in time for such end is set out in the clinical investigation plan. 3.   The sponsor shall notify each Member State in which a clinical investigation was being conducted of the end of that clinical investigation in that Member State. That notification shall be made within 15 days of the end of the clinical investigation in relation to that Member State. 4.   If an investigation is conducted in more than one Member State, the sponsor shall notify all Member States in which that clinical investigation was conducted of the end of the clinical investigation in all Member States. That notification shall be made within 15 days of that end of the clinical investigation. 5.   Irrespective of the outcome of the clinical investigation, within one year of the end of the clinical investigation or within three months of the early termination or temporary halt, the sponsor shall submit to the Member States in which a clinical investigation was conducted a clinical investigation report as referred to in Section 2.8 of Chapter I and Section 7 of Chapter III of Annex XV. The clinical investigation report shall be accompanied by a summary presented in terms that are easily understandable to the intended user. Both the report and summary shall be submitted by the sponsor by means of the electronic system referred to in Article 73. Where, for scientific reasons, it is not possible to submit the clinical investigation report within one year of the end of the investigation, it shall be submitted as soon as it is available. In such case, the clinical investigation plan referred to in Section 3 of Chapter II of Annex XV shall specify when the results of the clinical investigation are going to be available, together with a justification. 6.   The Commission shall issue guidelines regarding the content and structure of the summary of the clinical investigation report. In addition, the Commission may issue guidelines for the formatting and sharing of raw data, for cases where the sponsor decides to share raw data on a voluntary basis. Those guidelines may take as a basis and adapt, where possible, existing guidelines for sharing of raw data in the field of clinical investigations. 7.   The summary and the clinical investigation report referred to in paragraph 5 of this Article shall become publicly accessible through the electronic system referred to in Article 73, at the latest when the device is registered in accordance with Article 29 and before it is placed on the market. In cases of early termination or temporary halt, the summary and the report shall become publicly accessible immediately after submission. If the device is not registered in accordance with Article 29 within one year of the summary and the report having been entered into the electronic system pursuant to paragraph 5 of this Article, they shall become publicly accessible at that point in time. Article 78 Coordinated assessment procedure for clinical investigations 1.   By means of the electronic system referred to in Article 73, the sponsor of a clinical investigation to be conducted in more than one Member State may submit, for the purpose of Article 70, a single application that, upon receipt, is transmitted electronically to all Member States in which the clinical investigation is to be conducted. 2.   The sponsor shall propose in the single application referred to in paragraph 1 that one of the Member States in which the clinical investigation is to be conducted acts as coordinating Member State. The Member States in which the clinical investigation is to be conducted shall, within six days of submission of the application, agree on one of them taking the role of the coordinating Member State. If they do not agree on a coordinating Member State, the coordinating Member State proposed by the sponsor shall assume that role. 3.   Under the direction of the coordinating Member State referred to in paragraph 2, the Member States concerned shall coordinate their assessment of the application, in particular of the documentation referred to in Chapter II of Annex XV. However, the completeness of the documentation referred to in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV shall be assessed separately by each Member State concerned in accordance with Article 70(1) to (5). 4.   With regard to documentation other than that referred to in the second subparagraph of paragraph 3, the coordinating Member State shall: (a) within six days of receipt of the single application, notify the sponsor that it is the coordinating Member State (‘notification date’); (b) for the purpose of the validation of the application, take into account any considerations submitted within seven days of the notification date by any Member State concerned; (c) within 10 days of the notification date, assess whether the clinical investigation falls within the scope of this Regulation and whether the application is complete, and shall notify the sponsor accordingly. Article 70(1) and (3) to (5) shall apply to the coordinating Member State in relation to that assessment; (d) establish the results of its assessment in a draft assessment report to be transmitted within 26 days of the validation date to the Member States concerned. By day 38 after the validation date, the other Member States concerned shall transmit their comments and proposals on the draft assessment report and the underlying application to the coordinating Member State which shall take due account of those comments and proposals in its finalisation of the final assessment report, to be transmitted within 45 days of the validation date to the sponsor and the other Member States concerned. The final assessment report shall be taken into account by all Member States concerned when deciding on the sponsor's application in accordance with Article 70(7). 5.   As regards the assessment of the documentation referred to in the second subparagraph of paragraph 3, each Member State concerned may request, on a single occasion, additional information from the sponsor. The sponsor shall submit the requested additional information within the period set by the Member State concerned, which shall not exceed 12 days from the receipt of the request. The expiry of the last deadline pursuant to point (d) of paragraph 4 shall be suspended from the date of the request until such time as the additional information has been received. 6.   For class IIb and class III devices, the coordinating Member State may also extend the periods referred to in paragraph 4 by a further 50 days, for the purpose of consulting with experts. 7.   The Commission may, by means of implementing acts, further specify the procedures and timescales for coordinated assessments to be taken into account by Member States concerned when deciding on the sponsor's application. Such implementing acts may also set out the procedures and timescales for coordinated assessment in the case of substantial modifications pursuant to paragraph 12 of this Article, in the case of reporting of adverse events pursuant to Article 80(4) and in the case of clinical investigations of combination products between medical devices and medicinal products, where the latter are under a concurrent coordinated assessment of a clinical trial under Regulation (EU) No 536/2014. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 8.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the conduct of the clinical investigation is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of all Member States concerned. Notwithstanding the first subparagraph, a Member State concerned may only disagree with the conclusion of the coordinating Member State concerning the area of coordinated assessment on the following grounds: (a) when it considers that participation in the clinical investigation would lead to a subject receiving treatment inferior to that received in normal clinical practice in that Member State concerned; (b) infringement of national law; or (c) considerations as regards subject safety and data reliability and robustness submitted under point (b) of paragraph 4. Where one of the Member States concerned disagrees with the conclusion on the basis of the second subparagraph of this paragraph, it shall communicate its disagreement, together with a detailed justification, through the electronic system referred to in Article 73, to the Commission, to all other Member States concerned and to the sponsor. 9.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the clinical investigation is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned. 10.   A Member State concerned shall refuse to authorise a clinical investigation if it disagrees with the conclusion of the coordinating Member State as regards any of the grounds referred to in the second subparagraph of paragraph 8, or if it finds, on duly justified grounds, that the aspects addressed in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV are not complied with, or where an ethics committee has issued a negative opinion in relation to that clinical investigation, which is valid, in accordance with national law, for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal. 11.   Each Member State concerned shall notify the sponsor through the electronic system referred to in Article 73 as to whether the clinical investigation is authorised, whether it is authorised subject to conditions, or whether authorisation has been refused. Notification shall be done by way of one single decision within five days of the transmission, pursuant to point (d) of paragraph 4, by the coordinating Member State of the final assessment report. Where an authorisation of a clinical investigation is subject to conditions, those conditions may only be such that, by their nature, they cannot be fulfilled at the time of that authorisation. 12.   Any substantial modifications as referred to in Article 75 shall be notified to the Member States concerned by means of the electronic system referred to in Article 73. Any assessment as to whether there are grounds for disagreement as referred to in the second subparagraph of paragraph 8 of this Article shall be carried out under the direction of the coordinating Member State, except for substantial modifications concerning Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV, which shall be assessed separately by each Member State concerned. 13.   The Commission shall provide administrative support to the coordinating Member State in the accomplishment of its tasks under this Chapter. 14.   The procedure set out in this Article shall, until 27 May 2027, be applied only by those of the Member States in which the clinical investigation is to be conducted which have agreed to apply it. After 27 May 2027, all Member States shall be required to apply that procedure. Article 79 Review of coordinated assessment procedure By 27 May 2026, the Commission shall submit to the European Parliament and to the Council a report on experience gained from the application of Article 78 and, if necessary, propose a review of Article 78(14) and point (h) of Article 123(3). Article 80 Recording and reporting of adverse events that occur during clinical investigations 1.   The sponsor shall fully record all of the following: (a) any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation; (b) any serious adverse event; (c) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (d) any new findings in relation to any event referred to in points (a) to (c). 2.   The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of the following by means of the electronic system referred to in Article 73: (a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; (b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (c) any new findings in relation to any event referred to in points (a) and (b). The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the sponsor may submit an initial report that is incomplete followed up by a complete report. Upon request by any Member State in which the clinical investigation is being conducted, the sponsor shall provide all information referred to in paragraph 1. 3.   The sponsor shall also report to the Member States in which the clinical investigation is being conducted any event referred to in paragraph 2 of this Article that occurred in third countries in which a clinical investigation is performed under the same clinical investigation plan as the one applying to a clinical investigation covered by this Regulation by means of the electronic system referred to in Article 73. 4.   In the case of a clinical investigation for which the sponsor has used the single application referred to in Article 78, the sponsor shall report any event as referred to in paragraph 2 of this Article by means of the electronic system referred to in Article 73. Upon receipt, this report shall be transmitted electronically to all Member States in which the clinical investigation is being conducted. Under the direction of the coordinating Member State referred to in Article 78(2), the Member States shall coordinate their assessment of serious adverse events and device deficiencies to determine whether to modify, suspend or terminate the clinical investigation or whether to revoke the authorisation for that clinical investigation. This paragraph shall not affect the rights of the other Member States to perform their own evaluation and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating Member State and the Commission shall be kept informed of the outcome of any such evaluation and the adoption of any such measures. 5.   In the case of PMCF investigations referred to in Article 74(1), the provisions on vigilance laid down in Articles 87 to 90 and in the acts adopted pursuant to Article 91 shall apply instead of this Article. 6.   Notwithstanding paragraph 5, this Article shall apply where a causal relationship between the serious adverse event and the preceding investigational procedure has been established. Article 81 Implementing acts The Commission may, by means of implementing acts, establish the detailed arrangements and procedural aspects necessary for the implementation of this Chapter as regards the following: (a) harmonised electronic forms for the application for clinical investigations and their assessment as referred to in Articles 70 and 78, taking into account specific categories or groups of devices; (b) the functioning of the electronic system referred to in Article 73; (c) harmonised electronic forms for the notification of PMCF investigations as referred to in Article 74(1), and of substantial modifications as referred to in Article 75; (d) the exchange of information between Member States as referred to in Article 76; (e) harmonised electronic forms for the reporting of serious adverse events and device deficiencies as referred to in Article 80; (f) the timelines for the reporting of serious adverse events and device deficiencies, taking into account the severity of the event to be reported as referred to in Article 80; (g) uniform application of the requirements regarding the clinical evidence or data needed to demonstrate compliance with the general safety and performance requirements set out in Annex I. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 82 Requirements regarding other clinical investigations 1.   Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), shall comply with the provisions of Article 62 (2) and (3), points (b), (c), (d), (f), (h), and (l) of Article 62(4) and Article 62(6). 2.   In order to protect the rights, safety, dignity and well-being of subjects and the scientific and ethical integrity of clinical investigations not performed for any of the purposes listed in Article 62(1), each Member State shall define any additional requirements for such investigations, as appropriate for each Member State concerned. CHAPTER VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE SECTION 1 Post-market surveillance Article 83 Post-market surveillance system of the manufacturer 1.   For each device, manufacturers shall plan, establish, document, implement, maintain and update a post-market surveillance system in a manner that is proportionate to the risk class and appropriate for the type of device. That system shall be an integral part of the manufacturer's quality management system referred to in Article 10(9). 2.   The post-market surveillance system shall be suited to actively and systematically gathering, recording and analysing relevant data on the quality, performance and safety of a device throughout its entire lifetime, and to drawing the necessary conclusions and to determining, implementing and monitoring any preventive and corrective actions. 3.   Data gathered by the manufacturer's post-market surveillance system shall in particular be used: (a) to update the benefit-risk determination and to improve the risk management as referred to in Chapter I of Annex I; (b) to update the design and manufacturing information, the instructions for use and the labelling; (c) to update the clinical evaluation; (d) to update the summary of safety and clinical performance referred to in Article 32; (e) for the identification of needs for preventive, corrective or field safety corrective action; (f) for the identification of options to improve the usability, performance and safety of the device; (g) when relevant, to contribute to the post-market surveillance of other devices; and (h) to detect and report trends in accordance with Article 88. The technical documentation shall be updated accordingly. 4.   If, in the course of the post-market surveillance, a need for preventive or corrective action or both is identified, the manufacturer shall implement the appropriate measures and inform the competent authorities concerned and, where applicable, the notified body. Where a serious incident is identified or a field safety corrective action is implemented, it shall be reported in accordance with Article 87. Article 84 Post-market surveillance plan The post-market surveillance system referred to in Article 83 shall be based on a post-market surveillance plan, the requirements for which are set out in Section 1.1 of Annex III. For devices other than custom-made devices, the post-market surveillance plan shall be part of the technical documentation specified in Annex II. Article 85 Post-market surveillance report Manufacturers of class I devices shall prepare a post-market surveillance report summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. The report shall be updated when necessary and made available to the competent authority upon request. Article 86 Periodic safety update report 1.   Manufacturers of class IIa, class IIb and class III devices shall prepare a periodic safety update report (‘PSUR’) for each device and where relevant for each category or group of devices summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. Throughout the lifetime of the device concerned, that PSUR shall set out: (a) the conclusions of the benefit-risk determination; (b) the main findings of the PMCF; and (c) the volume of sales of the device and an estimate evaluation of the size and other characteristics of the population using the device and, where practicable, the usage frequency of the device. Manufacturers of class IIb and class III devices shall update the PSUR at least annually. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. Manufacturers of class IIa devices shall update the PSUR when necessary and at least every two years. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. For custom-made devices, the PSUR shall be part of the documentation referred to in Section 2 of Annex XIII. 2.   For class III devices or implantable devices, manufacturers shall submit PSURs by means of the electronic system referred to in Article 92 to the notified body involved in the conformity assessment in accordance with Article 52. The notified body shall review the report and add its evaluation to that electronic system with details of any action taken. Such PSURs and the evaluation by the notified body shall be made available to competent authorities through that electronic system. 3.   For devices other than those referred to in paragraph 2, manufacturers shall make PSURs available to the notified body involved in the conformity assessment and, upon request, to competent authorities. SECTION 2 Vigilance Article 87 Reporting of serious incidents and field safety corrective actions 1.   Manufacturers of devices made available on the Union market, other than investigational devices, shall report, to the relevant competent authorities, in accordance with Articles 92(5) and (7), the following: (a) any serious incident involving devices made available on the Union market, except expected side-effects which are clearly documented in the product information and quantified in the technical documentation and are subject to trend reporting pursuant to Article 88; (b) any field safety corrective action in respect of devices made available on the Union market, including any field safety corrective action undertaken in a third country in relation to a device which is also legally made available on the Union market, if the reason for the field safety corrective action is not limited to the device made available in the third country. The reports referred to in the first subparagraph shall be submitted through the electronic system referred to in Article 92. 2.   As a general rule, the period for the reporting referred to in paragraph 1 shall take account of the severity of the serious incident. 3.   Manufacturers shall report any serious incident as referred to in point (a) of paragraph 1 immediately after they have established the causal relationship between that incident and their device or that such causal relationship is reasonably possible and not later than 15 days after they become aware of the incident. 4.   Notwithstanding paragraph 3, in the event of a serious public health threat the report referred to in paragraph 1 shall be provided immediately, and not later than 2 days after the manufacturer becomes aware of that threat. 5.   Notwithstanding paragraph 3, in the event of death or an unanticipated serious deterioration in a person's state of health the report shall be provided immediately after the manufacturer has established or as soon as it suspects a causal relationship between the device and the serious incident but not later than 10 days after the date on which the manufacturer becomes aware of the serious incident. 6.   Where necessary to ensure timely reporting, the manufacturer may submit an initial report that is incomplete followed up by a complete report. 7.   If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report within the timeframe required in accordance with paragraphs 2 to 5. 8.   Except in cases of urgency in which the manufacturer needs to undertake field safety corrective action immediately, the manufacturer shall, without undue delay, report the field safety corrective action referred to in point (b) of paragraph 1 in advance of the field safety corrective action being undertaken. 9.   For similar serious incidents that occur with the same device or device type and for which the root cause has been identified or a field safety corrective action implemented or where the incidents are common and well documented, the manufacturer may provide periodic summary reports instead of individual serious incident reports, on condition that the coordinating competent authority referred to in Article 89(9), in consultation with the competent authorities referred to in point (a) of Article 92(8), has agreed with the manufacturer on the format, content and frequency of the periodic summary reporting. Where a single competent authority is referred to in points (a) and (b) of Article 92(8), the manufacturer may provide periodic summary reports following agreement with that competent authority. 10.   The Member States shall take appropriate measures such as organising targeted information campaigns, to encourage and enable healthcare professionals, users and patients to report to the competent authorities suspected serious incidents referred to in point (a) of paragraph 1. The competent authorities shall record centrally at national level reports they receive from healthcare professionals, users and patients. 11.   Where a competent authority of a Member State obtains such reports on suspected serious incidents referred to in point (a) of paragraph 1 from healthcare professionals, users or patients, it shall take the necessary steps to ensure that the manufacturer of the device concerned is informed of the suspected serious incident without delay. Where the manufacturer of the device concerned considers that the incident is a serious incident, it shall provide a report in accordance with paragraphs 1 to 5 of this Article on that serious incident to the competent authority of the Member State in which that serious incident occurred and shall take the appropriate follow-up action in accordance with Article 89. Where the manufacturer of the device concerned considers that the incident is not a serious incident or is an expected undesirable side-effect, which will be covered by trend reporting in accordance with Article 88, it shall provide an explanatory statement. If the competent authority does not agree with the conclusion of the explanatory statement, it may require the manufacturer to provide a report in accordance with paragraphs 1 to 5 of this Article and require it to ensure that appropriate follow-up action is taken in accordance with Article 89. Article 88 Trend reporting 1.   Manufacturers shall report, by means of the electronic system referred to in Article 92, any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side-effects that could have a significant impact on the benefit-risk analysis referred to in Sections 1 and 5 of Annex I and which have led or may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. The significant increase shall be established in comparison to the foreseeable frequency or severity of such incidents in respect of the device, or category or group of devices, in question during a specific period as specified in the technical documentation and product information. The manufacturer shall specify how to manage the incidents referred to in the first subparagraph and the methodology used for determining any statistically significant increase in the frequency or severity of such incidents, as well as the observation period, in the post-market surveillance plan referred to in Article 84. 2.   The competent authorities may conduct their own assessments on the trend reports referred to in paragraph 1 and require the manufacturer to adopt appropriate measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. Each competent authority shall inform the Commission, the other competent authorities and the notified body that issued the certificate, of the results of such assessment and of the adoption of such measures. Article 89 Analysis of serious incidents and field safety corrective actions 1.   Following the reporting of a serious incident pursuant to Article 87(1), the manufacturer shall, without delay, perform the necessary investigations in relation to the serious incident and the devices concerned. This shall include a risk assessment of the incident and field safety corrective action taking into account criteria as referred to in paragraph 3 of this Article as appropriate. The manufacturer shall co-operate with the competent authorities and where relevant with the notified body concerned during the investigations referred to in the first subparagraph and shall not perform any investigation which involves altering the device or a sample of the batch concerned in a way which may affect any subsequent evaluation of the causes of the incident, prior to informing the competent authorities of such action. 2.   Member States shall take the necessary steps to ensure that any information regarding a serious incident that has occurred within their territory, or a field safety corrective action that has been or is to be undertaken within their territory, and that is brought to their knowledge in accordance with Article 87 is evaluated centrally at national level by their competent authority, if possible together with the manufacturer, and, where relevant, the notified body concerned. 3.   In the context of the evaluation referred to in paragraph 2, the competent authority shall evaluate the risks arising from the reported serious incident and evaluate any related field safety corrective actions, taking into account the protection of public health and criteria such as causality, detectability and probability of recurrence of the problem, frequency of use of the device, probability of occurrence of direct or indirect harm, the severity of that harm, the clinical benefit of the device, intended and potential users, and population affected. The competent authority shall also evaluate the adequacy of the field safety corrective action envisaged or undertaken by the manufacturer and the need for, and kind of, any other corrective action, in particular taking into account the principle of inherent safety contained in Annex I. Upon request by the national competent authority, manufacturers shall provide all documents necessary for the risk assessment. 4.   The competent authority shall monitor the manufacturer's investigation of a serious incident. Where necessary, a competent authority may intervene in a manufacturer's investigation or initiate an independent investigation. 5.   The manufacturer shall provide a final report to the competent authority setting out its findings from the investigation by means of the electronic system referred to in Article 92. The report shall set out conclusions and where relevant indicate corrective actions to be taken. 6.   In the case of devices referred to in the first subparagraph of Article 1(8) and where the serious incident or field safety corrective action may be related to a substance which, if used separately, would be considered to be a medicinal product, the evaluating competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall, inform the national competent authority or the EMA, depending on which issued the scientific opinion on that substance under Article 52(9), of that serious incident or field safety corrective action. In the case of devices covered by this Regulation in accordance with point (g) of Article 1(6) and where the serious incident or field safety corrective action may be related to the derivatives of tissues or cells of human origin utilised for the manufacture of the device, and in the case of devices falling under this Regulation pursuant to Article 1(10), the competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall inform the competent authority for human tissues and cells that was consulted by the notified body in accordance with Article 52(10). 7.   After carrying out the evaluation in accordance with paragraph 3 of this Article, the evaluating competent authority shall, through the electronic system referred to in Article 92, inform, without delay, the other competent authorities of the corrective action taken or envisaged by the manufacturer or required of it to minimise the risk of recurrence of the serious incident, including information on the underlying events and the outcome of its assessment. 8.   The manufacturer shall ensure that information about the field safety corrective action taken is brought without delay to the attention of users of the device in question by means of a field safety notice. The field safety notice shall be edited in an official Union language or languages determined by the Member State in which the field safety corrective action is taken. Except in cases of urgency, the content of the draft field safety notice shall be submitted to the evaluating competent authority or, in the cases referred to in paragraph 9, to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice shall be consistent in all Member States. The field safety notice shall allow the correct identification of the device or devices involved, in particular by including the relevant UDIs, and the correct identification, in particular, by including the SRN, if already issued, of the manufacturer that has undertaken the field safety corrective action. The field safety notice shall explain, in a clear manner, without understating the level of risk, the reasons for the field safety corrective action with reference to the device malfunction and associated risks for patients, users or other persons, and shall clearly indicate all the actions to be taken by users. The manufacturer shall enter the field safety notice in the electronic system referred to in Article 92 through which that notice shall be accessible to the public. 9.   The competent authorities shall actively participate in a procedure in order to coordinate their assessments referred to in paragraph 3 in the following cases: (a) where there is concern regarding a particular serious incident or cluster of serious incidents relating to the same device or type of device of the same manufacturer in more than one Member State; (b) where the appropriateness of a field safety corrective action that is proposed by a manufacturer in more than one Member State is in question. That coordinated procedure shall cover the following: — designation of a coordinating competent authority on a case by case basis, when required; — defining the coordinated assessment process, including the tasks and responsibilities of the coordinating competent authority and the involvement of other competent authorities. Unless otherwise agreed between the competent authorities, the coordinating competent authority shall be the competent authority of the Member State in which the manufacturer has its registered place of business. The coordinating competent authority shall, through the electronic system referred to in Article 92, inform the manufacturer, the other competent authorities and the Commission that it has assumed the role of coordinating authority. 10.   The designation of a coordinating competent authority shall not affect the rights of the other competent authorities to perform their own assessment and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating competent authority and the Commission shall be kept informed of the outcome of any such assessment and the adoption of any such measures. 11.   The Commission shall provide administrative support to the coordinating competent authority in the accomplishment of its tasks under this Chapter. Article 90 Analysis of vigilance data The Commission shall, in collaboration with the Member States, put in place systems and processes to actively monitor the data available in the electronic system referred to in Article 92, in order to identify trends, patterns or signals in the data that may reveal new risks or safety concerns. Where a previously unknown risk is identified or the frequency of an anticipated risk significantly and adversely changes the benefit-risk determination, the competent authority or, where appropriate, the coordinating competent authority shall inform the manufacturer, or where applicable the authorised representative, which shall then take the necessary corrective actions. Article 91 Implementing acts The Commission may, by means of implementing acts, and after consultation of the MDCG, adopt the detailed arrangements and procedural aspects necessary for the implementation of Articles 85 to 90 and 92 as regards the following: (a) the typology of serious incidents and field safety corrective actions in relation to specific devices, or categories or groups of devices; (b) the reporting of serious incidents and field safety corrective actions and field safety notices, and the provision of periodic summary reports, post-market surveillance reports, PSURs and trend reports by manufacturers as referred to in Articles 85, 86, 87, 88 and 89 respectively; (c) standard structured forms for electronic and non-electronic reporting, including a minimum data set for reporting of suspected serious incidents by healthcare professionals, users and patients; (d) timelines for the reporting of field safety corrective actions, and for the provision by manufacturers of periodic summary reports and trend reports, taking into account the severity of the incident to be reported as referred to in Article 87; (e) harmonised forms for the exchange of information between competent authorities as referred to in Article 89; (f) procedures for the designation of a coordinating competent authority; the coordinated evaluation process, including tasks and responsibilities of the coordinating competent authority and involvement of other competent authorities in this process. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 92 Electronic system on vigilance and on post-market surveillance 1.   The Commission shall, in collaboration with the Member States, set up and manage an electronic system to collate and process the following information: (a) the reports by manufacturers on serious incidents and field safety corrective actions referred to in Article 87(1) and Article 89(5); (b) the periodic summary reports by manufacturers referred to in Article 87(9); (c) the reports by manufacturers on trends referred to in Article 88; (d) the PSURs referred to in Article 86; (e) the field safety notices by manufacturers referred to in Article 89(8); (f) the information to be exchanged between the competent authorities of the Member States and between them and the Commission in accordance with Article 89(7) and (9). That electronic system shall include relevant links to the UDI database. 2.   The information referred to in paragraph 1 of this Article shall be made available through the electronic system to the competent authorities of the Member States and to the Commission. The notified bodies shall also have access to that information to the extent that it relates to devices for which they issued a certificate in accordance with Article 53. 3.   The Commission shall ensure that healthcare professionals and the public have appropriate levels of access to the electronic system referred to in paragraph 1. 4.   On the basis of arrangements between the Commission and competent authorities of third countries or international organisations, the Commission may grant those competent authorities or international organisations access to the electronic system referred to in paragraph 1 at the appropriate level. Those arrangements shall be based on reciprocity and make provision for confidentiality and data protection equivalent to those applicable in the Union. 5.   The reports on serious incidents referred to in point (a) of Article 87(1) shall be automatically transmitted, upon receipt, via the electronic system referred to in paragraph 1 of this Article, to the competent authority of the Member State in which the incident occurred. 6.   The trend reports referred to in Article 88(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the Member State in which the incidents occurred. 7.   The reports on field safety corrective actions referred to in point (b) of Article 87(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the following Member States: (a) the Member States in which the field safety corrective action is being or is to be undertaken; (b) the Member State in which the manufacturer has its registered place of business. 8.   The periodic summary reports referred to in Article 87(9) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authority of: (a) the Member State or Member States participating in the coordination procedure in accordance with Article 89(9) and which have agreed on the periodic summary report; (b) the Member State in which the manufacturer has its registered place of business. 9.   The information referred to in paragraphs 5 to 8 of this Article shall be automatically transmitted, upon receipt, through the electronic system referred to in paragraph 1 of this Article, to the notified body that issued the certificate for the device in question in accordance with Article 56. SECTION 3 Market surveillance Article 93 Market surveillance activities 1.   The competent authorities shall perform appropriate checks on the conformity characteristics and performance of devices including, where appropriate, a review of documentation and physical or laboratory checks on the basis of adequate samples. The competent authorities shall, in particular, take account of established principles regarding risk assessment and risk management, vigilance data and complaints. 2.   The competent authorities shall draw up annual surveillance activity plans and allocate a sufficient number of material and competent human resources in order to carry out those activities taking into account the European market surveillance programme developed by the MDCG pursuant to Article 105 and local circumstances. 3.   In order to fulfil the obligations laid down in paragraph 1, the competent authorities: (a) may require economic operators to, inter alia, make available the documentation and information necessary for the purpose of carrying out the authorities' activities and, where justified, to provide the necessary samples of devices or access to devices free of charge; and (b) shall carry out both announced and, if necessary, unannounced inspections of the premises of economic operators, as well as suppliers and/or subcontractors, and, where necessary, at the facilities of professional users. 4.   The competent authorities shall prepare an annual summary of the results of their surveillance activities and make it accessible to other competent authorities by means of the electronic system referred to in Article 100. 5.   The competent authorities may confiscate, destroy or otherwise render inoperable devices that present an unacceptable risk or falsified devices where they deem it necessary to do so in the interests of the protection of public health. 6.   Following each inspection carried out for the purposes referred to in paragraph 1, the competent authority shall draw up a report on the findings of the inspection that concern compliance with the legal and technical requirements applicable under this Regulation. The report shall set out any corrective actions needed. 7.   The competent authority which carried out the inspection shall communicate the content of the report referred to in paragraph 6 of this Article to the economic operator that has been the subject of the inspection. Before adopting the final report, the competent authority shall give that economic operator the opportunity to submit comments. That final inspection report shall be entered in the electronic system provided for in Article 100. 8.   The Member States shall review and assess the functioning of their market surveillance activities. Such reviews and assessments shall be carried out at least every four years and the results thereof shall be communicated to the other Member States and the Commission. Each Member State shall make a summary of the results accessible to the public by means of the electronic system referred to in Article 100. 9.   The competent authorities of the Member States shall coordinate their market surveillance activities, cooperate with each other and share with each other and with the Commission the results thereof, to provide for a harmonised and high level of market surveillance in all Member States. Where appropriate, the competent authorities of the Member States shall agree on work-sharing, joint market surveillance activities and specialisation. 10.   Where more than one authority in a Member State is responsible for market surveillance and external border controls, those authorities shall cooperate with each other, by sharing information relevant to their role and functions. 11.   Where appropriate, the competent authorities of the Member States shall cooperate with the competent authorities of third countries with a view to exchanging information and technical support and promoting activities relating to market surveillance. Article 94 Evaluation of devices suspected of presenting an unacceptable risk or other non-compliance Where the competent authorities of a Member State, based on data obtained by vigilance or market surveillance activities or on other information, have reason to believe that a device: (a) may present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health; or (b) otherwise does not comply with the requirements laid down in this Regulation, they shall carry out an evaluation of the device concerned covering all requirements laid down in this Regulation relating to the risk presented by the device, or to any other non-compliance of the device. The relevant economic operators shall cooperate with the competent authorities. Article 95 Procedure for dealing with devices presenting an unacceptable risk to health and safety 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities find that the device presents an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall without delay require the manufacturer of the devices concerned, its authorised representative and all other relevant economic operators to take all appropriate and duly justified corrective action to bring the device into compliance with the requirements of this Regulation relating to the risk presented by the device and, in a manner that is proportionate to the nature of the risk, to restrict the making available of the device on the market, to subject the making available of the device to specific requirements, to withdraw the device from the market, or to recall it, within a reasonable period that is clearly defined and communicated to the relevant economic operator. 2.   The competent authorities shall, without delay, notify the Commission, the other Member States and, where a certificate has been issued in accordance with Article 56 for the device concerned, the notified body that issued that certificate, of the results of the evaluation and of the actions which they have required the economic operators to take, by means of the electronic system referred to in Article 100. 3.   The economic operators as referred to in paragraph 1 shall, without delay, ensure that all appropriate corrective action is taken throughout the Union in respect of all the devices concerned that they have made available on the market. 4.   Where the economic operator as referred to in paragraph 1 does not take adequate corrective action within the period referred to in paragraph 1, the competent authorities shall take all appropriate measures to prohibit or restrict the making available of the device on their national market, to withdraw the device from that market or to recall it. The competent authorities shall notify the Commission, the other Member States and the notified body referred to in paragraph 2 of this Article, without delay, of those measures, by means of the electronic system referred to in Article 100. 5.   The notification referred to in paragraph 4 shall include all available details, in particular the data necessary for the identification and tracing of the non-compliant device, the origin of the device, the nature of and the reasons for the non-compliance alleged and the risk involved, the nature and duration of the national measures taken and the arguments put forward by the relevant economic operator. 6.   Member States other than the Member State initiating the procedure shall, without delay, inform the Commission and the other Member States, by means of the electronic system referred to in Article 100, of any additional relevant information at their disposal relating to the non-compliance of the device concerned and of any measures adopted by them in relation to the device concerned. In the event of disagreement with the notified national measure, they shall, without delay, inform the Commission and the other Member States of their objections, by means of the electronic system referred to in Article 100. 7.   Where, within two months of receipt of the notification referred to in paragraph 4, no objection has been raised by either a Member State or the Commission in respect of any measures taken by a Member State, those measures shall be deemed to be justified. In that case, all Member States shall ensure that corresponding appropriate restrictive or prohibitive measures, including withdrawing, recalling or limiting the availability of the device on their national market, are taken without delay in respect of the device concerned. Article 96 Procedure for evaluating national measures at Union level 1.   Where, within two months of receipt of the notification referred to in Article 95(4), objections are raised by a Member State against a measure taken by another Member State, or where the Commission considers the measure to be contrary to Union law, the Commission shall, after consulting the competent authorities concerned and, where necessary, the economic operators concerned, evaluate that national measure. On the basis of the results of that evaluation, the Commission may decide, by means of implementing acts, whether or not the national measure is justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Where the Commission considers the national measure to be justified as referred to in paragraph 1 of this Article, the second subparagraph of Article 95(7) shall apply. If the Commission considers the national measure to be unjustified, the Member State concerned shall withdraw the measure. Where the Commission does not adopt a decision pursuant to paragraph 1 of this Article within eight months of receipt of the notification referred to in Article 95(4), the national measure shall be considered to be justified. 3.   Where a Member State or the Commission considers that the risk to health and safety emanating from a device cannot be mitigated satisfactorily by means of measures taken by the Member State or Member States concerned, the Commission, at the request of a Member State or on its own initiative, may take, by means of implementing acts, the necessary and duly justified measures to ensure the protection of health and safety, including measures restricting or prohibiting the placing on the market and putting into service of the device concerned. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 97 Other non-compliance 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities of a Member State find that a device does not comply with the requirements laid down in this Regulation but does not present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall require the relevant economic operator to bring the non-compliance concerned to an end within a reasonable period that is clearly defined and communicated to the economic operator and that is proportionate to the non-compliance. 2.   Where the economic operator does not bring the non-compliance to an end within the period referred to in paragraph 1 of this Article, the Member State concerned shall, without delay, take all appropriate measures to restrict or prohibit the product being made available on the market or to ensure that it is recalled or withdrawn from the market. That Member State shall inform the Commission and the other Member States, without delay, of those measures, by means of the electronic system referred to in Article 100. 3.   In order to ensure the uniform application of this Article, the Commission may, by means of implementing acts, specify appropriate measures to be taken by competent authorities to address given types of non-compliance. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 98 Preventive health protection measures 1.   Where a Member State, after having performed an evaluation which indicates a potential risk related to a device or a specific category or group of devices, considers that, in order to protect the health and safety of patients, users or other persons or other aspects of public health, the making available on the market or putting into service of a device or a specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled, it may take any necessary and justified measures. 2.   The Member State referred to in paragraph 1 shall immediately notify the Commission and all other Member States, giving the reasons for its decision, by means of the electronic system referred to in Article 100. 3.   The Commission, in consultation with the MDCG and, where necessary, the economic operators concerned, shall assess the national measures taken. The Commission may decide, by means of implementing acts, whether the national measures are justified or not. In the absence of a Commission decision within six months of their notification, the national measures shall be considered to be justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 4.   Where the assessment referred to in paragraph 3 of this Article demonstrates that the making available on the market or putting into service of a device, specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled in all Member States in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission may adopt implementing acts to take the necessary and duly justified measures. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 99 Good administrative practice 1.   Any measure adopted by the competent authorities of the Member States pursuant to Articles 95 to 98 shall state the exact grounds on which it is based. Where such a measure is addressed to a specific economic operator, the competent authority shall notify without delay the economic operator concerned of that measure, and shall at the same time inform that economic operator of the remedies available under the law or the administrative practice of the Member State concerned and of the time limits to which such remedies are subject. Where the measure is of general applicability, it shall be appropriately published. 2.   Except in cases where immediate action is necessary for reasons of unacceptable risk to human health or safety, the economic operator concerned shall be given the opportunity to make submissions to the competent authority within an appropriate period of time that is clearly defined before any measure is adopted. Where action has been taken without the economic operator having had the opportunity to make submissions as referred to in the first subparagraph, it shall be given the opportunity to make submissions as soon as possible and the action taken shall be reviewed promptly thereafter. 3.   Any measure adopted shall be immediately withdrawn or amended upon the economic operator's demonstrating that it has taken effective corrective action and that the device is in compliance with the requirements of this Regulation. 4.   Where a measure adopted pursuant to Articles 95 to 98 concerns a device for which a notified body has been involved in the conformity assessment, the competent authorities shall by means of the electronic system referred to in Article 100 inform the relevant notified body and the authority responsible for the notified body of the measure taken. Article 100 Electronic system on market surveillance 1.   The Commission, in collaboration with the Member States, shall set up and manage an electronic system to collate and process the following information: (a) summaries of the results of the surveillance activities referred to in Article 93(4); (b) the final inspection report referred to in Article 93(7); (c) information in relation to devices presenting an unacceptable risk to health and safety as referred to in Article 95(2), (4) and (6); (d) information in relation to non-compliance of products as referred to in Article 97(2); (e) information in relation to the preventive health protection measures referred to in Article 98(2); (f) summaries of the results of the reviews and assessments of the market surveillance activities of the Member States referred to in 93(8). 2.   The information referred to in paragraph 1 of this Article shall be immediately transmitted through the electronic system to all competent authorities concerned and, where applicable, to the notified body that issued a certificate in accordance with Article 56 for the device concerned and be accessible to the Member States and to the Commission. 3.   Information exchanged between Member States shall not be made public where to do so might impair market surveillance activities and co-operation between Member States. CHAPTER VIII COOPERATION BETWEEN MEMBER STATES, MEDICAL DEVICE COORDINATION GROUP, EXPERT LABORATORIES, EXPERT PANELS AND DEVICE REGISTERS Article 101 Competent authorities The Member States shall designate the competent authority or authorities responsible for the implementation of this Regulation. They shall entrust their authorities with the powers, resources, equipment and knowledge necessary for the proper performance of their tasks pursuant to this Regulation. The Member States shall communicate the names and contact details of the competent authorities to the Commission which shall publish a list of competent authorities. Article 102 Cooperation 1.   The competent authorities of the Member States shall cooperate with each other and with the Commission. The Commission shall provide for the organisation of exchanges of information necessary to enable this Regulation to be applied uniformly. 2.   Member States shall, with the support of the Commission, participate, where appropriate, in initiatives developed at international level with the aim of ensuring cooperation between regulatory authorities in the field of medical devices. Article 103 Medical Device Coordination Group 1.   A Medical Device Coordination Group (‘MDCG’) is hereby established. 2.   Each Member State shall appoint to the MDCG, for a three-year term which may be renewed, one member and one alternate each with expertise in the field of medical devices, and one member and one alternate with expertise in the field of in vitro diagnostic medical devices. A Member State may choose to appoint only one member and one alternate, each with expertise in both fields. The members of the MDCG shall be chosen for their competence and experience in the field of medical devices and in vitro diagnostic medical devices. They shall represent the competent authorities of the Member States. The names and affiliation of members shall be made public by the Commission. The alternates shall represent and vote for the members in their absence. 3.   The MDCG shall meet at regular intervals and, where the situation requires, upon request by the Commission or a Member State. The meetings shall be attended either by the members appointed for their role and expertise in the field of medical devices, or by the members appointed for their expertise in the field of in vitro diagnostic medical devices, or by the members appointed for their expertise in both fields, or their alternates, as appropriate. 4.   The MDCG shall use its best endeavours to reach consensus. If such consensus cannot be reached, the MDCG shall decide by a majority of its members. Members with diverging positions may request that their positions and the grounds on which they are based be recorded in the MDCG's position. 5.   The MDCG shall be chaired by a representative of the Commission. The chair shall not take part in votes of the MDCG. 6.   The MDCG may invite, on a case-by-case basis, experts and other third parties to attend meetings or provide written contributions. 7.   The MDCG may establish standing or temporary sub-groups. Where appropriate, organisations representing the interests of the medical device industry, healthcare professionals, laboratories, patients and consumers at Union level shall be invited to such sub-groups in the capacity of observers. 8.   The MDCG shall establish its rules of procedure which shall, in particular, lay down procedures for the following: — the adoption of opinions or recommendations or other positions, including in cases of urgency; — the delegation of tasks to reporting and co-reporting members; — the implementation of Article 107 regarding conflict of interests; — the functioning of sub-groups. 9.   The MDCG shall have the tasks laid down in Article 105 of this Regulation and Article 99 of Regulation (EU) 2017/746. Article 104 Support by the Commission The Commission shall support the functioning of the cooperation between national competent authorities. It shall, in particular, provide for the organisation of exchanges of experience between the competent authorities and provide technical, scientific and logistic support to the MDCG and its sub-groups. It shall organise the meetings of the MDCG and its sub-groups, participate in those meetings and ensure the appropriate follow-up. Article 105 Tasks of the MDCG Under this Regulation, the MDCG shall have the following tasks: (a) to contribute to the assessment of applicant conformity assessment bodies and notified bodies pursuant to the provisions set out in Chapter IV; (b) to advise the Commission, at its request, in matters concerning the coordination group of notified bodies as established pursuant to Article 49; (c) to contribute to the development of guidance aimed at ensuring effective and harmonised implementation of this Regulation, in particular regarding the designation and monitoring of notified bodies, application of the general safety and performance requirements and conduct of clinical evaluations and investigations by manufacturers, assessment by notified bodies and vigilance activities; (d) to contribute to the continuous monitoring of technical progress and assessment of whether the general safety and performance requirements laid down in this Regulation and Regulation (EU) 2017/746 are adequate to ensure safety and performance of devices, and thereby contribute to identifying whether there is a need to amend Annex I to this Regulation; (e) to contribute to the development of device standards, of CS and of scientific guidelines, including product specific guidelines, on clinical investigation of certain devices in particular implantable devices and class III devices; (f) to assist the competent authorities of the Member States in their coordination activities in particular in the fields of classification and the determination of the regulatory status of devices, clinical investigations, vigilance and market surveillance including the development and maintenance of a framework for a European market surveillance programme with the objective of achieving efficiency and harmonisation of market surveillance in the Union, in accordance with Article 93; (g) to provide advice, either on its own initiative or at request of the Commission, in the assessment of any issue related to the implementation of this Regulation; (h) to contribute to harmonised administrative practice with regard to devices in the Member States. Article 106 Provision of scientific, technical and clinical opinions and advice 1.   The Commission shall, by means of implementing acts and in consultation with the MDCG, make provision for expert panels to be designated for the assessment of the clinical evaluation in relevant medical fields as referred to in paragraph 9 of this Article and to provide views in accordance with Article 48(6) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices and, where necessary, for categories or groups of devices, or for specific hazards relating to categories or groups of devices, observing the principles of highest scientific competence, impartiality, independence and transparency. The same principles shall apply where the Commission decides to appoint expert laboratories in accordance with paragraph 7 of this Article. 2.   Expert panels and expert laboratories may be designated in areas where the Commission, in consultation with the MDCG, has identified a need for the provision of consistent scientific, technical and/or clinical advice or laboratory expertise in relation to the implementation of this Regulation. Expert panels and expert laboratories may be appointed on a standing or temporary basis. 3.   Expert panels shall consist of advisors appointed by the Commission on the basis of up-to-date clinical, scientific or technical expertise in the field and with a geographical distribution that reflects the diversity of scientific and clinical approaches in the Union. The Commission shall determine the number of members of each panel in accordance with the requisite needs. The members of expert panels shall perform their tasks with impartiality and objectivity. They shall neither seek nor take instructions from notified bodies or manufacturers. Each member shall draw up a declaration of interests, which shall be made publicly available. The Commission shall establish systems and procedures to actively manage and prevent potential conflicts of interest. 4.   Expert panels shall take into account relevant information provided by stakeholders including patients' organisations and healthcare professionals when preparing their scientific opinions. 5.   The Commission, following consultation with the MDCG, may appoint advisors to expert panels following publication in the Official Journal of the European Union and on the Commission website following a call for expressions of interest. Depending on the type of task and the need for specific expertise, advisors may be appointed to the expert panels for a maximum period of three years and their appointment may be renewed. 6.   The Commission, following consultation with the MDCG, may include advisors on a central list of available experts who, whilst not being formally appointed to a panel, are available to provide advice and to support the work of the expert panel as needed. That list shall be published on the Commission website. 7.   The Commission may, by means of implementing acts and following consultation with the MDCG, designate expert laboratories, on the basis of their expertise in: — physico-chemical characterisation, or — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical biological and toxicological testing of specific devices, categories or groups of devices. The Commission shall only designate expert laboratories for which a Member State or the Joint Research Centre has submitted an application for designation. 8.   Expert laboratories shall satisfy the following criteria: (a) have adequate and appropriately qualified staff with adequate knowledge and experience in the field of the devices for which they are designated; (b) possess the necessary equipment to carry out the tasks assigned to them; (c) have the necessary knowledge of international standards and best practices; (d) have an appropriate administrative organisation and structure; (e) ensure that their staff observe the confidentiality of information and data obtained in carrying out their tasks. 9.   Expert panels appointed for clinical evaluation in relevant medical fields shall fulfil the tasks provided for in Article 54(1) and Article 61(2) and Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. 10.   Expert panels and expert laboratories may have the following tasks, depending on the requisite needs: (a) to provide scientific, technical and clinical assistance to the Commission and the MDCG in relation to the implementation of this Regulation; (b) to contribute to the development and maintenance of appropriate guidance and CS for: — clinical investigations, — clinical evaluation and PMCF, — performance studies, — performance evaluation and post-market performance follow-up, — physico-chemical characterisation, and — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing for specific devices, or a category or group of devices, or for specific hazards related to a category or group of devices; (c) to develop and review clinical evaluation guidance and performance evaluation guidance for performance of conformity assessment in line with the state of the art with regard to clinical evaluation, performance evaluation, physico-chemical characterisation, and microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing; (d) to contribute to the development of standards at international level, ensuring that such standards reflect the state of the art; (e) to provide opinions in response to consultations by manufacturers in accordance with Article 61(2), notified bodies and Member States in accordance with paragraphs 11 to 13 of this Article. (f) to contribute to identification of concerns and emerging issues on the safety and performance of medical devices; (g) to provide views in accordance with Article 48(4) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices. 11.   The Commission, shall facilitate the access of Member States and notified bodies and manufacturers to advice provided by expert panels and expert laboratories concerning, inter alia, the criteria for an appropriate data set for assessment of the conformity of a device, in particular with regard to the clinical data required for clinical evaluation, with regard to physico-chemical characterisation, and with regard to microbiological, biocompatibility, mechanical, electrical, electronic and non-clinical toxicological testing. 12.   When adopting its scientific opinion in accordance with paragraph 9, the members of the expert panels shall use their best endeavours to reach consensus. If consensus cannot be reached, the expert panels shall decide by a majority of their members, and the scientific opinion shall mention the divergent positions and the grounds on which they are based. The Commission shall publish the scientific opinion and advice delivered in accordance with paragraphs 9 and 11 of this Article, ensuring consideration of aspects of confidentiality as set out in Article 109. The clinical evaluation guidance referred to in point (c) of paragraph 10 shall be published following consultation with the MDCG. 13.   The Commission may require manufacturers and notified bodies to pay fees for the advice provided by expert panels and expert laboratories. The structure and the level of fees as well as the scale and structure of recoverable costs shall be adopted by the Commission by means of implementing acts, taking into account the objectives of the adequate implementation of this Regulation, protection of health and safety, support of innovation and cost-effectiveness and the necessity to achieve active participation in the expert panels. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 14.   The fees payable to the Commission in accordance with the procedure under paragraph 13 of this Article shall be set in a transparent manner and on the basis of the costs for the services provided. The fees payable shall be reduced in the case of a clinical evaluation consultation procedure initiated in accordance with point (c) of Section 5.1 of Annex IX involving a manufacturer who is a micro, small or medium-sized enterprise within the meaning of Recommendation 2003/361/EC. 15.   The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the tasks of expert panels and expert laboratories referred to in paragraph 10 of this Article. Article 107 Conflict of interests 1.   Members of the MDCG, its sub-groups, and members of expert panels and expert laboratories shall not have financial or other interests in the medical device industry which could affect their impartiality. They shall undertake to act in the public interest and in an independent manner. They shall declare any direct or indirect interests they may have in the medical device industry and update that declaration whenever a relevant change occurs. The declaration of interests shall be made publicly available on the Commission website. This Article shall not apply to the representatives of stakeholder organisations participating in the sub-groups of the MDCG. 2.   Experts and other third parties invited by the MDCG on a case-by-case basis shall declare any interests they may have in the issue in question. Article 108 Device registers and databanks The Commission and the Member States shall take all appropriate measures to encourage the establishment of registers and databanks for specific types of devices setting common principles to collect comparable information. Such registers and databanks shall contribute to the independent evaluation of the long-term safety and performance of devices, or the traceability of implantable devices, or all of such characteristics. CHAPTER IX CONFIDENTIALITY, DATA PROTECTION, FUNDING AND PENALTIES Article 109 Confidentiality 1.   Unless otherwise provided for in this Regulation and without prejudice to existing national provisions and practices in the Member States on confidentiality, all parties involved in the application of this Regulation shall respect the confidentiality of information and data obtained in carrying out their tasks in order to protect the following: (a) personal data, in accordance with Article 110; (b) commercially confidential information and trade secrets of a natural or legal person, including intellectual property rights; unless disclosure is in the public interest; (c) the effective implementation of this Regulation, in particular for the purpose of inspections, investigations or audits. 2.   Without prejudice to paragraph 1, information exchanged on a confidential basis between competent authorities and between competent authorities and the Commission shall not be disclosed without the prior agreement of the originating authority. 3.   Paragraphs 1 and 2 shall not affect the rights and obligations of the Commission, Member States and notified bodies with regard to exchange of information and the dissemination of warnings, nor the obligations of the persons concerned to provide information under criminal law. 4.   The Commission and Member States may exchange confidential information with regulatory authorities of third countries with which they have concluded bilateral or multilateral confidentiality arrangements. Article 110 Data protection 1.   Member States shall apply Directive 95/46/EC to the processing of personal data carried out in the Member States pursuant to this Regulation. 2.   Regulation (EC) No 45/2001 shall apply to the processing of personal data carried out by the Commission pursuant to this Regulation. Article 111 Levying of fees 1.   This Regulation shall be without prejudice to the possibility for Member States to levy fees for the activities set out in this Regulation, provided that the level of the fees is set in a transparent manner and on the basis of cost-recovery principles. 2.   Member States shall inform the Commission and the other Member States at least three months before the structure and level of fees is to be adopted. The structure and level of fees shall be made publicly available on request. Article 112 Funding of activities related to designation and monitoring of notified bodies The costs associated with joint assessment activities shall be covered by the Commission. The Commission shall, by means of implementing acts, lay down the scale and structure of recoverable costs and other necessary implementing rules. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 113 Penalties The Member States shall lay down the rules on penalties applicable for infringement of the provisions of this Regulation and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be effective, proportionate, and dissuasive. The Member States shall notify the Commission of those rules and of those measures by 25 February 2020 and shall notify it, without delay, of any subsequent amendment affecting them. CHAPTER X FINAL PROVISIONS Article 114 Committee procedure 1.   The Commission shall be assisted by a Committee on Medical Devices. That Committee shall be a committee within the meaning of Regulation (EU) No 182/2011. 2.   Where reference is made to this paragraph, Article 4 of Regulation (EU) No 182/2011 shall apply. 3.   Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply. Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third subparagraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply. 4.   Where reference is made to this paragraph, Article 8 of Regulation (EU) No 182/2011, in conjunction with Article 4 or 5 thereof, as appropriate, shall apply. Article 115 Exercise of the delegation 1.   The power to adopt delegated acts is conferred on the Commission subject to the conditions laid down in this Article. 2.   The power to adopt delegated acts referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall be conferred on the Commission for a period of five years from 25 May 2017. The Commission shall draw up a report in respect of the delegation of power not later than nine months before the end of the five-year period. The delegation of power shall be tacitly extended for periods of an identical duration, unless the European Parliament or the Council opposes such extension not later than three months before the end of each period. 3.   The delegation of power referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) may be revoked at any time by the European Parliament or by the Council. A decision to revoke shall put an end to the delegation of the power specified in that decision. It shall take effect the day following the publication of the decision in the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity of any delegated acts already in force. 4.   Before adopting a delegated act, the Commission shall consult experts designated by each Member State in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making. 5.   As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament and to the Council. 6.   A delegated act adopted pursuant to Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall enter into force only if no objection has been expressed either by the European Parliament or by the Council within a period of three months of notification of that act to the European Parliament and the Council or if, before the expiry of that period, the European Parliament and the Council have both informed the Commission that they will not object. That period shall be extended by three months at the initiative of the European Parliament or of the Council. Article 116 Separate delegated acts for different delegated powers The Commission shall adopt a separate delegated act in respect of each power delegated to it pursuant to this Regulation. Article 117 Amendment to Directive 2001/83/EC In Annex I to Directive 2001/83/EC, point 12 of Section 3.2. is replaced by the following: ‘(12) Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question. Article 118 Amendment to Regulation (EC) No 178/2002 In the third paragraph of Article 2 of Regulation (EC) No 178/2002, the following point is added: ‘(i) medical devices within the meaning of Regulation (EU) 2017/745 of the European Parliament and of the Council (*2). Article 119 Amendment to Regulation (EC) No 1223/2009 In Article 2 of Regulation (EC) No 1223/2009, the following paragraph is added: ‘4.   The Commission may, at the request of a Member State or on its own initiative, adopt the necessary measures to determine whether or not a specific product or group of products falls within the definition ‘cosmetic product’. Those measures shall be adopted in accordance with the regulatory procedure referred to in Article 32(2).’. Article 120 Transitional provisions 1.   From 26 May 2020, any publication of a notification in respect of a notified body in accordance with Directives 90/385/EEC and 93/42/EEC shall become void. 2.   Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC prior to 25 May 2017 shall remain valid until the end of the period indicated on the certificate, except for certificates issued in accordance with Annex 4 to Directive 90/385/EEC or Annex IV to Directive 93/42/EEC which shall become void at the latest on 27 May 2022. Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC from 25 May 2017 shall remain valid until the end of the period indicated on the certificate, which shall not exceed five years from its issuance. They shall however become void at the latest on 27 May 2024. 3.   By way of derogation from Article 5 of this Regulation, a device with a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC and which is valid by virtue of paragraph 2 of this Article may only be placed on the market or put into service provided that from the date of application of this Regulation it continues to comply with either of those Directives, and provided there are no significant changes in the design and intended purpose. However, the requirements of this Regulation relating to post-market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in those Directives. Without prejudice to Chapter IV and paragraph 1 of this Article, the notified body that issued the certificate referred to in the first subparagraph shall continue to be responsible for the appropriate surveillance in respect of all of the applicable requirements relating to the devices it has certified. 4.   Devices lawfully placed on the market pursuant to Directives 90/385/EEC and 93/42/EEC prior to 26 May 2020, and devices placed on the market from 26 May 2020 by virtue of a certificate as referred to in paragraph 2 of this Article, may continue to be made available on the market or put into service until 27 May 2025. 5.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, devices which comply with this Regulation may be placed on the market prior to 26 May 2020. 6.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, conformity assessment bodies which comply with this Regulation may be designated and notified prior 26 May 2020. Notified bodies which are designated and notified in accordance with this Regulation may carry out the conformity assessment procedures laid down in this Regulation and issue certificates in accordance with this Regulation prior to 26 May 2020. 7.   As regards devices subject to the consultation procedure laid down in Article 54, paragraph 5 of this Article shall apply provided that the necessary appointments to the MDCG and expert panels have been made. 8.   By way of derogation from Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC and Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, manufacturers, authorised representatives, importers and notified bodies which, during the period starting on the later of the dates referred to point (d) of Article 123(3) and ending 18 months later, comply with Article 29(4) and Article 56(5) of this Regulation shall be considered to comply with the laws and regulations adopted by Member States in accordance with, respectively, Article 10a of Directive 90/385/EEC or Article 14(1) and (2) of Directive 93/42/EEC and with, respectively, point (a) of Article 10b(1) of Directive 90/385/EEC or points (a) and (b) of Article 14a(1) of Directive 93/42/EEC as specified in Decision 2010/227/EU. 9.   Authorisations granted by the competent authorities of the Member States in accordance with Article 9(9) of Directive 90/385/EEC or Article 11(13) of Directive 93/42/EEC shall keep the validity indicated in the authorisation. 10.   Devices falling within the scope of this Regulation in accordance with points (f) and (g) of Article 1(6) which have been legally placed on the market or put into service in accordance with the rules in force in the Member States prior to 26 May 2020 may continue to be placed on the market and put into service in the Member States concerned. 11.   Clinical investigations which have started to be conducted in accordance with Article 10 of Directive 90/385/EEC or Article 15 of Directive 93/42/EEC prior to 26 May 2020 may continue to be conducted. As of 26 May 2020, however, the reporting of serious adverse events and device deficiencies shall be carried out in accordance with this Regulation. 12.   Until the Commission has designated, pursuant to Article 27(2), issuing entities, GS1, HIBCC and ICCBBA shall be considered to be designated issuing entities. Article 121 Evaluation By 27 May 2027, the Commission shall assess the application of this Regulation and produce an evaluation report on the progress towards achievement of the objectives contained herein including an assessment of the resources required to implement this Regulation. Special attention shall be given to the traceability of medical devices through the storage, pursuant to Article 27, of the UDI by economic operators, health institutions and health professionals. Article 122 Repeal Without prejudice to Articles 120(3) and (4) of this Regulation, and without prejudice to the obligations of the Member States and manufacturers as regards vigilance and to the obligations of manufacturers as regards the making available of documentation, under Directives 90/385/EEC and 93/42/EEC, those Directives are repealed with effect from 26 May 2020, with the exception of: — Articles 8 and 10, points (b) and (c) of Article 10b(1), Article 10b(2) and Article 10b(3) of Directive 90/385/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10, points (c) and (d) of Article 14a(1), Article 14a(2), Article 14a(3) and Article 15 of Directive 93/42/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; and — Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation. As regards the devices referred to in Article 120 (3) and (4) of this Regulation, the Directives referred to in the first paragraph shall continue to apply until 27 May 2025 to the extent necessary for the application of those paragraphs. Notwithstanding the first paragraph, Regulations (EU) No 207/2012 and (EU) No 722/2012 shall remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. References to the repealed Directives shall be understood as references to this Regulation and shall be read in accordance with the correlation table laid down in Annex XVII to this Regulation. Article 123 Entry into force and date of application 1.   This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union. 2.   It shall apply from 26 May 2020. 3.   By way of derogation from paragraph 2: (a) Articles 35 to 50 shall apply from 26 November 2017. However, from that date until 26 May 2020, the obligations on notified bodies pursuant to Articles 35 to 50 shall apply only to those bodies which submit an application for designation in accordance with Article 38; (b) Articles 101 and 103 shall apply from 26 November 2017; (c) Article 102 shall apply from 26 May 2018; (d) without prejudice to the obligations on the Commission pursuant to Article 34, where, due to circumstances that could not reasonably have been foreseen when drafting the plan referred to in Article 34(1), Eudamed is not fully functional on 26 May 2020, the obligations and requirements that relate to Eudamed shall apply from the date corresponding to six months after the date of publication of the notice referred to in Article 34(3). The provisions referred to in the preceding sentence are: — Article 29, — Article 31, — Article 32, — Article 33(4), — the second sentence of Article 40(2), — Article 42(10), — Article 43(2), — the second subparagraph of Article 44(12), — points (d) and (e) of Article 46(7), — Article 53(2), — Article 54(3), — Article 55(1), — Articles 70 to 77, — paragraphs 1 to 13 of Article 78, — Articles 79 to 82, — Article 86(2), — Articles 87 and 88, — Article 89(5) and (7), and the third subparagraph of Article 89(8), — Article 90, — Article 93(4), (7) and (8), — Article 95(2) and (4), — the last sentence of Article 97(2), — Article 99(4), — the second sentence of the first subparagraph of Article 120(3). Until Eudamed is fully functional, the corresponding provisions of Directives 90/385/EEC and 93/42/EEC shall continue to apply for the purpose of meeting the obligations laid down in the provisions listed in the first paragraph of this point regarding exchange of information including, and in particular, information regarding vigilance reporting, clinical investigations, registration of devices and economic operators, and certificate notifications. (e) Article 29(4) and Article 56(5) shall apply from 18 months after the later of the dates referred to in point (d); (f) for implantable devices and for class III devices Article 27(4) shall apply from 26 May 2021. For class IIa and class IIb devices Article 27(4) shall apply from 26 May 2023. For class I devices Article 27(4) shall apply from 26 May 2025; (g) for reusable devices that shall bear the UDI carrier on the device itself, Article 27(4) shall apply from two years after the date referred to in point (f) of this paragraph for the respective class of devices in that point; (h) The procedure set out in Article 78 shall apply from 26 May 2027, without prejudice to Article 78(14); (i) Article 120(12) shall apply from 26 May 2019. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Strasbourg, 5 April 2017. For the European Parliament The President A. TAJANI For the Council The President I. BORG (1)  Opinion of 14 February 2013 (OJ C 133, 9.5.2013, p. 52). (2)  Position of the European Parliament of 2 April 2014 (not yet published in the Official Journal) and position of the Council at first reading of 7 March 2017 (not yet published in the Official Journal). (3)  Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (OJ L 189, 20.7.1990, p. 17). (4)  Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ L 169, 12.7.1993, p. 1). (5)  Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety (OJ L 31, 1.2.2002, p. 1). (6)  Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (OJ L 342, 22.12.2009, p. 59). (7)  Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67). (8)  Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121). (9)  Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (OJ L 102, 7.4.2004, p. 48). (10)  Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components (OJ L 33, 8.2.2003, p. 30). (11)  Commission Recommendation 2011/696/EU of 18 October 2011 on the definition of nanomaterial (OJ L 275, 20.10.2011, p. 38). (12)  Directive 2014/30/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to electromagnetic compatibility (OJ L 96, 29.3.2014. p. 79). (13)  Council Directive 2013/59/Euratom of 5 December 2013 laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (OJ L 13, 17.1.2014, p. 1). (14)  Directive (EU) 2015/1535 of the European Parliament and of the Council of 9 September 2015 laying down a procedure for the provision of information in the field of technical regulations and of rules on Information Society services (OJ L 241, 17.9.2015, p. 1). (15)  Regulation (EU) No 1025/2012 of the European Parliament and of the Council of 25 October 2012 on European standardisation, amending Council Directives 89/686/EEC and 93/15/EEC and Directives 94/9/EC, 94/25/EC, 95/16/EC, 97/23/EC, 98/34/EC, 2004/22/EC, 2007/23/EC, 2009/23/EC and 2009/105/EC of the European Parliament and of the Council and repealing Council Decision 87/95/EEC and Decision No 1673/2006/EC of the European Parliament and of the Council (OJ L 316, 14.11.2012, p. 12). (16)  Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (OJ L 331, 7.12.1998, p. 1). (17)  Regulation (EC) No 765/2008 of the European Parliament and of the Council of 9 July 2008 setting out the requirements for accreditation and market surveillance relating to the marketing of products and repealing Regulation (EEC) No 339/93 (OJ L 218, 13.8.2008, p. 30). (18)  Decision No 768/2008/EC of the European Parliament and of the Council of 9 July 2008 on a common framework for the marketing of products, and repealing Council Decision 93/465/EEC (OJ L 218, 13.8.2008, p. 82). (19)  Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of the Member States concerning liability for defective products (OJ L 210, 7.8.1985, p. 29). (20)  Judgment of 28 July 2011 in Orifarm and Paranova, joined cases C-400/09 and C-207/10, ECLI:EU:C:2011:519. (21)  Commission Decision 2010/227/EU of 19 April 2010 on the European Databank for Medical Devices (OJ L 102, 23.4.2010, p. 45). (22)  Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995, p. 31). (23)  Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data (OJ L 8, 12.1.2001, p. 1). (24)  Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes (OJ L 276, 20.10.2010, p. 33). (25)  Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (see page 176 of this Official Journal). (26)   OJ L 123, 12.5.2016, p. 1. (27)  Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the rules and general principles concerning mechanisms for control by Member States of the Commission's exercise of implementing powers (OJ L 55, 28.2.2011, p. 13). (28)  Commission Regulation (EU) No 207/2012 of 9 March 2012 on electronic instructions for use of medical devices (OJ L 72, 10.3.2012, p. 28). (29)  Commission Regulation (EU) No 722/2012 of 8 August 2012 concerning particular requirements as regards the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and medical devices manufactured utilising tissues of animal origin (OJ L 212, 9.8.2012, p. 3). (30)  Commission Directive 2003/12/EC of 3 February 2003 on the reclassification of breast implants in the framework of Directive 93/42/EEC concerning medical devices (OJ L 28, 4.2.2003, p. 43). (31)  Commission Directive 2005/50/EC of 11 August 2005 on the reclassification of hip, knee and shoulder joint replacements in the framework of Council Directive 93/42/EEC concerning medical devices (OJ L 210, 12.8.2005, p. 41). (32)  Commission Implementing Regulation (EU) No 920/2013 of 24 September 2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices (OJ L 253, 25.9.2013, p. 8). (33)   OJ C 358, 7.12.2013, p. 10. (34)  Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1). (35)  Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24). (36)  Commission Recommendation 2003/361/ΕC of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises (OJ L 124, 20.5.2003, p. 36). (37)  Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1). ANNEXES I    General safety and performance requirements II    Technical documentation III    Technical documentation on post-market surveillance IV    EU declaration of conformity V    CE marking of conformity VI    Information to be submitted upon the registration of devices and economic operators in accordance with Articles 29(4) and 31; core data elements to be provided to the UDI database together with the UDI-DI in accordance with Articles 28 and 29;and the UDI system VII    Requirements to be met by notified bodies VIII    Classification rules IX    Conformity assessment based on a quality management system and assessment of the technical documentation X    Conformity assessment based on type examination XI    Conformity assessment based on product conformity verification XII    Certificates issued by a notified body XIII    Procedure for custom-made devices XIV    Clinical evaluation and post-market clinical follow-up XV    Clinical investigations XVI    List of groups of products without an intended medical purpose referred to in Article 1(2) XVII    Correlation table ANNEX I GENERAL SAFETY AND PERFORMANCE REQUIREMENTS CHAPTER I GENERAL REQUIREMENTS 1.   Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose. They shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. 2.   The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio. 3.   Manufacturers shall establish, implement, document and maintain a risk management system. Risk management shall be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. In carrying out risk management manufacturers shall: (a) establish and document a risk management plan for each device; (b) identify and analyse the known and foreseeable hazards associated with each device; (c) estimate and evaluate the risks associated with, and occurring during, the intended use and during reasonably foreseeable misuse; (d) eliminate or control the risks referred to in point (c) in accordance with the requirements of Section 4; (e) evaluate the impact of information from the production phase and, in particular, from the post-market surveillance system, on hazards and the frequency of occurrence thereof, on estimates of their associated risks, as well as on the overall risk, benefit-risk ratio and risk acceptability; and (f) based on the evaluation of the impact of the information referred to in point (e), if necessary amend control measures in line with the requirements of Section 4. 4.   Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art. To reduce risks, Manufacturers shall manage risks so that the residual risk associated with each hazard as well as the overall residual risk is judged acceptable. In selecting the most appropriate solutions, manufacturers shall, in the following order of priority: (a) eliminate or reduce risks as far as possible through safe design and manufacture; (b) where appropriate, take adequate protection measures, including alarms if necessary, in relation to risks that cannot be eliminated; and (c) provide information for safety (warnings/precautions/contra-indications) and, where appropriate, training to users. Manufacturers shall inform users of any residual risks. 5.   In eliminating or reducing risks related to use error, the manufacturer shall: (a) reduce as far as possible the risks related to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and (b) give consideration to the technical knowledge, experience, education, training and use environment, where applicable, and the medical and physical conditions of intended users (design for lay, professional, disabled or other users). 6.   The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer's instructions. 7.   Devices shall be designed, manufactured and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer. 8.   All known and foreseeable risks, and any undesirable side-effects, shall be minimised and be acceptable when weighed against the evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use. 9.   For the devices referred to in Annex XVI, the general safety requirements set out in Sections 1 and 8 shall be understood to mean that the device, when used under the conditions and for the purposes intended, does not present a risk at all or presents a risk that is no more than the maximum acceptable risk related to the product's use which is consistent with a high level of protection for the safety and health of persons. CHAPTER II REQUIREMENTS REGARDING DESIGN AND MANUFACTURE 10.   Chemical, physical and biological properties 10.1.   Devices shall be designed and manufactured in such a way as to ensure that the characteristics and performance requirements referred to in Chapter I are fulfilled. Particular attention shall be paid to: (a) the choice of materials and substances used, particularly as regards toxicity and, where relevant, flammability; (b) the compatibility between the materials and substances used and biological tissues, cells and body fluids, taking account of the intended purpose of the device and, where relevant, absorption, distribution, metabolism and excretion; (c) the compatibility between the different parts of a device which consists of more than one implantable part; (d) the impact of processes on material properties; (e) where appropriate, the results of biophysical or modelling research the validity of which has been demonstrated beforehand; (f) the mechanical properties of the materials used, reflecting, where appropriate, matters such as strength, ductility, fracture resistance, wear resistance and fatigue resistance; (g) surface properties; and (h) the confirmation that the device meets any defined chemical and/or physical specifications. 10.2.   Devices shall be designed, manufactured and packaged in such a way as to minimise the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure. 10.3.   Devices shall be designed and manufactured in such a way that they can be used safely with the materials and substances, including gases, with which they enter into contact during their intended use; if the devices are intended to administer medicinal products they shall be designed and manufactured in such a way as to be compatible with the medicinal products concerned in accordance with the provisions and restrictions governing those medicinal products and that the performance of both the medicinal products and of the devices is maintained in accordance with their respective indications and intended use. 10.4.   Substances 10.4.1.   Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine-disrupting properties for which there is scientific evidence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been adopted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established therein. 10.4.2.   Justification regarding the presence of CMR and/or endocrine-disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the substance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer-reviewed studies, scientific opinions from relevant scientific committees and an analysis of the availability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit-risk ratios of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3. and 10.4.4. 10.4.3.   Guidelines on phthalates For the purposes of Section 10.4., the Commission shall, as soon as possible and by 26 May 2018, provide the relevant scientific committee with a mandate to prepare guidelines that shall be ready before 26 May 2020. The mandate for the committee shall encompass at least a benefit-risk assessment of the presence of phthalates which belong to either of the groups of substances referred to in points (a) and (b) of Section 10.4.1. The benefit-risk assessment shall take into account the intended purpose and context of the use of the device, as well as any available alternative substances and alternative materials, designs or medical treatments. When deemed appropriate on the basis of the latest scientific evidence, but at least every five years, the guidelines shall be updated. 10.4.4.   Guidelines on other CMR and endocrine-disrupting substances Subsequently, the Commission shall mandate the relevant scientific committee to prepare guidelines as referred to in Section 10.4.3. also for other substances referred to in points (a) and (b) of Section 10.4.1., where appropriate. 10.4.5.   Labelling Where devices, parts thereof or materials used therein as referred to in Section 10.4.1. contain substances referred to in points (a) or (b) of Section 10.4.1. in a concentration above 0,1 % weight by weight (w/w), the presence of those substances shall be labelled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging, with the list of such substances. If the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials, information on residual risks for those patient groups and, if applicable, on appropriate precautionary measures shall be given in the instructions for use. 10.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used. 10.6.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks linked to the size and the properties of particles which are or can be released into the patient's or user's body, unless they come into contact with intact skin only. Special attention shall be given to nanomaterials. 11.   Infection and microbial contamination 11.1.   Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users and, where applicable, other persons. The design shall: (a) reduce as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries, (b) allow easy and safe handling, (c) reduce as far as possible any microbial leakage from the device and/or microbial exposure during use, and (d) prevent microbial contamination of the device or its content such as specimens or fluids. 11.2.   Where necessary devices shall be designed to facilitate their safe cleaning, disinfection, and/or re-sterilisation. 11.3.   Devices labelled as having a specific microbial state shall be designed, manufactured and packaged to ensure that they remain in that state when placed on the market and remain so under the transport and storage conditions specified by the manufacturer. 11.4.   Devices delivered in a sterile state shall be designed, manufactured and packaged in accordance with appropriate procedures, to ensure that they are sterile when placed on the market and that, unless the packaging which is intended to maintain their sterile condition is damaged, they remain sterile, under the transport and storage conditions specified by the manufacturer, until that packaging is opened at the point of use. It shall be ensured that the integrity of that packaging is clearly evident to the final user. 11.5.   Devices labelled as sterile shall be processed, manufactured, packaged and, sterilised by means of appropriate, validated methods. 11.6.   Devices intended to be sterilised shall be manufactured and packaged in appropriate and controlled conditions and facilities. 11.7.   Packaging systems for non-sterile devices shall maintain the integrity and cleanliness of the product and, where the devices are to be sterilised prior to use, minimise the risk of microbial contamination; the packaging system shall be suitable taking account of the method of sterilisation indicated by the manufacturer. 11.8.   The labelling of the device shall distinguish between identical or similar devices placed on the market in both a sterile and a non-sterile condition additional to the symbol used to indicate that devices are sterile. 12.   Devices incorporating a substance considered to be a medicinal product and devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body. 12.1.   In the case of devices referred to in the first subparagraph of Article 1(8), the quality, safety and usefulness of the substance which, if used separately, would be considered to be a medicinal product within the meaning of point (2) of Article 1 of Directive 2001/83/EC, shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC, as required by the applicable conformity assessment procedure under this Regulation. 12.2.   Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation. 13.   Devices incorporating materials of biological origin 13.1.   For devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable covered by this Regulation in accordance with point (g) of Article 1(6), the following shall apply: (a) donation, procurement and testing of the tissues and cells shall be done in accordance with Directive 2004/23/EC; (b) processing, preservation and any other handling of those tissues and cells or their derivatives shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process; (c) the traceability system for those devices shall be complementary and compatible with the traceability and data protection requirements laid down in Directive 2004/23/EC and in Directive 2002/98/EC. 13.2.   For devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable the following shall apply: (a) where feasible taking into account the animal species, tissues and cells of animal origin, or their derivatives, shall originate from animals that have been subjected to veterinary controls that are adapted to the intended use of the tissues. Information on the geographical origin of the animals shall be retained by manufacturers; (b) sourcing, processing, preservation, testing and handling of tissues, cells and substances of animal origin, or their derivatives, shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular safety with regard to viruses and other transmissible agents shall be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process, except when the use of such methods would lead to unacceptable degradation compromising the clinical benefit of the device; (c) in the case of devices manufactured utilising tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 the particular requirements laid down in that Regulation shall apply. 13.3.   For devices manufactured utilising non-viable biological substances other than those referred to in Sections 13.1 and 13.2, the processing, preservation, testing and handling of those substances shall be carried out so as to provide safety for patients, users and, where applicable, other persons, including in the waste disposal chain. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. 14.   Construction of devices and interaction with their environment 14.1.   If the device is intended for use in combination with other devices or equipment the whole combination, including the connection system shall be safe and shall not impair the specified performance of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the instructions for use. Connections which the user has to handle, such as fluid, gas transfer, electrical or mechanical coupling, shall be designed and constructed in such a way as to minimise all possible risks, such as misconnection. 14.2.   Devices shall be designed and manufactured in such a way as to remove or reduce as far as possible: (a) the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional and where appropriate ergonomic features; (b) risks connected with reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, temperature, variations in pressure and acceleration or radio signal interferences; (c) the risks associated with the use of the device when it comes into contact with materials, liquids, and substances, including gases, to which it is exposed during normal conditions of use; (d) the risks associated with the possible negative interaction between software and the IT environment within which it operates and interacts; (e) the risks of accidental ingress of substances into the device; (f) the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given; and (g) risks arising where maintenance or calibration are not possible (as with implants), from ageing of materials used or loss of accuracy of any measuring or control mechanism. 14.3.   Devices shall be designed and manufactured in such a way as to minimise the risks of fire or explosion during normal use and in single fault condition. Particular attention shall be paid to devices the intended use of which includes exposure to or use in association with flammable or explosive substances or substances which could cause combustion. 14.4.   Devices shall be designed and manufactured in such a way that adjustment, calibration, and maintenance can be done safely and effectively. 14.5.   Devices that are intended to be operated together with other devices or products shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe. 14.6   Any measurement, monitoring or display scale shall be designed and manufactured in line with ergonomic principles, taking account of the intended purpose, users and the environmental conditions in which the devices are intended to be used. 14.7.   Devices shall be designed and manufactured in such a way as to facilitate their safe disposal and the safe disposal of related waste substances by the user, patient or other person. To that end, manufacturers shall identify and test procedures and measures as a result of which their devices can be safely disposed after use. Such procedures shall be described in the instructions for use. 15.   Devices with a diagnostic or measuring function 15.1.   Diagnostic devices and devices with a measuring function, shall be designed and manufactured in such a way as to provide sufficient accuracy, precision and stability for their intended purpose, based on appropriate scientific and technical methods. The limits of accuracy shall be indicated by the manufacturer. 15.2.   The measurements made by devices with a measuring function shall be expressed in legal units conforming to the provisions of Council Directive 80/181/EEC (4). 16.   Protection against radiation 16.1.   General (a) Devices shall be designed, manufactured and packaged in such a way that exposure of patients, users and other persons to radiation is reduced as far as possible, and in a manner that is compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes. (b) The operating instructions for devices emitting hazardous or potentially hazardous radiation shall contain detailed information as to the nature of the emitted radiation, the means of protecting the patient and the user, and on ways of avoiding misuse and of reducing the risks inherent to installation as far as possible and appropriate. Information regarding the acceptance and performance testing, the acceptance criteria, and the maintenance procedure shall also be specified. 16.2.   Intended radiation (a) Where devices are designed to emit hazardous, or potentially hazardous, levels of ionizing and/or non-ionizing radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent to the emission, it shall be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility of relevant variable parameters within an acceptable tolerance. (b) Where devices are intended to emit hazardous, or potentially hazardous, ionizing and/or non-ionizing radiation, they shall be fitted, where possible, with visual displays and/or audible warnings of such emissions. 16.3.   Devices shall be designed and manufactured in such a way that exposure of patients, users and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. Where possible and appropriate, methods shall be selected which reduce the exposure to radiation of patients, users and other persons who may be affected. 16.4.   Ionising radiation (a) Devices intended to emit ionizing radiation shall be designed and manufactured taking into account the requirements of the Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation. (b) Devices intended to emit ionising radiation shall be designed and manufactured in such a way as to ensure that, where possible, taking into account the intended use, the quantity, geometry and quality of the radiation emitted can be varied and controlled, and, if possible, monitored during treatment. (c) Devices emitting ionising radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve an image and/or output quality that are appropriate to the intended medical purpose whilst minimising radiation exposure of the patient and user. (d) Devices that emit ionising radiation and are intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type, energy and, where appropriate, the quality of radiation. 17.   Electronic programmable systems — devices that incorporate electronic programmable systems and software that are devices in themselves 17.1.   Devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, shall be designed to ensure repeatability, reliability and performance in line with their intended use. In the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks or impairment of performance. 17.2.   For devices that incorporate software or for software that are devices in themselves, the software shall be developed and manufactured in accordance with the state of the art taking into account the principles of development life cycle, risk management, including information security, verification and validation. 17.3.   Software referred to in this Section that is intended to be used in combination with mobile computing platforms shall be designed and manufactured taking into account the specific features of the mobile platform (e.g. size and contrast ratio of the screen) and the external factors related to their use (varying environment as regards level of light or noise). 17.4.   Manufacturers shall set out minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. 18.   Active devices and devices connected to them 18.1.   For non-implantable active devices, in the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks. 18.2.   Devices where the safety of the patient depends on an internal power supply shall be equipped with a means of determining the state of the power supply and an appropriate warning or indication for when the capacity of the power supply becomes critical. If necessary, such warning or indication shall be given prior to the power supply becoming critical. 18.3.   Devices where the safety of the patient depends on an external power supply shall include an alarm system to signal any power failure. 18.4.   Devices intended to monitor one or more clinical parameters of a patient shall be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient's state of health. 18.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks of creating electromagnetic interference which could impair the operation of the device in question or other devices or equipment in the intended environment. 18.6.   Devices shall be designed and manufactured in such a way as to provide a level of intrinsic immunity to electromagnetic interference such that is adequate to enable them to operate as intended. 18.7.   Devices shall be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks to the patient, user or any other person, both during normal use of the device and in the event of a single fault condition in the device, provided the device is installed and maintained as indicated by the manufacturer. 18.8.   Devices shall be designed and manufactured in such a way as to protect, as far as possible, against unauthorised access that could hamper the device from functioning as intended. 19.   Particular requirements for active implantable devices 19.1.   Active implantable devices shall be designed and manufactured in such a way as to remove or minimize as far as possible: (a) risks connected with the use of energy sources with particular reference, where electricity is used, to insulation, leakage currents and overheating of the devices, (b) risks connected with medical treatment, in particular those resulting from the use of defibrillators or high-frequency surgical equipment, and (c) risks which may arise where maintenance and calibration are impossible, including: — excessive increase of leakage currents, — ageing of the materials used, — excess heat generated by the device, — decreased accuracy of any measuring or control mechanism. 19.2.   Active implantable devices shall be designed and manufactured in such a way as to ensure — if applicable, the compatibility of the devices with the substances they are intended to administer, and — the reliability of the source of energy. 19.3.   Active implantable devices and, if appropriate, their component parts shall be identifiable to allow any necessary measure to be taken following the discovery of a potential risk in connection with the devices or their component parts. 19.4.   Active implantable devices shall bear a code by which they and their manufacturer can be unequivocally identified (particularly with regard to the type of device and its year of manufacture); it shall be possible to read this code, if necessary, without the need for a surgical operation. 20.   Protection against mechanical and thermal risks 20.1.   Devices shall be designed and manufactured in such a way as to protect patients and users against mechanical risks connected with, for example, resistance to movement, instability and moving parts. 20.2.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. 20.3.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance. 20.4.   Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user or other person has to handle, shall be designed and constructed in such a way as to minimise all possible risks. 20.5.   Errors likely to be made when fitting or refitting certain parts which could be a source of risk shall be made impossible by the design and construction of such parts or, failing this, by information given on the parts themselves and/or their housings. The same information shall be given on moving parts and/or their housings where the direction of movement needs to be known in order to avoid a risk. 20.6.   Accessible parts of devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings shall not attain potentially dangerous temperatures under normal conditions of use. 21.   Protection against the risks posed to the patient or user by devices supplying energy or substances 21.1.   Devices for supplying the patient with energy or substances shall be designed and constructed in such a way that the amount to be delivered can be set and maintained accurately enough to ensure the safety of the patient and of the user. 21.2.   Devices shall be fitted with the means of preventing and/or indicating any inadequacies in the amount of energy delivered or substances delivered which could pose a danger. Devices shall incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy or substances from an energy and/or substance source. 21.3.   The function of the controls and indicators shall be clearly specified on the devices. Where a device bears instructions required for its operation or indicates operating or adjustment parameters by means of a visual system, such information shall be understandable to the user and, as appropriate, the patient. 22.   Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons 22.1.   Devices for use by lay persons shall be designed and manufactured in such a way that they perform appropriately for their intended purpose taking into account the skills and the means available to lay persons and the influence resulting from variation that can be reasonably anticipated in the lay person's technique and environment. The information and instructions provided by the manufacturer shall be easy for the lay person to understand and apply. 22.2.   Devices for use by lay persons shall be designed and manufactured in such a way as to: — ensure that the device can be used safely and accurately by the intended user at all stages of the procedure, if necessary after appropriate training and/or information, — reduce, as far as possible and appropriate, the risk from unintended cuts and pricks such as needle stick injuries, and — reduce as far as possible the risk of error by the intended user in the handling of the device and, if applicable, in the interpretation of the results. 22.3.   Devices for use by lay persons shall, where appropriate, include a procedure by which the lay person: — can verify that, at the time of use, the device will perform as intended by the manufacturer, and — if applicable, is warned if the device has failed to provide a valid result. CHAPTER III REQUIREMENTS REGARDING THE INFORMATION SUPPLIED WITH THE DEVICE 23.   Label and instructions for use 23.1.   General requirements regarding the information supplied by the manufacturer Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate. Such information may appear on the device itself, on the packaging or in the instructions for use, and shall, if the manufacturer has a website, be made available and kept up to date on the website, taking into account the following: (a) The medium, format, content, legibility, and location of the label and instructions for use shall be appropriate to the particular device, its intended purpose and the technical knowledge, experience, education or training of the intended user(s). In particular, instructions for use shall be written in terms readily understood by the intended user and, where appropriate, supplemented with drawings and diagrams. (b) The information required on the label shall be provided on the device itself. If this is not practicable or appropriate, some or all of the information may appear on the packaging for each unit, and/or on the packaging of multiple devices. (c) Labels shall be provided in a human-readable format and may be supplemented by machine-readable information, such as radio-frequency identification (‘RFID’) or bar codes. (d) Instructions for use shall be provided together with devices. By way of exception, instructions for use shall not be required for class I and class IIa devices if such devices can be used safely without any such instructions and unless otherwise provided for elsewhere in this Section. (e) Where multiple devices are supplied to a single user and/or location, a single copy of the instructions for use may be provided if so agreed by the purchaser who in any case may request further copies to be provided free of charge. (f) Instructions for use may be provided to the user in non-paper format (e.g. electronic) to the extent, and only under the conditions, set out in Regulation (EU) No 207/2012 or in any subsequent implementing rules adopted pursuant to this Regulation. (g) Residual risks which are required to be communicated to the user and/or other person shall be included as limitations, contra-indications, precautions or warnings in the information supplied by the manufacturer. (h) Where appropriate, the information supplied by the manufacturer shall take the form of internationally recognised symbols. Any symbol or identification colour used shall conform to the harmonised standards or CS. In areas for which no harmonised standards or CS exist, the symbols and colours shall be described in the documentation supplied with the device. 23.2.   Information on the label The label shall bear all of the following particulars: (a) the name or trade name of the device; (b) the details strictly necessary for a user to identify the device, the contents of the packaging and, where it is not obvious for the user, the intended purpose of the device; (c) the name, registered trade name or registered trade mark of the manufacturer and the address of its registered place of business; (d) if the manufacturer has its registered place of business outside the Union, the name of the authorised representative and address of the registered place of business of the authorised representative; (e) where applicable, an indication that the device contains or incorporates: — a medicinal substance, including a human blood or plasma derivative, or — tissues or cells, or their derivatives, of human origin, or — tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012; (f) where applicable, information labelled in accordance with Section 10.4.5.; (g) the lot number or the serial number of the device preceded by the words LOT NUMBER or SERIAL NUMBER or an equivalent symbol, as appropriate; (h) the UDI carrier referred to in Article 27(4) and Part C of Annex VII; (i) an unambiguous indication of t the time limit for using or implanting the device safely, expressed at least in terms of year and month, where this is relevant; (j) where there is no indication of the date until when it may be used safely, the date of manufacture. This date of manufacture may be included as part of the lot number or serial number, provided the date is clearly identifiable; (k) an indication of any special storage and/or handling condition that applies; (l) if the device is supplied sterile, an indication of its sterile state and the sterilisation method; (m) warnings or precautions to be taken that need to be brought to the immediate attention of the user of the device, and to any other person. This information may be kept to a minimum in which case more detailed information shall appear in the instructions for use, taking into account the intended users; (n) if the device is intended for single use, an indication of that fact. A manufacturer's indication of single use shall be consistent across the Union; (o) if the device is a single-use device that has been reprocessed, an indication of that fact, the number of reprocessing cycles already performed, and any limitation as regards the number of reprocessing cycles; (p) if the device is custom-made, the words ‘custom-made device’; (q) an indication that the device is a medical device. If the device is intended for clinical investigation only, the words ‘exclusively for clinical investigation’; (r) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the overall qualitative composition of the device and quantitative information on the main constituent or constituents responsible for achieving the principal intended action; (s) for active implantable devices, the serial number, and for other implantable devices, the serial number or the lot number. 23.3.   Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’) The following particulars shall appear on the sterile packaging: (a) an indication permitting the sterile packaging to be recognised as such, (b) a declaration that the device is in a sterile condition, (c) the method of sterilisation, (d) the name and address of the manufacturer, (e) a description of the device, (f) if the device is intended for clinical investigations, the words ‘exclusively for clinical investigations’, (g) if the device is custom-made, the words ‘custom-made device’, (h) the month and year of manufacture, (i) an unambiguous indication of the time limit for using or implanting the device safely expressed at least in terms of year and month, and (j) an instruction to check the instructions for use for what to do if the sterile packaging is damaged or unintentionally opened before use. 23.4.   Information in the instructions for use The instructions for use shall contain all of the following particulars: (a) the particulars referred to in points (a), (c), (e), (f), (k), (l), (n) and (r) of Section 23.2; (b) the device's intended purpose with a clear specification of indications, contra-indications, the patient target group or groups, and of the intended users, as appropriate; (c) where applicable, a specification of the clinical benefits to be expected. (d) where applicable, links to the summary of safety and clinical performance referred to in Article 32; (e) the performance characteristics of the device; (f) where applicable, information allowing the healthcare professional to verify if the device is suitable and select the corresponding software and accessories; (g) any residual risks, contra-indications and any undesirable side-effects, including information to be conveyed to the patient in this regard; (h) specifications the user requires to use the device appropriately, e.g. if the device has a measuring function, the degree of accuracy claimed for it; (i) details of any preparatory treatment or handling of the device before it is ready for use or during its use, such as sterilisation, final assembly, calibration, etc., including the levels of disinfection required to ensure patient safety and all available methods for achieving those levels of disinfection; (j) any requirements for special facilities, or special training, or particular qualifications of the device user and/or other persons; (k) the information needed to verify whether the device is properly installed and is ready to perform safely and as intended by the manufacturer, together with, where relevant: — details of the nature, and frequency, of preventive and regular maintenance, and of any preparatory cleaning or disinfection, — identification of any consumable components and how to replace them, — information on any necessary calibration to ensure that the device operates properly and safely during its intended lifetime, and — methods for eliminating the risks encountered by persons involved in installing, calibrating or servicing devices; (l) if the device is supplied sterile, instructions in the event of the sterile packaging being damaged or unintentionally opened before use; (m) if the device is supplied non-sterile with the intention that it is sterilised before use, the appropriate instructions for sterilisation; (n) if the device is reusable, information on the appropriate processes for allowing reuse, including cleaning, disinfection, packaging and, where appropriate, the validated method of re-sterilisation appropriate to the Member State or Member States in which the device has been placed on the market. Information shall be provided to identify when the device should no longer be reused, e.g. signs of material degradation or the maximum number of allowable reuses; (o) an indication, if appropriate, that a device can be reused only if it is reconditioned under the responsibility of the manufacturer to comply with the general safety and performance requirements; (p) if the device bears an indication that it is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. This information shall be based on a specific section of the manufacturer's risk management documentation, where such characteristics and technical factors shall be addressed in detail. If in accordance with point (d) of Section 23.1. no instructions for use are required, this information shall be made available to the user upon request; (q) for devices intended for use together with other devices and/or general purpose equipment: — information to identify such devices or equipment, in order to obtain a safe combination, and/or — information on any known restrictions to combinations of devices and equipment; (r) if the device emits radiation for medical purposes: — detailed information as to the nature, type and where appropriate, the intensity and distribution of the emitted radiation, — the means of protecting the patient, user, or other person from unintended radiation during use of the device; (s) information that allows the user and/or patient to be informed of any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. That information shall, where relevant, allow the user to brief the patient about any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. The information shall cover, where appropriate: — warnings, precautions and/or measures to be taken in the event of malfunction of the device or changes in its performance that may affect safety, — warnings, precautions and/or measures to be taken as regards the exposure to reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, or temperature, — warnings, precautions and/or measures to be taken as regards the risks of interference posed by the reasonably foreseeable presence of the device during specific diagnostic investigations, evaluations, or therapeutic treatment or other procedures such as electromagnetic interference emitted by the device affecting other equipment, — if the device is intended to administer medicinal products, tissues or cells of human or animal origin, or their derivatives, or biological substances, any limitations or incompatibility in the choice of substances to be delivered, — warnings, precautions and/or limitations related to the medicinal substance or biological material that is incorporated into the device as an integral part of the device; and — precautions related to materials incorporated into the device that contain or consist of CMR substances or endocrine-disrupting substances, or that could result in sensitisation or an allergic reaction by the patient or user; (t) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, warnings and precautions, where appropriate, related to the general profile of interaction of the device and its products of metabolism with other devices, medicinal products and other substances as well as contra-indications, undesirable side-effects and risks relating to overdose; (u) in the case of implantable devices, the overall qualitative and quantitative information on the materials and substances to which patients can be exposed; (v) warnings or precautions to be taken in order to facilitate the safe disposal of the device, its accessories and the consumables used with it, if any. This information shall cover, where appropriate: — infection or microbial hazards such as explants, needles or surgical equipment contaminated with potentially infectious substances of human origin, and — physical hazards such as from sharps. If in accordance with the point (d) of Section 23.1 no instructions for use are required, this information shall be made available to the user upon request; (w) for devices intended for use by lay persons, the circumstances in which the user should consult a healthcare professional; (x) for the devices covered by this Regulation pursuant to Article 1(2), information regarding the absence of a clinical benefit and the risks related to use of the device; (y) date of issue of the instructions for use or, if they have been revised, date of issue and identifier of the latest revision of the instructions for use; (z) a notice to the user and/or patient that any serious incident that has occurred in relation to the device should be reported to the manufacturer and the competent authority of the Member State in which the user and/or patient is established; (aa) information to be supplied to the patient with an implanted device in accordance with Article 18; (ab) for devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. (1)  Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 ( OJ L 353, 31.12.2008, p. 1). (2)  Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (OJ L 396, 30.12.2006, p. 1). (3)  Regulation (EU) No 528/2012 of the European Parliament and the Council of 22 May 2012 concerning the making available on the market of and use of biocidal products (OJ L 167, 27.6.2012, p. 1). (4)  Council Directive 80/181/EEC of 20 December 1979 on the approximation of the laws of the Member States relating to units of measurement and on the repeal of Directive 71/354/EEC (OJ L 39, 15.2.1980, p. 40). ANNEX II TECHNICAL DOCUMENTATION The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex. 1.   DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 1.1.   Device description and specification (a) product or trade name and a general description of the device including its intended purpose and intended users; (b) the Basic UDI-DI as referred to in Part C of Annex VI assigned by the manufacturer to the device in question, as soon as identification of this device becomes based on a UDI system, or otherwise a clear identification by means of product code, catalogue number or other unambiguous reference allowing traceability; (c) the intended patient population and medical conditions to be diagnosed, treated and/or monitored and other considerations such as patient selection criteria, indications, contra-indications, warnings; (d) principles of operation of the device and its mode of action, scientifically demonstrated if necessary; (e) the rationale for the qualification of the product as a device; (f) the risk class of the device and the justification for the classification rule(s) applied in accordance with Annex VIII; (g) an explanation of any novel features; (h) a description of the accessories for a device, other devices and other products that are not devices, which are intended to be used in combination with it; (i) a description or complete list of the various configurations/variants of the device that are intended to be made available on the market; (j) a general description of the key functional elements, e.g. its parts/components (including software if appropriate), its formulation, its composition, its functionality and, where relevant, its qualitative and quantitative composition. Where appropriate, this shall include labelled pictorial representations (e.g. diagrams, photographs, and drawings), clearly indicating key parts/components, including sufficient explanation to understand the drawings and diagrams; (k) a description of the raw materials incorporated into key functional elements and those making either direct contact with the human body or indirect contact with the body, e.g., during extracorporeal circulation of body fluids; (l) technical specifications, such as features, dimensions and performance attributes, of the device and any variants/configurations and accessories that would typically appear in the product specification made available to the user, for example in brochures, catalogues and similar publications. 1.2.   Reference to previous and similar generations of the device (a) an overview of the previous generation or generations of the device produced by the manufacturer, where such devices exist; (b) an overview of identified similar devices available on the Union or international markets, where such devices exist. 2.   INFORMATION TO BE SUPPLIED BY THE MANUFACTURER A complete set of: — the label or labels on the device and on its packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions, in the languages accepted in the Member States where the device is envisaged to be sold; and — the instructions for use in the languages accepted in the Member States where the device is envisaged to be sold. 3.   DESIGN AND MANUFACTURING INFORMATION (a) information to allow the design stages applied to the device to be understood; (b) complete information and specifications, including the manufacturing processes and their validation, their adjuvants, the continuous monitoring and the final product testing. Data shall be fully included in the technical documentation; (c) identification of all sites, including suppliers and sub-contractors, where design and manufacturing activities are performed. 4.   GENERAL SAFETY AND PERFORMANCE REQUIREMENTS The documentation shall contain information for the demonstration of conformity with the general safety and performance requirements set out in Annex I that are applicable to the device taking into account its intended purpose, and shall include a justification, validation and verification of the solutions adopted to meet those requirements. The demonstration of conformity shall include: (a) the general safety and performance requirements that apply to the device and an explanation as to why others do not apply; (b) the method or methods used to demonstrate conformity with each applicable general safety and performance requirement; (c) the harmonised standards, CS or other solutions applied; and (d) the precise identity of the controlled documents offering evidence of conformity with each harmonised standard, CS or other method applied to demonstrate conformity with the general safety and performance requirements. The information referred to under this point shall incorporate a cross-reference to the location of such evidence within the full technical documentation and, if applicable, the summary technical documentation. 5.   BENEFIT-RISK ANALYSIS AND RISK MANAGEMENT The documentation shall contain information on: (a) the benefit-risk analysis referred to in Sections 1 and 8 of Annex I, and (b) the solutions adopted and the results of the risk management referred to in Section 3 of Annex I. 6.   PRODUCT VERIFICATION AND VALIDATION The documentation shall contain the results and critical analyses of all verifications and validation tests and/or studies undertaken to demonstrate conformity of the device with the requirements of this Regulation and in particular the applicable general safety and performance requirements. 6.1.   Pre-clinical and clinical data (a) results of tests, such as engineering, laboratory, simulated use and animal tests, and evaluation of published literature applicable to the device, taking into account its intended purpose, or to similar devices, regarding the pre-clinical safety of the device and its conformity with the specifications; (b) detailed information regarding test design, complete test or study protocols, methods of data analysis, in addition to data summaries and test conclusions regarding in particular: — the biocompatibility of the device including the identification of all materials in direct or indirect contact with the patient or user; — physical, chemical and microbiological characterisation; — electrical safety and electromagnetic compatibility; — software verification and validation (describing the software design and development process and evidence of the validation of the software, as used in the finished device. This information shall typically include the summary results of all verification, validation and testing performed both in-house and in a simulated or actual user environment prior to final release. It shall also address all of the different hardware configurations and, where applicable, operating systems identified in the information supplied by the manufacturer); — stability, including shelf life; and — performance and safety. Where applicable, conformity with the provisions of Directive 2004/10/EC of the European Parliament and of the Council (1) shall be demonstrated. Where no new testing has been undertaken, the documentation shall incorporate a rationale for that decision. An example of such a rationale would be that biocompatibility testing on identical materials was conducted when those materials were incorporated in a previous version of the device that has been legally placed on the market or put into service; (c) the clinical evaluation report and its updates and the clinical evaluation plan referred to in Article 61(12) and Part A of Annex XIV; (d) the PMCF plan and PMCF evaluation report referred to in Part B of Annex XIV or a justification why a PMCF is not applicable. 6.2.   Additional information required in specific cases (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as referred to in the first subparagraph of Article 1(8), a statement indicating this fact. In this case, the documentation shall identify the source of that substance and contain the data of the tests conducted to assess its safety, quality and usefulness, taking account of the intended purpose of the device. (b) Where a device is manufactured utilising tissues or cells of human or animal origin, or their derivatives, and is covered by this Regulation in accordance with points (f) and (g) of Article 1(6, and where a device incorporates, as an integral part, tissues or cells of human origin or their derivatives that have an action ancillary to that of the device and is covered by this Regulation in accordance with the first subparagraph of Article 1(10), a statement indicating this fact. In such a case, the documentation shall identify all materials of human or animal origin used and provide detailed information concerning the conformity with Sections 13.1. or 13.2., respectively, of Annex I. (c) In the case of devices that are composed of substances or combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, detailed information, including test design, complete test or study protocols, methods of data analysis, and data summaries and test conclusions, regarding studies in relation to: — absorption, distribution, metabolism and excretion; — possible interactions of those substances, or of their products of metabolism in the human body, with other devices, medicinal products or other substances, considering the target population, and its associated medical conditions; — local tolerance; and — toxicity, including single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, as applicable depending on the level and nature of exposure to the device. In the absence of such studies, a justification shall be provided. (d) In the case of devices containing CMR or endocrine-disrupting substances referred to in Section 10.4.1 of Annex I, the justification referred to in Section 10.4.2 of that Annex. (e) In the case of devices placed on the market in a sterile or defined microbiological condition, a description of the environmental conditions for the relevant manufacturing steps. In the case of devices placed on the market in a sterile condition, a description of the methods used, including the validation reports, with respect to packaging, sterilisation and maintenance of sterility. The validation report shall address bioburden testing, pyrogen testing and, if applicable, testing for sterilant residues. (f) In the case of devices placed on the market with a measuring function, a description of the methods used in order to ensure the accuracy as given in the specifications. (g) If the device is to be connected to other device(s) in order to operate as intended, a description of this combination/configuration including proof that it conforms to the general safety and performance requirements when connected to any such device(s) having regard to the characteristics specified by the manufacturer. (1)  Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances (OJ L 50, 20.2.2004, p. 44). ANNEX III TECHNICAL DOCUMENTATION ON POST-MARKET SURVEILLANCE The technical documentation on post-market surveillance to be drawn up by the manufacturer in accordance with Articles 83 to 86 shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements described in this Annex. 1.1.   The post-market surveillance plan drawn up in accordance with Article 84. The manufacturer shall prove in a post-market surveillance plan that it complies with the obligation referred to in Article 83. (a) The post-market surveillance plan shall address the collection and utilization of available information, in particular: — information concerning serious incidents, including information from PSURs, and field safety corrective actions; — records referring to non-serious incidents and data on any undesirable side-effects; — information from trend reporting; — relevant specialist or technical literature, databases and/or registers; — information, including feedbacks and complaints, provided by users, distributors and importers; and — publicly available information about similar medical devices. (b) The post-market surveillance plan shall cover at least: — a proactive and systematic process to collect any information referred to in point (a). The process shall allow a correct characterisation of the performance of the devices and shall also allow a comparison to be made between the device and similar products available on the market; — effective and appropriate methods and processes to assess the collected data; — suitable indicators and threshold values that shall be used in the continuous reassessment of the benefit-risk analysis and of the risk management as referred to in Section 3 of Annex I; — effective and appropriate methods and tools to investigate complaints and analyse market-related experience collected in the field; — methods and protocols to manage the events subject to the trend report as provided for in Article 88, including the methods and protocols to be used to establish any statistically significant increase in the frequency or severity of incidents as well as the observation period; — methods and protocols to communicate effectively with competent authorities, notified bodies, economic operators and users; — reference to procedures to fulfil the manufacturers obligations laid down in Articles 83, 84 and 86; — systematic procedures to identify and initiate appropriate measures including corrective actions; — effective tools to trace and identify devices for which corrective actions might be necessary; and — a PMCF plan as referred to in Part B of Annex XIV, or a justification as to why a PMCF is not applicable. 1.2.   The PSUR referred to in Article 86 and the post-market surveillance report referred to in Article 85. ANNEX IV EU DECLARATION OF CONFORMITY The EU declaration of conformity shall contain all of the following information: 1. Name, registered trade name or registered trade mark and, if already issued, SRN as referred to in Article 31 of the manufacturer, and, if applicable, its authorised representative, and the address of their registered place of business where they can be contacted and their location be established; 2. A statement that the EU declaration of conformity is issued under the sole responsibility of the manufacturer; 3. The Basic UDI-DI as referred to in Part C of Annex VI; 4. Product and trade name, product code, catalogue number or other unambiguous reference allowing identification and traceability of the device covered by the EU declaration of conformity, such as a photograph, where appropriate, as well as its intended purpose. Except for the product or trade name, the information allowing identification and traceability may be provided by the Basic UDI-DI referred to in point 3; 5. Risk class of the device in accordance with the rules set out in Annex VIII; 6. A statement that the device that is covered by the present declaration is in conformity with this Regulation and, if applicable, with any other relevant Union legislation that provides for the issuing of an EU declaration of conformity; 7. References to any CS used and in relation to which conformity is declared; 8. Where applicable, the name and identification number of the notified body, a description of the conformity assessment procedure performed and identification of the certificate or certificates issued; 9. Where applicable, additional information; 10. Place and date of issue of the declaration, name and function of the person who signed it as well as an indication for, and on behalf of whom, that person signed, signature. ANNEX V CE MARKING OF CONFORMITY 1. The CE marking shall consist of the initials ‘CE’ taking the following form: 2. If the CE marking is reduced or enlarged, the proportions given in the above graduated drawing shall be respected. 3. The various components of the CE marking shall have substantially the same vertical dimension, which may not be less than 5 mm. This minimum dimension may be waived for small-scale devices. ANNEX VI INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31, CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29, AND THE UDI SYSTEM PART A INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31 Manufacturers or, when applicable, authorised representatives, and, when applicable, importers shall submit the information referred to in Section 1 and shall ensure that the information on their devices referred to in Section 2 is complete, correct and updated by the relevant party. 1.   Information relating to the economic operator 1.1. type of economic operator(manufacturer, authorised representative, or importer), 1.2. name, address and contact details of the economic operator, 1.3. where submission of information is carried out by another person on behalf of any of the economic operators mentioned under Section 1.1, the name, address and contact details of that person, 1.4. name address and contact details of the person or persons responsible for regulatory compliance referred to in Article 15. 2.   Information relating to the device 2.1. Basic UDI-DI, 2.2. type, number and expiry date of the certificate issued by the notified body and the name or identification number of that notified body and the link to the information that appears on the certificate and was entered by the notified body in the electronic system on notified bodies and certificates, 2.3. Member State in which the device is to or has been placed on the market in the Union, 2.4. in the case of class IIa, class IIb or class III devices: Member States where the device is or is to be made available, 2.5. risk class of the device, 2.6. reprocessed single-use device (y/n), 2.7. presence of a substance which, if used separately, may be considered to be a medicinal product and name of that substance, 2.8. presence of a substance which, if used separately, may be considered to be a medicinal product derived from human blood or human plasma and name of this substance, 2.9. presence of tissues or cells of human origin, or their derivatives (y/n), 2.10. presence of tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 (y/n), 2.11. where applicable, the single identification number of the clinical investigation or investigations conducted in relation to the device or a link to the clinical investigation registration in the electronic system on clinical investigations, 2.12. in the case of devices listed in Annex XVI, specification as to whether the intended purpose of the device is other than a medical purpose, 2.13. in the case of devices designed and manufactured by another legal or natural person as referred in Article 10(15), the name, address and contact details of that legal or natural person, 2.14. in the case of class III or implantable devices, the summary of safety and clinical performance, 2.15. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART B CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29 The manufacturer shall provide to the UDI database the UDI-DI and all of the following information relating to the manufacturer and the device: 1. quantity per package configuration, 2. the Basic UDI-DI as referred to in Article 29 and any additional UDI-DIs, 3. the manner in which production of the device is controlled (expiry date or manufacturing date, lot number, serial number), 4. if applicable, the unit of use UDI-DI (where a UDI is not labelled on the device at the level of its unit of use, a ‘unit of use’ DI shall be assigned so as to associate the use of a device with a patient), 5. name and address of the manufacturer (as indicated on the label), 6. the SRN issued in accordance with Article 31(2), 7. if applicable, name and address of the authorised representative (as indicated on the label), 8. the medical device nomenclature code as provided for in Article 26, 9. risk class of the device, 10. if applicable, name or trade name, 11. if applicable, device model, reference, or catalogue number, 12. if applicable, clinical size (including volume, length, gauge, diameter), 13. additional product description (optional), 14. if applicable, storage and/or handling conditions (as indicated on the label or in the instructions for use), 15. if applicable, additional trade names of the device, 16. labelled as a single-use device (y/n), 17. if applicable, the maximum number of reuses, 18. device labelled sterile (y/n), 19. need for sterilisation before use (y/n), 20. containing latex (y/n), 21. where applicable, information labelled in accordance with Section 10.4.5 of Annex I, 22. URL for additional information, such as electronic instructions for use (optional), 23. if applicable, critical warnings or contra-indications, 24. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART C THE UDI SYSTEM 1.   Definitions Automatic identification and data capture (‘AIDC’) AIDC is a technology used to automatically capture data. AIDC technologies include bar codes, smart cards, biometrics and RFID. Basic UDI-DI The Basic UDI-DI is the primary identifier of a device model. It is the DI assigned at the level of the device unit of use. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity. Unit of Use DI The Unit of Use DI serves to associate the use of a device with a patient in instances in which a UDI is not labelled on the individual device at the level of its unit of use, for example in the event of several units of the same device being packaged together. Configurable device A configurable device is a device that consists of several components which can be assembled by the manufacturer in multiple configurations. Those individual components may be devices in themselves. Configurable devices include computed tomography (CT) systems, ultrasound systems, anaesthesia systems, physiological Monitoring systems, radiology information systems (RIS). Configuration Configuration is a combination of items of equipment, as specified by the manufacturer, that operate together as a device to achieve an intended purpose. The combination of items may be modified, adjusted or customized to meet specific needs. Configurations include inter alia: — gantries, tubes, tables, consoles and other items of equipment that can be configured/combined to deliver an intended function in computed tomography. — ventilators, breathing circuits, vaporizers combined to deliver an intended function in anaesthesia. UDI-DI The UDI-DI is a unique numeric or alphanumeric code specific to a model of device and that is also used as the ‘access key’ to information stored in a UDI database. Human Readable Interpretation (‘HRI’) HRI is a legible interpretation of the data characters encoded in the UDI carrier. Packaging levels Packaging levels means the various levels of device packaging that contain a defined quantity of devices, such as a carton or case. UDI-PI The UDI-PI is a numeric or alphanumeric code that identifies the unit of device production. The different types of UDI-PIs include serial number, lot number, software identification and manufacturing or expiry date or both types of date. Radio Frequency Identification RFID RFID is a technology that uses communication through the use of radio waves to exchange data between a reader and an electronic tag attached to an object, for the purpose of identification. Shipping containers A shipping container is a container in relation to which traceability is controlled by a process specific to logistics systems. Unique Device Identifier (‘UDI’) The UDI is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific device on the market. The UDI is comprised of the UDI-DI and the UDI-PI. The word ‘Unique’ does not imply serialisation of individual production units. UDI carrier The UDI carrier is the means of conveying the UDI by using AIDC and, if applicable, its HRI. UDI carriers include, inter alia, ID/linear bar code, 2D/Matrix bar code, RFID. 2.   General requirements 2.1.   The affixing of the UDI is an additional requirement — it does not replace any other marking or labelling requirements laid down in Annex I to this Regulation. 2.2.   The manufacturer shall assign and maintain unique UDIs for its devices. 2.3.   Only the manufacturer may place the UDI on the device or its packaging. 2.4.   Only coding standards provided by issuing entities designated by the Commission pursuant to Article 27(2) may be used. 3.   The UDI 3.1.   A UDI shall be assigned to the device itself or its packaging. Higher levels of packaging shall have their own UDI. 3.2.   Shipping containers shall be exempted from the requirement in Section 3.1. By way of example, a UDI shall not be required on a logistics unit; where a healthcare provider orders multiple devices using the UDI or model number of individual devices and the manufacturer places those devices in a container for shipping or to protect the individually packaged devices, the container (logistics unit) shall not be subject to UDI requirements. 3.3.   The UDI shall contain two parts: a UDI-DI and a UDI-PI. 3.4.   The UDI-DI shall be unique at each level of device packaging. 3.5.   If a lot number, serial number, software identification or expiry date appears on the label, it shall be part of the UDI-PI. If there is also a manufacturing date on the label, it does not need to be included in the UDI-PI. If there is only a manufacturing date on the label, this shall be used as the UDI-PI. 3.6.   Each component that is considered to be a device and is commercially available on its own shall be assigned a separate UDI unless the components are part of a configurable device that is marked with its own UDI. 3.7.   Systems and procedure packs as referred to in Article 22 shall be assigned and bear their own UDI. 3.8.   The manufacturer shall assign the UDI to a device following the relevant coding standard. 3.9.   A new UDI-DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability; in particular, any change of one of the following UDI database data elements shall require a new UDI-DI: (a) name or trade name, (b) device version or model, (c) labelled as single use, (d) packaged sterile, (e) need for sterilization before use, (f) quantity of devices provided in a package, (g) critical warnings or contra-indications: e.g. containing latex or DEHP. 3.10.   Manufacturers that repackage and/or relabel devices, with their own label shall retain a record of the original device manufacturer's UDI. 4.   UDI carrier 4.1.   The UDI carrier (AIDC and HRI representation of the UDI) shall be placed on the label or on the device itself and on all higher levels of device packaging. Higher levels do not include shipping containers. 4.2.   In the event of there being significant space constraints on the unit of use packaging, the UDI carrier may be placed on the next higher packaging level. 4.3.   For single-use devices of classes I and IIa packaged and labelled individually, the UDI carrier shall not be required to appear on the packaging but it shall appear on a higher level of packaging, e.g. a carton containing several individually packaged devices. However, when the healthcare provider is not expected to have access, in cases such as in home healthcare settings, to the higher level of device packaging, the UDI shall be placed on the packaging of the individual device. 4.4.   For devices exclusively intended for retail point of sale the UDI-PIs in AIDC shall not be required to appear on the point of sale packaging. 4.5.   When AIDC carriers other than the UDI carrier are part of the product labelling, the UDI carrier shall be readily identifiable. 4.6.   If linear bar codes are used, the UDI-DI and UDI-PI may be concatenated or non-concatenated in two or more bar codes. All parts and elements of the linear bar code shall be distinguishable and identifiable. 4.7.   If there are significant constraints limiting the use of both AIDC and HRI on the label, only the AIDC format shall be required to appear on the label. For devices intended to be used outside healthcare facilities, such as devices for home care, the HRI shall however appear on the label even if this results in there being no space for the AIDC. 4.8.   The HRI format shall follow the rules of the UDI code-issuing entity. 4.9.   If the manufacturer is using RFID technology, a linear or 2D bar code in line with the standard provided by the issuing entities shall also be provided on the label. 4.10.   Devices that are reusable shall bear a UDI carrier on the device itself. The UDI carrier for reusable devices that require cleaning, disinfection, sterilisation or refurbishing between patient uses shall be permanent and readable after each process performed to make the device ready for the subsequent use throughout the intended lifetime of the device. The requirement of this Section shall not apply to devices in the following circumstances: (a) any type of direct marking would interfere with the safety or performance of the device; (b) the device cannot be directly marked because it is not technologically feasible. 4.11.   The UDI carrier shall be readable during normal use and throughout the intended lifetime of the device. 4.12.   If the UDI carrier is readily readable or, in the case of AIDC, scannable, through the device's packaging, the placing of the UDI carrier on the packaging shall not be required. 4.13.   In the case of single finished devices made up of multiple parts that must be assembled before their first use, it shall be sufficient to place the UDI carrier on only one part of each device. 4.14.   The UDI carrier shall be placed in a manner such that the AIDC can be accessed during normal operation or storage. 4.15.   Bar code carriers that include both a UDI-DI and a UDI-PI may also include essential data for the device to operate or other data. 5.   General principles of the UDI database 5.1.   The UDI database shall support the use of all core UDI database data elements referred to in Part B of this Annex. 5.2.   Manufacturers shall be responsible for the initial submission and updates of the identifying information and other device data elements in the UDI database. 5.3.   Appropriate methods/procedures for validation of the data provided shall be implemented. 5.4.   Manufacturers shall periodically verify the correctness of all of the data relevant to devices they have placed on the market, except for devices that are no longer available on the market. 5.5.   The presence of the device UDI-DI in the UDI database shall not be assumed to mean that the device is in conformity with this Regulation. 5.6.   The database shall allow for the linking of all the packaging levels of the device. 5.7.   The data for new UDI-DIs shall be available at the time the device is placed on the market. 5.8.   Manufacturers shall update the relevant UDI database record within 30 days of a change being made to an element, which does not require a new UDI-DI. 5.9.   Internationally-accepted standards for data submission and updates shall, wherever possible, be used by the UDI database. 5.10.   The user interface of the UDI database shall be available in all official languages of the Union. The use of free-text fields shall, however, be minimized in order to reduce translations. 5.11.   Data relating to devices that are no longer available on the market shall be retained in the UDI database. 6.   Rules for specific device types 6.1.   Implantable devices: 6.1.1. Implantable devices shall, at their lowest level of packaging (‘unit packs’), be identified, or marked using AIDC, with a UDI (UDI-DI + UDI-PI); 6.1.2. The UDI-PI shall have at least the following characteristics: (a) the serial number for active implantable devices, (b) the serial number or lot number for other implantable devices. 6.1.3. The UDI of the implantable device shall be identifiable prior to implantation. 6.2.   Reusable devices requiring cleaning, disinfection, sterilisation or refurbishing between uses 6.2.1.   The UDI of such devices shall be placed on the device and be readable after each procedure to make the device ready for the next use. 6.2.2.   The UDI-PI characteristics such as the lot or serial number shall be defined by the manufacturer. 6.3.   Systems and procedure packs as referred to in Article 22 6.3.1.   The natural or legal person referred to in Article 22 shall be responsible for identifying the system or procedure pack with a UDI including both UDI-DI and UDI-PI. 6.3.2.   Device contents of system or procedure packs shall bear a UDI carrier on their packaging or on the device itself. Exemptions: (a) individual single-use disposable devices, the uses of which are generally known to the persons by whom they are intended to be used, which are contained within a system or procedure pack, and which are not intended for individual use outside the context of the system or procedure pack, shall not be required to bear their own UDI carrier; (b) devices that are exempted from bearing a UDI carrier on the relevant level of packaging shall not be required to bear a UDI carrier when included within a system or procedure pack. 6.3.3.   Placement of the UDI carrier on systems or procedure packs (a) The system or procedure pack UDI carrier shall as a general rule be affixed to the outside of the packaging. (b) The UDI carrier shall be readable, or, in the case of AIDC, scannable, whether placed on the outside of the packaging of the system or procedure pack or inside transparent packaging. 6.4.   Configurable devices: 6.4.1.   A UDI shall be assigned to the configurable device in its entirety and shall be called the configurable device UDI. 6.4.2.   The configurable device UDI-DI shall be assigned to groups of configurations, not per configuration within the group. A group of configurations is defined as the collection of possible configurations for a given device as described in the technical documentation. 6.4.3.   A configurable device UDI-PI shall be assigned to each individual configurable device. 6.4.4.   The carrier of the configurable device UDI shall be placed on the assembly that is most unlikely to be exchanged during the lifetime of the system and shall be identified as the configurable device UDI. 6.4.5.   Each component that is considered a device and is commercially available on its own shall be assigned a separate UDI. 6.5.   Device Software 6.5.1.   UDI assignment Criteria The UDI shall be assigned at the system level of the software. Only software which is commercially available on its own and software which constitutes a device in itself shall be subject to that requirement. The software identification shall be considered to be the manufacturing control mechanism and shall be displayed in the UDI-PI. 6.5.2.   A new UDI-DI shall be required whenever there is a modification that changes: (a) the original performance; (b) the safety or the intended use of the software; (c) interpretation of data. Such modifications include new or modified algorithms, database structures, operating platform, architecture or new user interfaces or new channels for interoperability. 6.5.3.   Minor software revisions shall require a new UDI-PI and not a new UDI-DI. Minor software revisions are generally associated with bug fixes, usability enhancements that are not for safety purposes, security patches or operating efficiency. Minor software revisions shall be identified by a manufacturer-specific form of identification. 6.5.4.   UDI placement criteria for software (a) where the software is delivered on a physical medium, e.g. CD or DVD, each packaging level shall bear the human readable and AIDC representation of the complete UDI. The UDI that is applied to the physical medium containing the software and its packaging shall be identical to the UDI assigned to the system level software; (b) the UDI shall be provided on a readily accessible screen for the user in an easily-readable plain-text format, such as an ‘about’ file, or included on the start-up screen; (c) software lacking a user interface such as middleware for image conversion, shall be capable of transmitting the UDI through an application programming interface (API); (d) only the human readable portion of the UDI shall be required in electronic displays of the software. The marking of UDI using AIDC shall not be required in the electronic displays, such as ‘about’ menu, splash screen etc.; (e) the human readable format of the UDI for the software shall include the Application Identifiers (AI) for the standard used by the issuing entities, so as to assist the user in identifying the UDI and determining which standard is being used to create the UDI. ANNEX VII REQUIREMENTS TO BE MET BY NOTIFIED BODIES 1.   ORGANISATIONAL AND GENERAL REQUIREMENTS 1.1.   Legal status and organisational structure 1.1.1.   Each notified body shall be established under the national law of a Member State, or under the law of a third country with which the Union has concluded an agreement in this respect. Its legal personality and status shall be fully documented. Such documentation shall include information about ownership and the legal or natural persons exercising control over the notified body. 1.1.2.   If the notified body is a legal entity that is part of a larger organisation, the activities of that organisation as well as its organisational structure and governance, and the relationship with the notified body shall be clearly documented. In such cases, the requirements of Section 1.2 are applicable to both the notified body and the organisation to which it belongs. 1.1.3.   If a notified body wholly or partly owns legal entities established in a Member State or in a third country or is owned by another legal entity, the activities and responsibilities of those entities, as well as their legal and operational relationships with the notified body, shall be clearly defined and documented. Personnel of those entities performing conformity assessment activities under this Regulation shall be subject to the applicable requirements of this Regulation. 1.1.4.   The organisational structure, allocation of responsibilities, reporting lines and operation of the notified body shall be such that they ensure that there is confidence in the performance by the notified body and in the results of the conformity assessment activities it conducts. 1.1.5.   The notified body shall clearly document its organisational structure and the functions, responsibilities and authority of its top-level management and of other personnel who may have an influence upon the performance by the notified body and upon the results of its conformity assessment activities. 1.1.6.   The notified body shall identify the persons in top-level management that have overall authority and responsibility for each of the following: — the provision of adequate resources for conformity assessment activities; — the development of procedures and policies for the operation of the notified body; — the supervision of implementation of the procedures, policies and quality management systems of the notified body; — the supervision of the notified body's finances; — the activities and decisions taken by the notified body, including contractual agreements; — the delegation of authority to personnel and/or committees, where necessary, for the performance of defined activities; — the interaction with the authority responsible for notified bodies and the obligations regarding communications with other competent authorities, the Commission and other notified bodies. 1.2.   Independence and impartiality 1.2.1.   The notified body shall be a third-party body that is independent of the manufacturer of the device in relation to which it performs conformity assessment activities. The notified body shall also be independent of any other economic operator having an interest in the device as well as of any competitors of the manufacturer. This does not preclude the notified body from carrying out conformity assessment activities for competing manufacturers. 1.2.2.   The notified body shall be organised and operated so as to safeguard the independence, objectivity and impartiality of its activities. The notified body shall document and implement a structure and procedures for safeguarding impartiality and for promoting and applying the principles of impartiality throughout its organisation, personnel and assessment activities. Such procedures shall provide for the identification, investigation and resolution of any case in which a conflict of interest may arise, including involvement in consultancy services in the field of devices prior to taking up employment with the notified body. The investigation, outcome and its resolution shall be documented. 1.2.3.   The notified body, its top-level management and the personnel responsible for carrying out the conformity assessment tasks shall not: (a) be the designer, manufacturer, supplier, installer, purchaser, owner or maintainer of devices which they assess, nor the authorised representative of any of those parties. Such restriction shall not preclude the purchase and use of assessed devices that are necessary for the operations of the notified body and the conduct of the conformity assessment, or the use of such devices for personal purposes; (b) be involved in the design, manufacture or construction, marketing, installation and use, or maintenance of the devices for which they are designated, nor represent the parties engaged in those activities; (c) engage in any activity that may conflict with their independence of judgement or integrity in relation to conformity assessment activities for which they are designated; (d) offer or provide any service which may jeopardise the confidence in their independence, impartiality or objectivity. In particular, they shall not offer or provide consultancy services to the manufacturer, its authorised representative, a supplier or a commercial competitor as regards the design, construction, marketing or maintenance of devices or processes under assessment, and (e) be linked to any organisation which itself provides consultancy services as referred to in point (d). Such restriction does not preclude general training activities that are not client specific and that relate to regulation of devices or to related standards. 1.2.4.   Involvement in consultancy services in the field of devices prior to taking up employment with a notified body shall be fully documented at the time of employment and potential conflicts of interest shall be monitored and resolved in accordance with this Annex. Personnel who were formerly employed by a specific client, or provided consultancy services in the field of devices to that specific client prior to taking up employment with a notified body, shall not be assigned for conformity assessment activities for that specific client or companies belonging to the same group for a period of three years. 1.2.5.   The impartiality of notified bodies, of their top-level management and of the assessment personnel shall be guaranteed. The level of the remuneration of the top-level management and assessment personnel of a notified body and subcontractors, involved in assessment activities shall not depend on the results of the assessments. Notified bodies shall make publicly available the declarations of interest of their top-level management. 1.2.6.   If a notified body is owned by a public entity or institution, independence and absence of any conflict of interest shall be ensured and documented between, on the one hand, the authority responsible for notified bodies and/or the competent authority and, on the other hand, the notified body. 1.2.7.   The notified body shall ensure and document that the activities of its subsidiaries or subcontractors, or of any associated body, including the activities of its owners do not affect its independence, impartiality or the objectivity of its conformity assessment activities. 1.2.8.   The notified body shall operate in accordance with a set of consistent, fair and reasonable terms and conditions, taking into account the interests of small and medium-sized enterprises as defined in Recommendation 2003/361/EC in relation to fees. 1.2.9.   The requirements laid down in this Section in no way preclude exchanges of technical information and regulatory guidance between a notified body and a manufacturer applying for conformity assessment. 1.3.   Confidentiality 1.3.1.   The notified body shall have documented procedures in place ensuring that its personnel, committees, subsidiaries, subcontractors, and any associated body or personnel of external bodies respect the confidentiality of the information which comes into its possession during the performance of conformity assessment activities, except when disclosure is required by law. 1.3.2.   The personnel of a notified body shall observe professional secrecy in carrying out their tasks under this Regulation or any provision of national law giving effect to it, except in relation to the authorities responsible for notified bodies, competent authorities for medical devices in the Member States or the Commission. Proprietary rights shall be protected. The notified body shall have documented procedures in place in respect of the requirements of this Section. 1.4.   Liability 1.4.1.   The notified body shall take out appropriate liability insurance for its conformity assessment activities, unless liability is assumed by the Member State in question in accordance with national law or that Member State is directly responsible for the conformity assessment. 1.4.2.   The scope and overall financial value of the liability insurance shall correspond to the level and geographic scope of activities of the notified body and be commensurate with the risk profile of the devices certified by the notified body. The liability insurance shall cover cases where the notified body may be obliged to withdraw, restrict or suspend certificates. 1.5.   Financial requirements The notified body shall have at its disposal the financial resources required to conduct its conformity assessment activities within its scope of designation and related business operations. It shall document and provide evidence of its financial capacity and its long-term economic viability, taking into account, where relevant, any specific circumstances during an initial start-up phase. 1.6.   Participation in coordination activities 1.6.1.   The notified body shall participate in, or ensure that its assessment personnel is informed of, any relevant standardisation activities and in the activities of the notified body coordination group referred to in Article 49 and that its assessment and decision-making personnel are informed of all relevant legislation, guidance and best practice documents adopted in the framework of this Regulation. 1.6.2.   The notified body shall take into consideration guidance and best practice documents. 2.   QUALITY MANAGEMENT REQUIREMENTS 2.1.   The notified body shall establish, document, implement, maintain and operate a quality management system that is appropriate to the nature, area and scale of its conformity assessment activities and is capable of supporting and demonstrating the consistent fulfilment of the requirements of this Regulation. 2.2.   The quality management system of the notified body shall address at least the following: — management system structure and documentation, including policies and objectives for its activities; — policies for assignment of activities and responsibilities to personnel; — assessment and decision-making processes in accordance with the tasks, responsibilities and role of the notified body's personnel and top-level management; — the planning, conduct, evaluation and, if necessary, adaptation of its conformity assessment procedures; — control of documents; — control of records; — management reviews; — internal audits; — corrective and preventive actions; — complaints and appeals; and — continuous training. Where documents are used in various languages, the notified body shall ensure and control that they have the same content. 2.3.   The top-level management of the notified body shall ensure that the quality management system is fully understood, implemented and maintained throughout the notified body organisation including subsidiaries and subcontractors involved in conformity assessment activities pursuant to this Regulation. 2.4.   The notified body shall require all personnel to formally commit themselves by a signature or equivalent to comply with the procedures defined by the notified body. That commitment shall cover aspects relating to confidentiality and to independence from commercial and other interests, and any existing or prior association with clients. The personnel shall be required to complete written statements indicating their compliance with confidentiality, independence and impartiality principles. 3.   RESOURCE REQUIREMENTS 3.1.   General 3.1.1.   Notified bodies shall be capable of carrying out all the tasks falling to them under this Regulation with the highest degree of professional integrity and the requisite competence in the specific field, whether those tasks are carried out by notified bodies themselves or on their behalf and under their responsibility. In particular, notified bodies shall have the necessary personnel and possess or have access to all equipment, facilities and competence needed to perform properly the technical, scientific and administrative tasks entailed in the conformity assessment activities in relation to which they have been designated. Such requirement presupposes at all times and for each conformity assessment procedure and each type of devices in relation to which they have been designated, that the notified body has permanent availability of sufficient administrative, technical and scientific personnel who possess experience and knowledge relating to the relevant devices and the corresponding technologies. Such personnel shall be in sufficient numbers to ensure that the notified body in question can perform the conformity assessment tasks, including the assessment of the medical functionality, clinical evaluations and the performance and safety of devices, for which it has been designated, having regard to the requirements of this Regulation, in particular, those set out in Annex I. A notified body's cumulative competences shall be such as to enable it to assess the types of devices for which it is designated. The notified body shall have sufficient internal competence to critically evaluate assessments conducted by external expertise. Tasks which a notified body is precluded from subcontracting are set out in Section 4.1. Personnel involved in the management of the operation of a notified body's conformity assessment activities for devices shall have appropriate knowledge to set up and operate a system for the selection of assessment and verification staff, for verification of their competence, for authorisation and allocation of their tasks, for organisation of their initial and ongoing training and for the assignment of their duties and the monitoring of those staff, in order to ensure that personnel who carry out and perform assessment and verification operations are competent to fulfil the tasks required of them. The notified body shall identify at least one individual within its top-level management as having overall responsibility for all conformity assessment activities in relation to devices. 3.1.2.   The notified body shall ensure that personnel involved in conformity assessment activities maintain their qualification and expertise by implementing a system for exchange of experience and a continuous training and education programme. 3.1.3.   The notified body shall clearly document the extent and limits of duties and responsibilities and the level of authorisation of the personnel, including any subcontractors and external experts, involved in conformity assessment activities and inform those personnel accordingly. 3.2.   Qualification criteria in relation to personnel 3.2.1.   The Notified Body shall establish and document qualification criteria and procedures for selection and authorisation of persons involved in conformity assessment activities, including as regards knowledge, experience and other competence required, and the required initial and ongoing training. The qualification criteria shall address the various functions within the conformity assessment process, such as auditing, product evaluation or testing, technical documentation review and decision-making, as well as the devices, technologies and areas, such as biocompatibility, sterilisation, tissues and cells of human and animal origin and clinical evaluation, covered by the scope of designation. 3.2.2.   The qualification criteria referred to in Section 3.2.1 shall refer to the scope of a notified body's designation in accordance with the scope description used by the Member State for the notification referred to in Article 42(3), providing a sufficient level of detail for the required qualification within the subdivisions of the scope description. Specific qualification criteria shall be defined at least for the assessment of: — the pre-clinical evaluation, — clinical evaluation, — tissues and cells of human and animal origin, — functional safety, — software, — packaging, — devices that incorporate as an integral part a medicinal product, — devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body and — the different types of sterilisation processes. 3.2.3.   The personnel responsible for establishing qualification criteria and for authorising other personnel to perform specific conformity assessment activities shall be employed by the notified body itself and shall not be external experts or subcontracted. They shall have proven knowledge and experience in all of the following: — Union devices legislation and relevant guidance documents; — the conformity assessment procedures provided for in this Regulation; — a broad base of knowledge of device technologies and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualification criteria; — training relevant to personnel involved in conformity assessment activities in relation to devices; — adequate experience in conformity assessments under this Regulation or previously applicable law within a notified body. 3.2.4.   The notified body shall have permanent availability of personnel with relevant clinical expertise and where possible such personnel shall be employed by the notified body itself. Such personnel shall be integrated throughout the notified body's assessment and decision-making process in order to: — identify when specialist input is required for the assessment of the clinical evaluation conducted by the manufacturer and identify appropriately qualified experts; — appropriately train external clinical experts in the relevant requirements of this Regulation, CS, guidance and harmonised standards and ensure that the external clinical experts are fully aware of the context and implications of their assessment and the advice they provide; — be able to review and scientifically challenge the clinical data contained within the clinical evaluation, and any associated clinical investigations, and appropriately guide external clinical experts in the assessment of the clinical evaluation presented by the manufacturer; — be able to scientifically evaluate and, if necessary, challenge the clinical evaluation presented, and the results of the external clinical experts' assessment of the manufacturer's clinical evaluation; — be able to ascertain the comparability and consistency of the assessments of clinical evaluations conducted by clinical experts; — be able to make an assessment of the manufacturer's clinical evaluation and a clinical judgement of the opinion provided by any external expert and make a recommendation to the notified body's decision maker; and — be able to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.5.   The personnel responsible for carrying out product-related reviews (product reviewers), such as technical documentation reviews or type examination, including aspects such as clinical evaluation, biological safety, sterilisation and software validation, shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, e.g. medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the design, manufacture, testing or use of the device or technology to be assessed or related to the scientific aspects to be assessed; — knowledge of device legislation, including the general safety and performance requirements set out in Annex I; — appropriate knowledge and experience of relevant harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge and experience of clinical evaluation; — appropriate knowledge of the devices which they are assessing; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those assessments; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.6.   The personnel responsible for carrying out audits of the manufacturer's quality management system (site auditors) shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, such as medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the area of quality management; — appropriate knowledge of devices legislation as well as related harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge of quality management systems and related standards and guidance documents; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those audits; — training in auditing techniques enabling them to challenge quality management systems; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.7.   The personnel with overall responsibility for final reviews and decision-making on certification shall be employed by the notified body itself and shall not be external experts or be subcontracted. Those personnel shall, as a group, have proven knowledge and comprehensive experience of all of the following: — devices legislation and relevant guidance documents; — the device conformity assessments relevant to this Regulation; — the types of qualifications, experience and expertise relevant to device conformity assessment; — a broad base of knowledge of device technologies, including sufficient experience of conformity assessment of devices being reviewed for certification, the device industry and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualifications for personnel involved; — the ability to draw up records and reports demonstrating that the conformity assessment activities have been appropriately carried out. 3.3.   Documentation of qualification, training and authorisation of personnel 3.3.1.   The notified body shall have a procedure in place to fully document the qualification of each member of personnel involved in conformity assessment activities and the satisfaction of the qualification criteria referred to in Section 3.2. Where in exceptional circumstances the fulfilment of the qualification criteria set out in Section 3.2. cannot be fully demonstrated, the notified body shall justify to the authority responsible for notified bodies the authorisation of those members of personnel to carry out specific conformity assessment activities. 3.3.2.   For all of its personnel referred to in Sections 3.2.3 to 3.2.7, the notified body shall establish and maintain up to date: — a matrix detailing the authorisations and responsibilities of the personnel in respect of conformity assessment activities; and — records attesting to the required knowledge and experience for the conformity assessment activity for which they are authorised. The records shall contain a rationale for defining the scope of the responsibilities for each of the assessment personnel and records of the conformity assessment activities carried out by each of them. 3.4.   Subcontractors and external experts 3.4.1.   Notified bodies may, without prejudice to Section 3.2, subcontract certain clearly defined component parts of a conformity assessment activity. The subcontracting of the auditing of quality management systems or of product related reviews as a whole shall not be permitted; nevertheless parts of those activities may be conducted by subcontractors and external auditors and experts working on behalf of the notified body. The notified body in question shall retain full responsibility for being able to produce appropriate evidence of the competence of subcontractors and experts to fulfil their specific tasks, for making a decision based on a subcontractor's assessment and for the work conducted by subcontractors and experts on its behalf. The following activities may not be subcontracted by notified bodies: — review of the qualifications and monitoring of the performance of external experts; — auditing and certification activities where the subcontracting in question is to auditing or certification organisations; — allocation of work to external experts for specific conformity assessment activities; and — final review and decision making functions. 3.4.2.   Where a notified body subcontracts certain conformity assessment activities either to an organisation or an individual, it shall have a policy describing the conditions under which subcontracting may take place, and shall ensure that: — the subcontractor meets the relevant requirements of this Annex; — subcontractors and external experts do not further subcontract work to organisations or personnel; and — the natural or legal person that applied for conformity assessment has been informed of the requirements referred to in the first and second indent. Any subcontracting or consultation of external personnel shall be properly documented, shall not involve any intermediaries and shall be subject to a written agreement covering, among other things, confidentiality and conflicts of interest. The notified body in question shall take full responsibility for the tasks performed by subcontractors. 3.4.3.   Where subcontractors or external experts are used in the context of a conformity assessment, in particular regarding novel, invasive and implantable devices or technologies, the notified body in question shall have internal competence in each product area for which it is designated that is adequate for the purpose of leading the overall conformity assessment, verifying the appropriateness and validity of expert opinions and making decisions on certification. 3.5.   Monitoring of competences, training and exchange of experience 3.5.1.   The notified body shall establish procedures for the initial evaluation and on-going monitoring of the competence, conformity assessment activities and performance of all internal and external personnel, and subcontractors, involved in conformity assessment activities. 3.5.2.   Notified bodies shall review at regular intervals, the competence of their personnel, identify training needs and draw up a training plan to maintain the required level of qualification and knowledge of individual personnel. That review shall at a minimum, verify that personnel: — are aware of Union and national law in force on devices, relevant harmonised standards, CS, guidance documents and the results of the coordination activities referred to in Section 1.6; and — take part in the internal exchange of experience and the continuous training and education programme referred to in Section 3.1.2. 4.   PROCESS REQUIREMENTS 4.1.   General The notified body shall have in place documented processes and sufficiently detailed procedures for the conduct of each conformity assessment activity for which it is designated, comprising the individual steps from pre-application activities up to decision making and surveillance and taking into account, when necessary, the respective specificities of the devices. The requirements laid down in Sections 4.3, 4.4, 4.7 and 4.8 shall be fulfilled as part of the internal activities of notified bodies and shall not be subcontracted. 4.2.   Notified body quotations and pre-application activities The notified body shall: (a) publish a publicly available description of the application procedure by which manufacturers can obtain certification from it. That description shall include which languages are acceptable for submission of documentation and for any related correspondence; (b) have documented procedures relating to, and documented details about, fees charged for specific conformity assessment activities and any other financial conditions relating to notified bodies' assessment activities for devices; (c) have documented procedures in relation to advertising of their conformity assessment services. Those procedures shall ensure that advertising or promotional activities in no way imply or are capable of leading to an inference that their conformity assessment will offer manufacturers earlier market access or be quicker, easier or less stringent than that of other notified bodies; (d) have documented procedures requiring the review of pre-application information, including the preliminary verification that the product is covered by this Regulation and its classification, prior to issuing any quotation to the manufacturer relating to a specific conformity assessment; and (e) ensure that all contracts relating to the conformity assessment activities covered by this Regulation are concluded directly between the manufacturer and the notified body and not with any other organisation. 4.3.   Application review and contract The notified body shall require a formal application signed by a manufacturer or an authorised representative containing all of the information and the manufacturer's declarations required by the relevant conformity assessment as referred to in Annexes IX to XI. The contract between a notified body and a manufacturer shall take the form of a written agreement signed by both parties. It shall be kept by the notified body. This contract shall have clear terms and conditions and contain obligations that enable the notified body to act as required under this Regulation, including an obligation on the manufacturer to inform the notified body of vigilance reports, the right of the notified body to suspend, restrict or withdraw certificates issued and the duty of the notified body to fulfil its information obligations. The notified body shall have documented procedures to review applications, addressing: (a) the completeness of those applications with respect to the requirements of the relevant conformity assessment procedure, as referred to in the corresponding Annex, under which approval has been sought, (b) the verification of the qualification of products covered by those applications as devices and their respective classifications, (c) whether the conformity assessment procedures chosen by the applicant are applicable to the device in question under this Regulation, (d) the ability of the notified body to assess the application based on its designation, and (e) the availability of sufficient and appropriate resources. The outcome of each review of an application shall be documented. Refusals or withdrawals of applications shall be notified to the electronic system referred to in Article 57 and shall be accessible to other notified bodies. 4.4.   Allocation of resources The notified body shall have documented procedures to ensure that all conformity assessment activities are conducted by appropriately authorised and qualified personnel who are sufficiently experienced in the evaluation of the devices, systems and processes and related documentation that are subject to conformity assessment. For each application, the notified body shall determine the resources needed and identify one individual responsible for ensuring that the assessment of that application is conducted in accordance with the relevant procedures and for ensuring that the appropriate resources including personnel are utilised for each of the tasks of the assessment. The allocation of tasks required to be carried out as part of the conformity assessment and any changes subsequently made to this allocation shall be documented. 4.5.   Conformity assessment activities 4.5.1.   General The notified body and its personnel shall carry out the conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific fields. The notified body shall have expertise, facilities and documented procedures that are sufficient to effectively conduct the conformity assessment activities for which the notified body in question is designated, taking account of the relevant requirements set out in Annexes IX to XI, and in particular all of the following requirements: — appropriately plan the conduct of each individual project, — ensure that the composition of the assessment teams is such that there is sufficient experience in relation to the technology concerned, and that there is continuous objectivity and independence, and to provide for rotation of the members of the assessment team at appropriate intervals, — specify the rationale for fixing time limits for completion of conformity assessment activities, — assess the manufacturer's technical documentation and the solutions adopted to meet the requirements laid down in Annex I, — review the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects, — review the manufacturer's procedures and documentation relating to clinical evaluation, — address the interface between the manufacturer's risk management process and its appraisal and analysis of the pre-clinical and clinical evaluation and to evaluate their relevance for the demonstration of conformity with the relevant requirements in Annex I, — carry out the specific procedures referred to in Sections 5.2 to 5.4 of Annex IX, — in the case of class IIa or class IIb devices, assess the technical documentation of devices selected on a representative basis, — plan and periodically carry out appropriate surveillance audits and assessments, carry out or request certain tests to verify the proper functioning of the quality management system and to perform unannounced on site audits, — relating to the sampling of devices, verify that the manufactured device is in conformity with the technical documentation; such requirements shall define the relevant sampling criteria and testing procedure prior to sampling, — evaluate and verify a manufacturer's compliance with relevant Annexes. The notified body shall, where relevant, take into consideration available CS, guidance and best practice documents and harmonised standards, even if the manufacturer does not claim to be in compliance. 4.5.2.   Quality management system auditing (a) As part of the assessment of the quality management system, a notified body shall prior to an audit and in accordance with its documented procedures: — assess the documentation submitted in accordance with the relevant conformity assessment Annex, and draw up an audit programme which clearly identifies the number and sequence of activities required to demonstrate complete coverage of a manufacturer's quality management system and to determine whether it meets the requirements of this Regulation, — identify links between, and allocation of responsibilities among, the various manufacturing sites, and identify relevant suppliers and/or subcontractors of the manufacturer, and consider the need to specifically audit any of those suppliers or subcontractors or both, — clearly define, for each audit identified in the audit programme, the objectives, criteria and scope of the audit, and draw up an audit plan that adequately addresses and takes account of the specific requirements for the devices, technologies and processes involved, — draw up and keep up to date, for class IIa and class IIb devices, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III covering the range of such devices covered by the manufacturer's application. That plan shall ensure that all devices covered by the certificate are sampled over the period of validity of the certificate, and — select and assign appropriately qualified and authorised personnel for conducting the individual audits. The respective roles, responsibilities and authorities of the team members shall be clearly defined and documented. (b) Based on the audit programme it has drawn up, the notified body shall, in accordance with its documented procedures: — audit the manufacturer's quality management system, in order to verify that the quality management system ensures that the devices covered conform to the relevant provisions of this Regulation which apply to devices at every stage, from design through final quality control to ongoing surveillance, and shall determine whether the requirements of this Regulation are met, — based on relevant technical documentation and in order to determine whether the manufacturer meets the requirements referred to in the relevant conformity assessment Annex, review and audit the manufacturer's processes and subsystems, in particular for: — design and development, — production and process controls, — product documentation, — purchasing controls including verification of purchased devices, — corrective and preventive actions, including for post-market surveillance, and — PMCF, and review and audit requirements and provisions adopted by the manufacturer, including those in relation to fulfilling the general safety and performance requirements set out in Annex I. The documentation shall be sampled in such a manner as to reflect the risks associated with the intended use of the device, the complexity of the manufacturing technologies, the range and classes of devices produced and any available post-market surveillance information, — if not already covered by the audit programme, audit the control of processes on the premises of the manufacturer's suppliers, when the conformity of finished devices is significantly influenced by the activity of suppliers and, in particular when the manufacturer cannot demonstrate sufficient control over its suppliers, — conduct assessments of the technical documentation based on its sampling plan and taking account of Sections 4.5.4. and 4.5.5. for pre-clinical and clinical evaluations, and — the notified body shall ensure that audit findings are appropriately and consistently classified in accordance with the requirements of this Regulation and with relevant standards, or with best practice documents developed or adopted by the MDCG. 4.5.3.   Product verification Assessment of the technical documentation For assessment of the technical documentation conducted in accordance with Chapter II of Annex IX, notified bodies shall have sufficient expertise, facilities and documented procedures for: — the allocation of appropriately qualified and authorised personnel for the examination of individual aspects such as use of the device, biocompatibility, clinical evaluation, risk management, and sterilisation, and — the assessment of conformity of the design with this Regulation, and for taking account of Sections 4.5.4. to 4.5.6. That assessment shall include examination of the implementation by manufacturers of incoming, in-process and final checks and the results thereof. If further tests or other evidence is required for the assessment of conformity with the requirements of this Regulation, the notified body in question shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. Type-examinations The notified body shall have documented procedures, sufficient expertise and facilities for the type-examination of devices in accordance with Annex X including the capacity to: — examine and assess the technical documentation taking account of Sections 4.5.4. to 4.5.6., and verify that the type has been manufactured in conformity with that documentation; — establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility; — document its rationale for the selection of those parameters; — carry out the appropriate examinations and tests in order to verify that the solutions adopted by the manufacturer meet the general safety and performance requirements set out in Annex I. Such examinations and tests shall include all tests necessary to verify that the manufacturer has in fact applied the relevant standards it has opted to use; — agree with the applicant as to where the necessary tests will be performed if they are not to be carried out directly by the notified body; and — assume full responsibility for test results. Test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. Verification by examination and testing of every product The notified body shall: (a) have documented procedures, sufficient expertise and facilities for the verification by examination and testing of every product in accordance with Part B of Annex XI; (b) establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility in order to: — verify, for class IIb devices, the conformity of the device with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to those devices, — confirm, for class IIa devices, the conformity with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to those devices; (c) document its rationale for the selection of the parameters referred to in point (b); (d) have documented procedures to carry out the appropriate assessments and tests in order to verify the conformity of the device with the requirements of this Regulation by examining and testing every product as specified in Section 15 of Annex XI; (e) have documented procedures providing for the reaching of an agreement with the applicant concerning when and where necessary tests that are not to be carried out by the notified body itself are to be performed; and (f) assume full responsibility for test results in accordance with documented procedures; test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. 4.5.4.   Pre-clinical evaluation assessment The notified body shall have documented procedures in place for the review of the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects. The notified body shall examine, validate and verify that the manufacturer's procedures and documentation adequately address: (a) the planning, conduct, assessment, reporting and, where appropriate, updating of the pre-clinical evaluation, in particular of — the scientific pre-clinical literature search, and — the pre-clinical testing, for example laboratory testing, simulated use testing, computer modelling, the use of animal models, (b) the nature and duration of body contact and the specific associated biological risks, (c) the interface with the risk management process, and (d) the appraisal and analysis of the available pre-clinical data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I. The notified body's assessment of pre-clinical evaluation procedures and documentation shall address the results of literature searches and all validation, verification and testing performed and conclusions drawn, and shall typically include considering the use of alternative materials and substances and take account of the packaging, stability, including shelf life, of the finished device. Where no new testing has been undertaken by a manufacturer or where there are deviations from procedures, the notified body in question shall critically examine the justification presented by the manufacturer. 4.5.5.   Clinical evaluation assessment The notified body shall have documented procedures in place relating to the assessment of a manufacturer's procedures and documentation relating to clinical evaluation both for initial conformity assessment and on an ongoing basis. The notified body shall examine, validate and verify that manufacturers' procedures and documentation adequately address: — the planning, conduct, assessment, reporting and updating of the clinical evaluation as referred to in Annex XIV, — post-market surveillance and PMCF, — the interface with the risk management process, — the appraisal and analysis of the available data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I, and — the conclusions drawn with regard to the clinical evidence and drawing up of the clinical evaluation report. These procedures referred to in the first paragraph shall take into consideration available CS, guidance and best practice documents. The notified body's assessment of clinical evaluations as referred to in Annex XIV shall cover: — the intended use specified by the manufacturer and claims for the device defined by it, — the planning of the clinical evaluation, — the methodology for the literature search, — relevant documentation from the literature search, — the clinical investigation, — validity of equivalence claimed in relation to other devices, the demonstration of equivalence, the suitability and conclusions data from equivalent and similar devices, — post-market surveillance and PMCF, — the clinical evaluation report, and — justifications in relation to non-performance of clinical investigations or PMCF. In relation to clinical data from clinical investigations included within the clinical evaluation, the notified body in question shall ensure that the conclusions drawn by the manufacturer are valid in the light of the approved clinical investigation plan. The notified body shall ensure that the clinical evaluation adequately addresses the relevant safety and performance requirements provided for in Annex I, that it is appropriately aligned with the risk management requirements, that it is conducted in accordance with Annex XIV and that it is appropriately reflected in the information provided relating to the device. 4.5.6.   Specific Procedures The notified body shall have documented procedures, sufficient expertise and facilities for the procedures referred to in Sections 5 and 6 of Annex IX, Section 6 of Annex X and Section 16 of Annex XI, for which they are designated. In the case of devices manufactured utilising tissues or cells of animal origin or their derivatives, such as from TSE susceptible species, as referred to in Regulation (EU) No 722/2012, the notified body shall have documented procedures in place that fulfil the requirements laid down in that Regulation, including for the preparation of a summary evaluation report for the relevant competent authority. 4.6.   Reporting The notified body shall: — ensure that all steps of the conformity assessment are documented so that the conclusions of the assessment are clear and demonstrate compliance with the requirements of this Regulation and can represent objective evidence of such compliance to persons that are not themselves involved in the assessment, for example personnel in designating authorities, — ensure that records that are sufficient to provide a discernible audit trail are available for quality management system audits, — clearly document the conclusions of its assessment of clinical evaluation in a clinical evaluation assessment report, and — for each specific project, provide a detailed report which shall be based on a standard format containing a minimum set of elements determined by the MDCG. The report of the notified body shall: — clearly document the outcome of its assessment and draw clear conclusions from the verification of the manufacturer's conformity with the requirements of this Regulation, — make a recommendation for a final review and for a final decision to be taken by the notified body; this recommendation shall be signed off by the member of personnel responsible in the notified body, and — be provided to the manufacturer in question. 4.7.   Final review The notified body shall prior to making a final decision: — ensure that the personnel assigned for the final review and decision-making on specific projects are appropriately authorised and are different from the personnel who have conducted the assessments, — verify that the report or reports and supporting documentation needed for decision making, including concerning resolution of non-conformities noted during assessment, are complete and sufficient with respect to the scope of the application, and — verify whether there are any unresolved non-conformities preventing issuance of a certificate. 4.8.   Decisions and Certifications The notified body shall have documented procedures for decision-making including as regards the allocation of responsibilities for the issuance, suspension, restriction and withdrawal of certificates. Those procedures shall include the notification requirements laid down in Chapter V of this Regulation. The procedures shall allow the notified body in question to: — decide, based on the assessment documentation and additional information available, whether the requirements of this Regulation are fulfilled, — decide, based on the results of its assessment of the clinical evaluation and risk management, whether the post-market surveillance plan, including the PMCF plan, is adequate, — decide on specific milestones for further review by the notified body of the up to date clinical evaluation, — decide whether specific conditions or provisions need to be defined for the certification, — decide, based on the novelty, risk classification, clinical evaluation and conclusions from the risk analysis of the device, on a period of certification not exceeding five years, — clearly document decision making and approval steps including approval by signature of the members of personnel responsible, — clearly document responsibilities and mechanisms for communication of decisions, in particular, where the final signatory of a certificate differs from the decision maker or decision makers or does not fulfil the requirements laid down in Section 3.2.7, — issue a certificate or certificates in accordance with the minimum requirements laid down in Annex XII for a period of validity not exceeding five years and shall indicate whether there are specific conditions or limitations associated with the certification, — issue a certificate or certificates for the applicant alone and shall not issue certificates covering multiple entities, and — ensure that the manufacturer is notified of the outcome of the assessment and the resultant decision and that they are entered into the electronic system referred to in Article 57. 4.9.   Changes and modifications The notified body shall have documented procedures and contractual arrangements with manufacturers in place relating to the manufacturers' information obligations and the assessment of changes to: — the approved quality management system or systems or to the product-range covered, — the approved design of a device, — the intended use of or claims made for the device, — the approved type of a device, and — any substance incorporated in or utilised for the manufacturing of a device and being subject to the specific procedures in accordance with Section 4.5.6. The procedures and contractual arrangements referred to in the first paragraph shall include measures for checking the significance of the changes referred to in the first paragraph. In accordance with its documented procedures, the notified body in question shall: — ensure that manufacturers submit for prior approval plans for changes as referred to in the first paragraph and relevant information relating to such changes, — assess the changes proposed and verify whether, after these changes, the quality management system, or the design of a device or type of a device, still meets the requirements of this Regulation, and — notify the manufacturer of its decision and provide a report or as applicable a supplementary report, which shall contain the justified conclusions of its assessment. 4.10.   Surveillance activities and post-certification monitoring The notified body shall have documented procedures: — defining how and when surveillance activities of manufacturers are to be conducted. Those procedures shall include arrangements for unannounced on-site audits of manufacturers and, where applicable, subcontractors and suppliers carrying out product tests and the monitoring of compliance with any conditions binding manufacturers and associated with certification decisions, such as updates to clinical data at defined intervals, — for screening relevant sources of scientific and clinical data and post-market information relating to the scope of their designation. Such information shall be taken into account in the planning and conduct of surveillance activities, and — to review vigilance data to which they have access under Article 92(2) in order to estimate its impact, if any, on the validity of existing certificates. The results of the evaluation and any decisions taken shall be thoroughly documented. The notified body in question shall, upon receipt of information about vigilance cases from a manufacturer or competent authorities, decide which of the following options to apply: — not to take action on the basis that the vigilance case is clearly not related to the certification granted, — observe the manufacturer's and competent authority's activities and the results of the manufacturer's investigation so as to determine whether the certification granted is at risk or whether adequate corrective action has been taken, — perform extraordinary surveillance measures, such as document reviews, short-notice or unannounced audits and product testing, where it is likely that the certification granted is at risk, — increase the frequency of surveillance audits, — review specific products or processes on the occasion of the next audit of the manufacturer, or — take any other relevant measure. In relation to surveillance audits of manufacturers, the notified body shall have documented procedures to: — conduct surveillance audits of the manufacturer on at least an annual basis which shall be planned and conducted in line with the relevant requirements in Section 4.5, — ensure adequate assessment of the manufacturer's documentation on, and application of the provisions on, vigilance, the post-market surveillance, and PMCF, — sample and test devices and technical documentation, during audits, according to pre-defined sampling criteria and testing procedures to ensure that the manufacturer continuously applies the approved quality management system, — ensure that the manufacturer complies with the documentation and information obligations laid down in the relevant Annexes and that its procedures take into account best practices in the implementation of quality management systems, — ensure that the manufacturer does not use quality management system or device approvals in a misleading manner, — gather sufficient information to determine if the quality management system continues to comply with the requirements of this Regulation, — ask the manufacturer, if non-conformities are detected, for corrections, corrective actions and, where applicable, preventive actions, and — where necessary, impose specific restrictions on the relevant certificate, or suspend or withdraw it. The notified body shall, if listed as part of the conditions for certification: — conduct an in-depth review of the clinical evaluation as most recently updated by the manufacturer based on the manufacturer's post-market surveillance, on its PMCF and on clinical literature relevant to the condition being treated with the device or on clinical literature relevant to similar devices, — clearly document the outcome of the in-depth review and address any specific concerns to the manufacturer or impose any specific conditions on it, and — ensure that the clinical evaluation as most recently updated, is appropriately reflected in the instructions for use and, where applicable, the summary of safety and performance. 4.11.   Re-certification The notified body shall have documented procedures in place relating to the re-certification reviews and the renewal of certificates. Re-certification of approved quality management systems or EU technical documentation assessment certificates or EU type-examination certificates shall occur at least every five years. The notified body shall have documented procedures relating to renewals of EU technical documentation assessment certificates and EU type-examination certificates and those procedures shall require the manufacturer in question to submit a summary of changes and scientific findings for the device, including: (a) all changes to the originally approved device, including changes not yet notified, (b) experience gained from post-market surveillance, (c) experience from risk management, (d) experience from updating the proof of compliance with the general safety and performance requirements set out in Annex I, (e) experience from reviews of the clinical evaluation, including the results of any clinical investigations and PMCF, (f) changes to the requirements, to components of the device or to the scientific or regulatory environment, (g) changes to applied or new harmonised standards, CS or equivalent documents, and (h) changes in medical, scientific and technical knowledge, such as: — new treatments, — changes in test methods, — new scientific findings on materials and components, including findings on their biocompatibility, — experience from studies on comparable devices, — data from registers and registries, — experience from clinical investigations with comparable devices. The notified body shall have documented procedures to assess the information referred to in the second paragraph and shall pay particular attention to clinical data from post-market surveillance and PMCF activities undertaken since the previous certification or re-certification, including appropriate updates to manufacturers' clinical evaluation reports. For the decision on re-certification, the notified body in question shall use the same methods and principles as for the initial certification decision. If necessary, separate forms shall be established for re-certification taking into account the steps taken for certification such as application and application review. ANNEX VIII CLASSIFICATION RULES CHAPTER I DEFINITIONS SPECIFIC TO CLASSIFICATION RULES 1.   DURATION OF USE 1.1.    ‘Transient’ means normally intended for continuous use for less than 60 minutes. 1.2.    ‘Short term’ means normally intended for continuous use for between 60 minutes and 30 days. 1.3.    ‘Long term’ means normally intended for continuous use for more than 30 days. 2.   INVASIVE AND ACTIVE DEVICES 2.1.    ‘Body orifice’ means any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma. 2.2.    ‘Surgically invasive device’ means: (a) an invasive device which penetrates inside the body through the surface of the body, including through mucous membranes of body orifices with the aid or in the context of a surgical operation; and (b) a device which produces penetration other than through a body orifice. 2.3.    ‘Reusable surgical instrument’ means an instrument intended for surgical use in cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without a connection to an active device and which is intended by the manufacturer to be reused after appropriate procedures such as cleaning, disinfection and sterilisation have been carried out. 2.4.    ‘Active therapeutic device’ means any active device used, whether alone or in combination with other devices, to support, modify, replace or restore biological functions or structures with a view to treatment or alleviation of an illness, injury or disability. 2.5.    ‘Active device intended for diagnosis and monitoring’ means any active device used, whether alone or in combination with other devices, to supply information for detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities. 2.6.    ‘Central circulatory system’ means the following blood vessels: arteriae pulmonales, aorta ascendens, arcus aortae, aorta descendens to the bifurcatio aortae, arteriae coronariae, arteria carotis communis, arteria carotis externa, arteria carotis interna, arteriae cerebrales, truncus brachiocephalicus, venae cordis, venae pulmonales, vena cava superior and vena cava inferior. 2.7.    ‘Central nervous system’ means the brain, meninges and spinal cord. 2.8.    ‘Injured skin or mucous membrane’ means an area of skin or a mucous membrane presenting a pathological change or change following disease or a wound. CHAPTER II IMPLEMENTING RULES 3.1.   Application of the classification rules shall be governed by the intended purpose of the devices. 3.2.   If the device in question is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. Accessories for a medical device and for a product listed in Annex XVI shall be classified in their own right separately from the device with which they are used. 3.3.   Software, which drives a device or influences the use of a device, shall fall within the same class as the device. If the software is independent of any other device, it shall be classified in its own right. 3.4.   If the device is not intended to be used solely or principally in a specific part of the body, it shall be considered and classified on the basis of the most critical specified use. 3.5.   If several rules, or if, within the same rule, several sub-rules, apply to the same device based on the device's intended purpose, the strictest rule and sub-rule resulting in the higher classification shall apply. 3.6.   In calculating the duration referred to in Section 1, continuous use shall mean: (a) the entire duration of use of the same device without regard to temporary interruption of use during a procedure or temporary removal for purposes such as cleaning or disinfection of the device. Whether the interruption of use or the removal is temporary shall be established in relation to the duration of the use prior to and after the period when the use is interrupted or the device removed; and (b) the accumulated use of a device that is intended by the manufacturer to be replaced immediately with another of the same type. 3.7.   A device is considered to allow direct diagnosis when it provides the diagnosis of the disease or condition in question by itself or when it provides decisive information for the diagnosis. CHAPTER III CLASSIFICATION RULES 4.   NON-INVASIVE DEVICES 4.1.   Rule 1 All non-invasive devices are classified as class I, unless one of the rules set out hereinafter applies. 4.2.   Rule 2 All non-invasive devices intended for channelling or storing blood, body liquids, cells or tissues, liquids or gases for the purpose of eventual infusion, administration or introduction into the body are classified as class IIa: — if they may be connected to a class IIa, class IIb or class III active device; or — if they are intended for use for channelling or storing blood or other body liquids or for storing organs, parts of organs or body cells and tissues, except for blood bags; blood bags are classified as class IIb. In all other cases, such devices are classified as class I. 4.3.   Rule 3 All non-invasive devices intended for modifying the biological or chemical composition of human tissues or cells, blood, other body liquids or other liquids intended for implantation or administration into the body are classified as class IIb, unless the treatment for which the device is used consists of filtration, centrifugation or exchanges of gas, heat, in which case they are classified as class IIa. All non-invasive devices consisting of a substance or a mixture of substances intended to be used in vitro in direct contact with human cells, tissues or organs taken from the human body or used in vitro with human embryos before their implantation or administration into the body are classified as class III. 4.4.   Rule 4 All non-invasive devices which come into contact with injured skin or mucous membrane are classified as: — class I if they are intended to be used as a mechanical barrier, for compression or for absorption of exudates; — class IIb if they are intended to be used principally for injuries to skin which have breached the dermis or mucous membrane and can only heal by secondary intent; — class IIa if they are principally intended to manage the micro-environment of injured skin or mucous membrane; and — class IIa in all other cases. This rule applies also to the invasive devices that come into contact with injured mucous membrane. 5.   INVASIVE DEVICES 5.1.   Rule 5 All invasive devices with respect to body orifices, other than surgically invasive devices, which are not intended for connection to an active device or which are intended for connection to a class I active device are classified as: — class I if they are intended for transient use; — class IIa if they are intended for short-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity, in which case they are classified as class I; and — class IIb if they are intended for long-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity and are not liable to be absorbed by the mucous membrane, in which case they are classified as class IIa. All invasive devices with respect to body orifices, other than surgically invasive devices, intended for connection to a class IIa, class IIb or class III active device, are classified as class IIa. 5.2.   Rule 6 All surgically invasive devices intended for transient use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are reusable surgical instruments, in which case they are classified as class I; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionising radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class IIb; or — are intended to administer medicinal products by means of a delivery system, if such administration of a medicinal product is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are classified as class IIb. 5.3.   Rule 7 All surgically invasive devices intended for short-term use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionizing radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class IIb, except if the devices are placed in the teeth; or — are intended to administer medicines, in which case they are classified as class IIb. 5.4.   Rule 8 All implantable devices and long-term surgically invasive devices are classified as class IIb unless they: — are intended to be placed in the teeth, in which case they are classified as class IIa; — are intended to be used in direct contact with the heart, the central circulatory system or the central nervous system, in which case they are classified as class III; — have a biological effect or are wholly or mainly absorbed, in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class III, except if the devices are placed in the teeth; — are intended to administer medicinal products, in which case they are classified as class III; — are active implantable devices or their accessories, in which cases they are classified as class III; — are breast implants or surgical meshes, in which cases they are classified as class III; — are total or partial joint replacements, in which case they are classified as class III, with the exception of ancillary components such as screws, wedges, plates and instruments; or — are spinal disc replacement implants or are implantable devices that come into contact with the spinal column, in which case they are classified as class III with the exception of components such as screws, wedges, plates and instruments. 6.   ACTIVE DEVICES 6.1.   Rule 9 All active therapeutic devices intended to administer or exchange energy are classified as class IIa unless their characteristics are such that they may administer energy to or exchange energy with the human body in a potentially hazardous way, taking account of the nature, the density and site of application of the energy, in which case they are classified as class IIb. All active devices intended to control or monitor the performance of active therapeutic class IIb devices, or intended directly to influence the performance of such devices are classified as class IIb. All active devices intended to emit ionizing radiation for therapeutic purposes, including devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. All active devices that are intended for controlling, monitoring or directly influencing the performance of active implantable devices are classified as class III. 6.2.   Rule 10 Active devices intended for diagnosis and monitoring are classified as class IIa: — if they are intended to supply energy which will be absorbed by the human body, except for devices intended to illuminate the patient's body, in the visible spectrum, in which case they are classified as class I; — if they are intended to image in vivo distribution of radiopharmaceuticals; or — if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for monitoring of vital physiological parameters and the nature of variations of those parameters is such that it could result in immediate danger to the patient, for instance variations in cardiac performance, respiration, activity of the central nervous system, or they are intended for diagnosis in clinical situations where the patient is in immediate danger, in which cases they are classified as class IIb. Active devices intended to emit ionizing radiation and intended for diagnostic or therapeutic radiology, including interventional radiology devices and devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. 6.3.   Rule 11 Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: — death or an irreversible deterioration of a person's state of health, in which case it is in class III; or — a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. 6.4.   Rule 12 All active devices intended to administer and/or remove medicinal products, body liquids or other substances to or from the body are classified as class IIa, unless this is done in a manner that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the mode of application in which case they are classified as class IIb. 6.5.   Rule 13 All other active devices are classified as class I. 7.   SPECIAL RULES 7.1.   Rule 14 All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the devices, are classified as class III. 7.2.   Rule 15 All devices used for contraception or prevention of the transmission of sexually transmitted diseases are classified as class IIb, unless they are implantable or long term invasive devices, in which case they are classified as class III. 7.3.   Rule 16 All devices intended specifically to be used for disinfecting, cleaning, rinsing or, where appropriate, hydrating contact lenses are classified as class IIb. All devices intended specifically to be used for disinfecting or sterilising medical devices are classified as class IIa, unless they are disinfecting solutions or washer-disinfectors intended specifically to be used for disinfecting invasive devices, as the end point of processing, in which case they are classified as class IIb. This rule does not apply to devices that are intended to clean devices other than contact lenses by means of physical action only. 7.4.   Rule 17 Devices specifically intended for recording of diagnostic images generated by X-ray radiation are classified as class IIa. 7.5.   Rule 18 All devices manufactured utilising tissues or cells of human or animal origin, or their derivatives, which are non-viable or rendered non-viable, are classified as class III, unless such devices are manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable and are devices intended to come into contact with intact skin only. 7.6.   Rule 19 All devices incorporating or consisting of nanomaterial are classified as: — class III if they present a high or medium potential for internal exposure; — class IIb if they present a low potential for internal exposure; and — class IIa if they present a negligible potential for internal exposure. 7.7.   Rule 20 All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are classified as class IIa, unless their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or they are intended to treat life-threatening conditions, in which case they are classified as class IIb. 7.8.   Rule 21 Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as: — class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose; — class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body; — class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities; and — class IIb in all other cases. 7.9.   Rule 22 Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. ANNEX IX CONFORMITY ASSESSMENT BASED ON A QUALITY MANAGEMENT SYSTEM AND ON ASSESSMENT OF TECHNICAL DOCUMENTATION CHAPTER I QUALITY MANAGEMENT SYSTEM 1.   The manufacturer shall establish, document and implement a quality management system as described in Article 10(9) and maintain its effectiveness throughout the life cycle of the devices concerned. The manufacturer shall ensure the application of the quality management system as specified in Section 2 and shall be subject to audit, as laid down in Sections 2.3 and 2.4, and to surveillance as specified in Section 3. 2.   Quality management system assessment 2.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — the name of the manufacturer and address of its registered place of business and any additional manufacturing site covered by the quality management system, and, if the manufacturer's application is lodged by its authorised representative, the name of the authorised representative and the address of the authorised representative's registered place of business, — all relevant information on the device or group of devices covered by the quality management system, — a written declaration that no application has been lodged with any other notified body for the same device-related quality management system, or information about any previous application for the same device-related quality management system, — a draft of an EU declaration of conformity in accordance with Article 19 and Annex IV for the device model covered by the conformity assessment procedure, — the documentation on the manufacturer's quality management system, — a documented description of the procedures in place to fulfil the obligations arising from the quality management system and required under this Regulation and the undertaking by the manufacturer in question to apply those procedures, — a description of the procedures in place to ensure that the quality management system remains adequate and effective, and the undertaking by the manufacturer to apply those procedures, — the documentation on the manufacturer's post-market surveillance system and, where applicable, on the PMCF plan, and the procedures put in place to ensure compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, — a description of the procedures in place to keep up to date the post-market surveillance system, and, where applicable, the PMCF plan, and the procedures ensuring compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, as well as the undertaking by the manufacturer to apply those procedures, — documentation on the clinical evaluation plan, and — a description of the procedures in place to keep up to date the clinical evaluation plan, taking into account the state of the art. 2.2.   Implementation of the quality management system shall ensure compliance with this Regulation. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures such as quality programmes, quality plans and quality records. Moreover, the documentation to be submitted for the assessment of the quality management system shall include an adequate description of, in particular: (a) the manufacturer's quality objectives; (b) the organisation of the business and in particular: — the organisational structures with the assignment of staff responsibilities in relation to critical procedures, the responsibilities of the managerial staff and their organisational authority, — the methods of monitoring whether the operation of the quality management system is efficient and in particular the ability of that system to achieve the desired design and device quality, including control of devices which fail to conform, — where the design, manufacture and/or final verification and testing of the devices, or parts of any of those processes, is carried out by another party, the methods of monitoring the efficient operation of the quality management system and in particular the type and extent of control applied to the other party, and — where the manufacturer does not have a registered place of business in a Member State, the draft mandate for the designation of an authorised representative and a letter of intention from the authorised representative to accept the mandate; (c) the procedures and techniques for monitoring, verifying, validating and controlling the design of the devices and the corresponding documentation as well as the data and records arising from those procedures and techniques. Those procedures and techniques shall specifically cover: — the strategy for regulatory compliance, including processes for identification of relevant legal requirements, qualification, classification, handling of equivalence, choice of and compliance with conformity assessment procedures, — identification of applicable general safety and performance requirements and solutions to fulfil those requirements, taking applicable CS and, where opted for, harmonised standards or other adequate solutions into account, — risk management as referred to in Section 3 of Annex I, — the clinical evaluation, pursuant to Article 61 and Annex XIV, including post-market clinical follow-up, — solutions for fulfilling the applicable specific requirements regarding design and construction, including appropriate pre-clinical evaluation, in particular the requirements of Chapter II of Annex I, — solutions for fulfilling the applicable specific requirements regarding the information to be supplied with the device, in particular the requirements of Chapter III of Annex I, — the device identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture, and — management of design or quality management system changes; and (d) the verification and quality assurance techniques at the manufacturing stage and in particular the processes and procedures which are to be used, particularly as regards sterilisation and the relevant documents; and (e) the appropriate tests and trials which are to be carried out before, during and after manufacture, the frequency with which they are to take place, and the test equipment to be used; it shall be possible to trace back adequately the calibration of that test equipment. In addition, the manufacturer shall grant the notified body access to the technical documentation referred to in Annexes II and III. 2.3.   Audit The notified body shall audit the quality management system to determine whether it meets the requirements referred to in Section 2.2. Where the manufacturer uses a harmonised standard or CS related to a quality management system, the notified body shall assess conformity with those standards or CS. The notified body shall assume that a quality management system which satisfies the relevant harmonised standards or CS conforms to the requirements covered by those standards or CS, unless it duly substantiates not doing so. The audit team of the notified body shall include at least one member with past experience of assessments of the technology concerned in accordance with Sections 4.3. to 4.5. of Annex VII. In circumstances where such experience is not immediately obvious or applicable, the notified body shall provide a documented rationale for the composition of that team. The assessment procedure shall include an audit on the manufacturer's premises and, if appropriate, on the premises of the manufacturer's suppliers and/or subcontractors to verify the manufacturing and other relevant processes. Moreover, in the case of class IIa and class IIb devices, the quality management system assessment shall be accompanied by the assessment of technical documentation for devices selected on a representative basis in accordance with Sections 4.4 to 4.8. In choosing representative samples, the notified body shall take into account the published guidance developed by the MDCG pursuant to Article 105 and in particular the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended purpose and the results of any previous relevant assessments such as with regard to physical, chemical, biological or clinical properties, that have been carried out in accordance with this Regulation. The notified body in question shall document its rationale for the samples taken. If the quality management system conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality management system certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. The decision shall contain the conclusions of the audit and a reasoned report. 2.4.   The manufacturer in question shall inform the notified body which approved the quality management system of any plan for substantial changes to the quality management system, or the device-range covered. The notified body shall assess the changes proposed, determine the need for additional audits and verify whether after those changes the quality management system still meets the requirements referred to in Section 2.2. It shall notify the manufacturer of its decision which shall contain the conclusions of the assessment, and where applicable, conclusions of additional audits. The approval of any substantial change to the quality management system or the device-range covered shall take the form of a supplement to the EU quality management system certificate. 3.   Surveillance assessment applicable to class IIa, class IIb and class III devices 3.1.   The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations arising from the approved quality management system. 3.2.   The manufacturer shall give authorisation to the notified body to carry out all the necessary audits, including on-site audits, and supply it with all relevant information, in particular: — the documentation on its quality management system, — documentation on any findings and conclusions resulting from the application of the post-market surveillance plan, including the PMCF plan, for a representative sample of devices, and of the provisions on vigilance set out in Articles 87 to 92, — the data stipulated in the part of the quality management system relating to design, such as the results of analyses, calculations, tests and the solutions adopted regarding the risk-management as referred to in Section 4 of Annex I, and — the data stipulated in the part of the quality management system relating to manufacture, such as quality control reports and test data, calibration data, and records on the qualifications of the personnel concerned. 3.3.   Notified bodies shall periodically, at least once every 12 months, carry out appropriate audits and assessments to make sure that the manufacturer in question applies the approved quality management system and the post-market surveillance plan. Those audits and assessments shall include audits on the premises of the manufacturer and, if appropriate, of the manufacturer's suppliers and/or subcontractors. At the time of such on-site audits, the notified body shall, where necessary, carry out or ask for tests in order to check that the quality management system is working properly. It shall provide the manufacturer with a surveillance audit report and, if a test has been carried out, with a test report. 3.4.   The notified body shall randomly perform at least once every five years unannounced audits on the site of the manufacturer and, where appropriate, of the manufacturer's suppliers and/or subcontractors, which may be combined with the periodic surveillance assessment referred to in Section 3.3. or be performed in addition to that surveillance assessment. The notified body shall establish a plan for such unannounced on-site audits but shall not disclose it to the manufacturer. Within the context of such unannounced on-site audits, the notified body shall test an adequate sample of the devices produced or an adequate sample from the manufacturing process to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to unannounced on-site audits, the notified body shall specify the relevant sampling criteria and testing procedure. Instead of, or in addition to, sampling referred to in the second paragraph, the notified body shall take samples of devices from the market to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to the sampling, the notified body in question shall specify the relevant sampling criteria and testing procedure. The notified body shall provide the manufacturer in question with an on-site audit report which shall include, if applicable, the result of the sample test. 3.5.   In the case of class IIa and class IIb devices, the surveillance assessment shall also include an assessment of the technical documentation as referred to in Sections 4.4 to 4.8 for the device or devices concerned on the basis of further representative samples chosen in accordance with the rationale documented by the notified body in accordance with the second paragraph of Section 2.3. In the case of class III devices, the surveillance assessment shall also include a test of the approved parts and/or materials that are essential for the integrity of the device, including, where appropriate, a check that the quantities of produced or purchased parts and/or materials correspond to the quantities of finished devices. 3.6.   The notified body shall ensure that the composition of the assessment team is such that there is sufficient experience with the evaluation of the devices, systems and processes concerned, continuous objectivity and neutrality; this shall include a rotation of the members of the assessment team at appropriate intervals. As a general rule, a lead auditor shall neither lead nor attend audits for more than three consecutive years in respect of the same manufacturer. 3.7.   If the notified body finds a divergence between the sample taken from the devices produced or from the market and the specifications laid down in the technical documentation or the approved design, it shall suspend or withdraw the relevant certificate or impose restrictions on it. CHAPTER II ASSESSMENT OF THE TECHNICAL DOCUMENTATION 4.   Assessment of the technical documentation applicable to class III devices and to the class IIb devices referred to in the second subparagraph of Article 52(4) 4.1.   In addition to the obligations laid down in Section 2, the manufacturer shall lodge with the notified body an application for assessment of the technical documentation relating to the device which it plans to place on the market or put into service and which is covered by the quality management system referred to in Section 2. 4.2.   The application shall describe the design, manufacture and performance of the device in question. It shall include the technical documentation as referred to in Annexes II and III. 4.3.   The notified body shall examine the application by using staff, employed by it, with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of the Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. 4.4.   The notified body shall review the clinical evidence presented by the manufacturer in the clinical evaluation report and the related clinical evaluation that was conducted. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or the clinical condition in which it is utilised, for the purposes of that review. 4.5.   The notified body shall, in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity. For any characteristic of the device claimed as innovative by the manufacturer or for new indications, the notified body shall assess to what extent specific claims are supported by specific pre-clinical and clinical data and risk analysis. 4.6.   The notified body shall verify that the clinical evidence and the clinical evaluation are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. That verification shall include consideration of the adequacy of the benefit-risk determination, the risk management, the instructions for use, the user training and the manufacturer's post-market surveillance plan, and include a review of the need for, and the adequacy of, the PMCF plan proposed, where applicable. 4.7.   Based on its assessment of the clinical evidence, the notified body shall consider the clinical evaluation and the benefit-risk determination, and whether specific milestones need to be defined to allow the notified body to review updates to the clinical evidence that result from post-market surveillance and PMCF data. 4.8.   The notified body shall clearly document the outcome of its assessment in the clinical evaluation assessment report. 4.9.   The notified body shall provide the manufacturer with a report on the technical documentation assessment, including a clinical evaluation assessment report. If the device conforms to the relevant provisions of this Regulation, the notified body shall issue an EU technical documentation assessment certificate. The certificate shall contain the conclusions of the technical documentation assessment, the conditions of the certificate's validity, the data needed for identification of the approved design, and, where appropriate, a description of the intended purpose of the device. 4.10.   Changes to the approved device shall require approval from the notified body which issued the EU technical documentation assessment certificate where such changes could affect the safety and performance of the device or the conditions prescribed for use of the device. Where the manufacturer plans to introduce any of the above-mentioned changes it shall inform the notified body which issued the EU technical documentation assessment certificate thereof. The notified body shall assess the planned changes and decide whether the planned changes require a new conformity assessment in accordance with Article 52 or whether they could be addressed by means of a supplement to the EU technical documentation assessment certificate. In the latter case, the notified body shall assess the changes, notify the manufacturer of its decision and, where the changes are approved, provide it with a supplement to the EU technical documentation assessment certificate. 5.   Specific additional procedures 5.1.   Assessment procedure for certain class III and class IIb devices (a) For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product as referred to in Section 6.4. of Annex VIII (Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer referred to in Article 61(12), prepare a clinical evaluation assessment report which sets out its conclusions concerning the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication or indications and the PMCF plan referred to in Article 10(3) and Part B of Annex XIV. The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer's clinical evaluation documentation, referred to in points (c) and (d) of Section 6.1 of Annex II, to the Commission. The Commission shall immediately transmit those documents to the relevant expert panel referred to in Article 106. (b) The notified body may be requested to present its conclusions as referred to in point (a) to the expert panel concerned. (c) The expert panel shall decide, under the supervision of the Commission, on the basis of all of the following criteria: (i) the novelty of the device or of the related clinical procedure involved, and the possible major clinical or health impact thereof; (ii) a significantly adverse change in the benefit-risk profile of a specific category or group of devices due to scientifically valid health concerns in respect of components or source material or in respect of the impact on health in the case of failure of the device; (iii) a significantly increased rate of serious incidents reported in accordance with Article 87 in respect of a specific category or group of devices, whether to provide a scientific opinion on the clinical evaluation assessment report of the notified body based on the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the medical indication or indications and the PMCF plan. That scientific opinion shall be provided within a period of 60 days, starting on the day of receipt of the documents from the Commission as referred to in point (a). The reasons for the decision to provide a scientific opinion on the basis of the criteria in points (i), (ii) and (iii) shall be included in the scientific opinion. Where the information submitted is not sufficient for the expert panel to reach a conclusion, this shall be stated in the scientific opinion. (d) The expert panel may decide, under the supervision of the Commission, on the basis of the criteria laid down in point (c) not to provide a scientific opinion, in which case it shall inform the notified body as soon as possible and in any event within 21 days of receipt of the documents as referred to in point (a) from the Commission. The expert panel shall within that time limit provide the notified body and the Commission with the reasons for its decision, whereupon the notified body may proceed with the certification procedure of that device. (e) The expert panel shall within 21 days of receipt of the documents from the Commission notify the Commission, through Eudamed whether it intends to provide a scientific opinion, pursuant to point (c), or whether it intends not to provide a scientific opinion, pursuant to point (d). (f) Where no opinion has been delivered within a period of 60 days, the notified body may proceed with the certification procedure of the device in question. (g) The notified body shall give due consideration to the views expressed in the scientific opinion of the expert panel. Where the expert panel finds that the level of clinical evidence is not sufficient or otherwise gives rise to serious concerns about the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication(s), and with the PMCF plan, the notified body shall, if necessary, advise the manufacturer to restrict the intended purpose of the device to certain groups of patients or certain medical indications and/or to impose a limit on the duration of validity of the certificate, to undertake specific PMCF studies, to adapt the instructions for use or the summary of safety and performance, or to impose other restrictions in its conformity assessment report, as appropriate. The notified body shall provide a full justification where it has not followed the advice of the expert panel in its conformity assessment report and the Commission shall without prejudice to Article 109 make both the scientific opinion of the expert panel and the written justification provided by the notified body publicly available via Eudamed. (h) The Commission, after consultation with the Member States and relevant scientific experts shall provide guidance for expert panels for consistent interpretation of the criteria in point (c) before 26 May 2020. 5.2.   Procedure in the case of devices incorporating a medicinal substance (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (b) Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device. Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA. (c) When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body. (d) The medicinal products authority consulted shall provide its opinion to the notified body within 210 days of receipt of all the necessary documentation. (e) The scientific opinion of the medicinal products authority consulted, and any possible update of that opinion, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision. The notified body shall not deliver the certificate if the scientific opinion is unfavourable and shall convey its final decision to the medicinal products authority consulted. (f) Before any change is made with respect to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the manufacturer shall inform the notified body of the changes. That notified body shall seek the opinion of the medicinal products authority consulted, in order to confirm that the quality and safety of the ancillary substance remain unchanged. The medicinal products authority consulted shall take into account the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The medicinal products authority consulted shall provide its opinion within 60 days after receipt of all the necessary documentation regarding the changes. The notified body shall not deliver the supplement to the EU technical documentation assessment certificate if the scientific opinion provided by the medicinal products authority consulted is unfavourable. The notified body shall convey its final decision to the medicinal products authority consulted. (g) Where the medicinal products authority consulted obtains information on the ancillary substance, which could have an impact on the risk or benefit previously established concerning the incorporation of the substance into the device, it shall advise the notified body as to whether this information has an impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The notified body shall take that advice into account in reconsidering its assessment of the conformity assessment procedure. 5.3.   Procedure in the case of devices manufactured utilising, or incorporating, tissues or cells of human or animal origin, or their derivatives, that are non-viable or rendered non-viable 5.3.1.   Tissues or cells of human origin or their derivatives (a) For devices manufactured utilising derivatives of tissues or cells of human origin that are covered by this Regulation in accordance with point (g) of Article 1(6) and for devices that incorporate, as an integral part, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, that have an action ancillary to that of the device, the notified body shall, prior to issuing an EU technical documentation assessment certificate, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2004/23/EC (‘human tissues and cells competent authority’) on the aspects relating to the donation, procurement and testing of tissues or cells of human origin or their derivatives. The notified body shall submit a summary of the preliminary conformity assessment which provides, among other things, information about the non-viability of the human tissues or cells in question, their donation, procurement and testing and the risk or benefit of the incorporation of the tissues or cells of human origin or their derivatives into the device. (b) Within 120 days of receipt of all the necessary documentation, the human tissues and cells competent authority shall provide to the notified body its opinion. (c) The scientific opinion of the human tissues and cells competent authority, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion of the human tissues and cells competent authority when making its decision. The notified body shall not deliver the certificate if that scientific opinion is unfavourable. It shall convey its final decision to the human tissues and cells competent authority concerned. (d) Before any change is made with respect to non-viable tissues or cells of human origin or their derivatives incorporated in a device, in particular relating to their donation, testing or procurement, the manufacturer shall inform the notified body of the intended changes. The notified body shall consult the authority that was involved in the initial consultation, in order to confirm that the quality and safety of the tissues or cells of human origin or their derivatives incorporated in the device are maintained. The human tissues and cells competent authority concerned shall take into account the data relating to the usefulness of incorporation of the tissues or cells of human origin or their derivatives into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit-risk ratio of the addition of the tissues or cells of human origin or their derivatives in the device. It shall provide its opinion within 60 days of receipt of all the necessary documentation regarding the intended changes. The notified body shall not deliver a supplement to the EU technical documentation assessment certificate if the scientific opinion is unfavourable and shall convey its final decision to the human tissues and cells competent authority concerned. 5.3.2.   Tissues or cells of animal origin or their derivatives In the case of devices manufactured utilising animal tissue which is rendered non-viable or utilising non-viable products derived from animal tissue, as referred to in Regulation (EU) No 722/2012, the notified body shall apply the relevant requirements laid down in that Regulation. 5.4.   Procedure in the case of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body (a) The quality and safety of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by, or locally dispersed in, the human body, shall be verified where applicable and only in respect of the requirements not covered by this Regulation, in accordance with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. (b) In addition, for devices, or their products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, the notified body shall seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the compliance of the device with the relevant requirements laid down in Annex I to Directive 2001/83/EC. (c) The opinion of the medicinal products authority consulted shall be drawn up within 150 days of receipt of all the necessary documentation. (d) The scientific opinion of the medicinal products authority consulted, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision and shall convey its final decision to the medicinal products authority consulted. 6.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in Article 1(8) Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. CHAPTER III ADMINISTRATIVE PROVISIONS 7.   The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 and in particular the data and records arising from the procedures referred to in point (c) of the second paragraph of Section 2.2, — information on the changes referred to in Section 2.4, — the documentation referred to in Section 4.2, and — the decisions and reports from the notified body as referred to in this Annex. 8.   Each Member State shall require that the documentation referred to in Section 7 is kept at the disposal of competent authorities for the period indicated in that Section in case a manufacturer, or its authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of that period. ANNEX X CONFORMITY ASSESSMENT BASED ON TYPE-EXAMINATION 1.   EU type-examination is the procedure whereby a notified body ascertains and certifies that a device, including its technical documentation and relevant life cycle processes and a corresponding representative sample of the device production envisaged, fulfils the relevant provisions of this Regulation. 2.   Application The manufacturer shall lodge an application for assessment with a notified body. The application shall include: — the name of the manufacturer and address of the registered place of business of the manufacturer and, if the application is lodged by the authorised representative, the name of the authorised representative and the address of its registered place of business, — the technical documentation referred to in Annexes II and III. The applicant shall make a representative sample of the device production envisaged (‘type’) available to the notified body. The notified body may request other samples as necessary, and — a written declaration that no application has been lodged with any other notified body for the same type, or information about any previous application for the same type that was refused by another notified body or was withdrawn by the manufacturer or its authorised representative before that other notified body made its final assessment. 3.   Assessment The notified body shall: (a) examine the application by using staff with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of this Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests; (b) examine and assess the technical documentation for conformity with the requirements of this Regulation that are applicable to the device and verify that the type has been manufactured in conformity with that documentation; it shall also record the items designed in conformity with the applicable standards referred to in Article 8 or with applicable CS, and record the items not designed on the basis of the relevant standards referred to in Article 8 or of the relevant CS; (c) review the clinical evidence presented by the manufacturer in the clinical evaluation report in accordance with Section 4 of Annex XIV. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or to the clinical condition in which it is utilised, for the purposes of that review; (d) in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be similar or equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity; (e) clearly document the outcome of its assessment in a pre-clinical and clinical evaluation assessment report as part of the EU type examination report referred to in point (i); (f) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether the solutions adopted by the manufacturer meet the general safety and performance requirements laid down in this Regulation, in the event that the standards referred to in Article 8 or the CS have not been applied. Where the device has to be connected to another device or devices in order to operate as intended, proof shall be provided that it conforms to the general safety and performance requirements when connected to any such device or devices having the characteristics specified by the manufacturer; (g) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether, in the event that the manufacturer has chosen to apply the relevant harmonised standards, those standards have actually been applied; (h) agree with the applicant on the place where the necessary assessments and tests are to be carried out; and (i) draw up an EU type-examination report on the results of the assessments and tests carried out under points (a) to (g). 4.   Certificate If the type conforms to this Regulation, the notified body shall issue an EU type-examination certificate. The certificate shall contain the name and address of the manufacturer, the conclusions of the type examination assessment, the conditions of the certificate's validity and the data needed for identification of the type approved. The certificate shall be drawn up in accordance with Annex XII. The relevant parts of the documentation shall be annexed to the certificate and a copy kept by the notified body. 5.   Changes to the type 5.1.   The applicant shall inform the notified body which issued the EU type-examination certificate of any planned change to the approved type or of its intended purpose and conditions of use. 5.2.   Changes to the approved device including limitations of its intended purpose and conditions of use shall require approval from the notified body which issued the EU type-examination certificate where such changes may affect conformity with the general safety and performance requirements or with the conditions prescribed for use of the product. The notified body shall examine the planned changes, notify the manufacturer of its decision and provide him with a supplement to the EU type-examination report. The approval of any change to the approved type shall take the form of a supplement to the EU type-examination certificate. 5.3.   Changes to the intended purpose and conditions of use of the approved device, with the exception of limitations of the intended purpose and conditions of use, shall necessitate a new application for a conformity assessment. 6.   Specific additional procedures Section 5 of Annex IX shall apply with the proviso that any reference to an EU technical documentation assessment certificate shall be understood as a reference to an EU type-examination certificate. 7.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the documentation referred to in the second indent of Section 2, — information on the changes referred to in Section 5, and — copies of EU type-examination certificates, scientific opinions and reports and their additions/supplements. Section 8 of Annex IX shall apply. ANNEX XI CONFORMITY ASSESSMENT BASED ON PRODUCT CONFORMITY VERIFICATION 1.   The objective of the conformity assessment based on product conformity verification is to ensure that devices conform to the type for which an EU type-examination certificate has been issued, and that they meet the provisions of this Regulation which apply to them. 2.   Where an EU type-examination certificate has been issued in accordance with Annex X, the manufacturer may either apply the procedure set out in Part A (production quality assurance) or the procedure set out in Part B (product verification) of this Annex. 3.   By way of derogation from Sections 1 and 2 above, the procedures in this Annex coupled with the drawing up of technical documentation as set out in Annexes II and III may also be applied by manufacturers of class IIa devices. PART A PRODUCTION QUALITY ASSURANCE 4.   The manufacturer shall ensure that the quality management system approved for the manufacture of the devices concerned is implemented, shall carry out a final verification, as specified in Section 6, and shall be subject to the surveillance referred to in Section 7. 5.   When the manufacturer fulfils the obligations laid down in Section 4, it shall draw up and keep an EU declaration of conformity in accordance with Article 19 and Annex IV for the device covered by the conformity assessment procedure. By issuing an EU declaration of conformity, the manufacturer shall be deemed to ensure and to declare that the device concerned conforms to the type described in the EU type-examination certificate and meets the requirements of this Regulation which apply to the device. 6.   Quality management system 6.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — all elements listed in Section 2.1 of Annex IX, — the technical documentation referred to in Annexes II and III for the types approved, and — a copy of the EU type-examination certificates referred to in Section 4 of Annex X; if the EU type-examination certificates have been issued by the same notified body with which the application is lodged, a reference to the technical documentation and its updates and the certificates issued shall also be included in the application. 6.2.   Implementation of the quality management system shall be such as to ensure that there is compliance with the type described in the EU type-examination certificate and with the provisions of this Regulation which apply to the devices at each stage. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures, such as quality programmes, quality plans and quality records. That documentation shall, in particular, include an adequate description of all elements listed in points (a), (b), (d) and (e) of Section 2.2 of Annex IX. 6.3.   The first and second paragraph of Section 2.3 of Annex IX shall apply. If the quality management system is such that it ensures that the devices conform to the type described in the EU type-examination certificate and that it conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality assurance certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. That decision shall contain the conclusions of the notified body's audit and a reasoned assessment. 6.4.   Section 2.4 of Annex IX shall apply. 7.   Surveillance Section 3.1, the first, second and fourth indents of Section 3.2, Sections 3.3, 3.4, 3.6 and 3.7 of Annex IX shall apply. In the case of class III devices, surveillance shall also include a check that the quantities of produced or purchased raw material or crucial components approved for the type and correspond to the quantities of finished devices. 8.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 9.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 of Annex IX, — the documentation referred to in the eighth indent of Section 2.1 of Annex IX, including the EU type-examination certificate referred to in Annex X, — information on the changes referred to in Section 2.4 of Annex IX, and — the decisions and reports from the notified body as referred to in Sections 2.3, 3.3 and 3.4 of Annex IX. Section 8 of Annex IX shall apply. 10.   Application to class IIa devices 10.1.   By way of derogation from Section 5, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 10.2.   For class IIa devices the notified body shall assess, as part of the assessment referred to in Section 6.3, whether the technical documentation as referred to in Annexes II and III for the devices selected on a representative basis is compliant with this Regulation. In choosing a representative sample or samples of devices, the notified body shall take into account the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended use and the results of any previous relevant assessments (e.g. with regard to physical, chemical, biological or clinical properties) that have been carried out in accordance with this Regulation. The notified body shall document its rationale for the sample or samples of devices taken. 10.3.   Where the assessment under Section 10.2. confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 10.4.   Samples additional to those taken for the initial conformity assessment of devices shall be assessed by the notified body as part of the surveillance assessment referred to in Section 7. 10.5.   By way of derogation from Section 6, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 10.3. Section 8 of Annex IX shall apply. PART B PRODUCT VERIFICATION 11.   Product verification shall be understood to be the procedure whereby after examination of every manufactured device, the manufacturer, by issuing an EU declaration of conformity in accordance with Article 19 and Annex IV, shall be deemed to ensure and to declare that the devices which have been subject to the procedure set out in Sections 14 and 15 conform to the type described in the EU type-examination certificate and meet the requirements of this Regulation which apply to them. 12.   The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which conform to the type described in the EU type-examination certificate and to the requirements of the Regulation which apply to them. Prior to the start of manufacture, the manufacturer shall prepare documents defining the manufacturing process, in particular as regards sterilisation where necessary, together with all routine, pre-established procedures to be implemented to ensure homogeneous production and, where appropriate, conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. In addition, for devices placed on the market in a sterile condition, and only for those aspects of the manufacturing process designed to secure and maintain sterility, the manufacturer shall apply the provisions of Sections 6 and 7. 13.   The manufacturer shall undertake to institute and keep up to date a post-market surveillance plan, including a PMCF plan, and the procedures ensuring compliance with the obligations of the manufacturer resulting from the provisions on vigilance and post-market surveillance system set out in Chapter VII. 14.   The notified body shall carry out the appropriate examinations and tests in order to verify the conformity of the device with the requirements of the Regulation by examining and testing every product as specified in Section 15. The examinations and tests referred to in the first paragraph of this Section shall not apply to aspects of the manufacturing process designed to secure sterility. 15.   Verification by examination and testing of every product 15.1.   Every device shall be examined individually and the appropriate physical or laboratory tests as defined in the relevant standard or standards referred to in Article 8, or equivalent tests and assessments, shall be carried out in order to verify, where appropriate, the conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. 15.2.   The notified body shall affix, or have affixed, its identification number to each approved device and shall draw up an EU product verification certificate relating to the tests and assessments carried out. 16.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 17.   Administrative provisions The manufacturer or its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in Section 12, — the certificate referred to in Section 15.2, and — the EU type-examination certificate referred to in Annex X. Section 8 of Annex IX shall apply. 18.   Application to class IIa devices 18.1.   By way of derogation from Section 11, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 18.2.   The verification conducted by the notified body in accordance with Section 14 is intended to confirm the conformity of the class IIa devices in question with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to them. 18.3.   If the verification referred to in Section 18.2 confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 18.4.   By way of derogation from Section 17, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 18.3. Section 8 of Annex IX shall apply. ANNEX XII CERTIFICATES ISSUED BY A NOTIFIED BODY CHAPTER I GENERAL REQUIREMENTS 1. Certificates shall be drawn up in one of the official languages of the Union. 2. Each certificate shall refer to only one conformity assessment procedure. 3. Certificates shall only be issued to one manufacturer. The name and address of the manufacturer included in the certificate shall be the same as that registered in the electronic system referred to in Article 30. 4. The scope of the certificates shall unambiguously identify the device or devices covered: (a) EU technical documentation assessment certificates, EU type-examination certificates and EU product verification certificates shall include a clear identification, including the name, model and type, of the device or devices, the intended purpose, as included by the manufacturer in the instructions for use and in relation to which the device has been assessed in the conformity assessment procedure, risk classification and the Basic UDI-DI as referred to in Article 27(6); (b) EU quality management system certificates and EU quality assurance certificates shall include the identification of the devices or groups of devices, the risk classification, and, for class IIb devices, the intended purpose. 5. The notified body shall be able to demonstrate on request, which (individual) devices are covered by the certificate. The notified body shall set up a system that enables the determination of the devices, including their classification, covered by the certificate. 6. Certificates shall contain, if applicable, a note that, for the placing on the market of the device or devices it covers, another certificate issued in accordance with this Regulation is required. 7. EU quality management system certificates and EU quality assurance certificates for class I devices for which the involvement of a notified body is required pursuant to Article 52(7) shall include a statement that the audit by the notified body of the quality management system was limited to the aspects required under that paragraph. 8. Where a certificate is supplemented, modified or re-issued, the new certificate shall contain a reference to the preceding certificate and its date of issue with identification of the changes. CHAPTER II MINIMUM CONTENT OF THE CERTIFICATES 1. name, address and identification number of the notified body; 2. name and address of the manufacturer and, if applicable, of the authorised representative; 3. unique number identifying the certificate; 4. if already issued, the SRN of the manufacturer referred to in to Article 31(2); 5. date of issue; 6. date of expiry; 7. data needed for the unambiguous identification of the device or devices where applicable as specified in Section 4 of Part I; 8. if applicable, reference to any previous certificate as specified in Section 8 of Chapter I; 9. reference to this Regulation and the relevant Annex in accordance with which the conformity assessment has been carried out; 10. examinations and tests performed, e.g. reference to relevant CS, harmonised standards, test reports and audit report(s); 11. if applicable, reference to the relevant parts of the technical documentation or other certificates required for the placing on the market of the device or devices covered; 12. if applicable, information about the surveillance by the notified body; 13. conclusions of the notified body's conformity assessment with regard to the relevant Annex; 14. conditions for or limitations to the validity of the certificate; 15. legally binding signature of the notified body in accordance with the applicable national law. ANNEX XIII PROCEDURE FOR CUSTOM-MADE DEVICES 1. For custom-made devices, the manufacturer or its authorised representative shall draw up a statement containing all of the following information: — the name and address of the manufacturer, and of all manufacturing sites, — if applicable, the name and address of the authorised representative, — data allowing identification of the device in question, — a statement that the device is intended for exclusive use by a particular patient or user, identified by name, an acronym or a numerical code, — the name of the person who made out the prescription and who is authorised by national law by virtue of their professional qualifications to do so, and, where applicable, the name of the health institution concerned, — the specific characteristics of the product as indicated by the prescription, — a statement that the device in question conforms to the general safety and performance requirements set out in Annex I and, where applicable, indicating which general safety and performance requirements have not been fully met, together with the grounds, — where applicable, an indication that the device contains or incorporates a medicinal substance, including a human blood or plasma derivative, or tissues or cells of human origin, or of animal origin as referred to in Regulation (EU) No 722/2012. 2. The manufacturer shall undertake to keep available for the competent national authorities documentation that indicates its manufacturing site or sites and allows an understanding to be formed of the design, manufacture and performance of the device, including the expected performance, so as to allow assessment of conformity with the requirements of this Regulation. 3. The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which are manufactured in accordance with the documentation referred to in Section 2. 4. The statement referred to in the introductory part of Section 1 shall be kept for a period of at least 10 years after the device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Section 8 of Annex IX shall apply. 5. The manufacturer shall review and document experience gained in the post-production phase, including from PMCF as referred to in Part B of Annex XIV, and implement appropriate means to apply any necessary corrective action, In that context, it shall report in accordance with Article 87(1) to the competent authorities any serious incidents or field safety corrective actions or both as soon as it learns of them. ANNEX XIV CLINICAL EVALUATION AND POST-MARKET CLINICAL FOLLOW-UP PART A CLINICAL EVALUATION 1.   To plan, continuously conduct and document a clinical evaluation, manufacturers shall: (a) establish and update a clinical evaluation plan, which shall include at least: — an identification of the general safety and performance requirements that require support from relevant clinical data; — a specification of the intended purpose of the device; — a clear specification of intended target groups with clear indications and contra-indications; — a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters; — a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects; — an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device; — an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non-viable animal or human tissues, are to be addressed; and — a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF as referred to in Part B of this Annex with an indication of milestones and a description of potential acceptance criteria; (b) identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review; (c) appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device; (d) generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues; and (e) analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits. 2.   The clinical evaluation shall be thorough and objective, and take into account both favourable and unfavourable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer's claims in respect of the device. 3.   A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: — Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements; — Biological: the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables; — Clinical: the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence. 4.   The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device. The clinical evidence together with non-clinical data generated from non-clinical testing methods and other relevant documentation shall allow the manufacturer to demonstrate conformity with the general safety and performance requirements and shall be part of the technical documentation for the device in question. Both favourable and unfavourable data considered in the clinical evaluation shall be included in the technical documentation. PART B POST-MARKET CLINICAL FOLLOW-UP 5.   PMCF shall be understood to be a continuous process that updates the clinical evaluation referred to in Article 61 and Part A of this Annex and shall be addressed in the manufacturer's post-market surveillance plan. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data from the use in or on humans of a device which bears the CE marking and is placed on the market or put into service within its intended purpose as referred to in the relevant conformity assessment procedure, with the aim of confirming the safety and performance throughout the expected lifetime of the device, of ensuring the continued acceptability of identified risks and of detecting emerging risks on the basis of factual evidence. 6.   PMCF shall be performed pursuant to a documented method laid down in a PMCF plan. 6.1.   The PMCF plan shall specify the methods and procedures for proactively collecting and evaluating clinical data with the aim of: (a) confirming the safety and performance of the device throughout its expected lifetime, (b) identifying previously unknown side-effects and monitoring the identified side-effects and contraindications, (c) identifying and analysing emergent risks on the basis of factual evidence, (d) ensuring the continued acceptability of the benefit-risk ratio referred to in Sections 1 and 9 of Annex I, and (e) identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct. 6.2.   The PMCF plan shall include at least: (a) the general methods and procedures of the PMCF to be applied, such as gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of clinical data; (b) the specific methods and procedures of PMCF to be applied, such as evaluation of suitable registers or PMCF studies; (c) a rationale for the appropriateness of the methods and procedures referred to in points (a) and (b); (d) a reference to the relevant parts of the clinical evaluation report referred to in Section 4 and to the risk management referred to in Section 3 of Annex I; (e) the specific objectives to be addressed by the PMCF; (f) an evaluation of the clinical data relating to equivalent or similar devices; (g) reference to any relevant CS, harmonised standards when used by the manufacturer, and relevant guidance on PMCF; and (h) a detailed and adequately justified time schedule for PMCF activities (e.g. analysis of PMCF data and reporting) to be undertaken by the manufacturer. 7.   The manufacturer shall analyse the findings of the PMCF and document the results in a PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation. 8.   The conclusions of the PMCF evaluation report shall be taken into account for the clinical evaluation referred to in Article 61 and Part A of this Annex and in the risk management referred to in Section 3 of Annex I. If, through the PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer shall implement them. ANNEX XV CLINICAL INVESTIGATIONS CHAPTER I GENERAL REQUIREMENTS 1.   Ethical principles Each step in the clinical investigation, from the initial consideration of the need for and justification of the study to the publication of the results, shall be carried out in accordance with recognised ethical principles. 2.   Methods 2.1.   Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the manufacturer's claims regarding the safety, performance and aspects relating to benefit-risk of devices as referred to in Article 62(1); the clinical investigations shall include an adequate number of observations to guarantee the scientific validity of the conclusions. The rationale for the design and chosen statistical methodology shall be presented as further described in Section 3.6 of Chapter II of this Annex. 2.2.   The procedures used to perform the clinical investigation shall be appropriate to the device under investigation. 2.3.   The research methodologies used to perform the clinical investigation shall be appropriate to the device under investigation. 2.4.   Clinical investigations shall be performed in accordance with the clinical investigation plan by a sufficient number of intended users and in a clinical environment that is representative of the intended normal conditions of use of the device in the target patient population. Clinical investigations shall be in line with the clinical evaluation plan as referred to in Part A of Annex XIV. 2.5.   All the appropriate technical and functional features of the device, in particular those involving safety and performance, and their expected clinical outcomes shall be appropriately addressed in the investigational design. A list of the technical and functional features of the device and the related expected clinical outcomes shall be provided. 2.6.   The endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant. 2.7.   Investigators shall have access to the technical and clinical data regarding the device. Personnel involved in the conduct of an investigation shall be adequately instructed and trained in the proper use of the investigational device, and as regards the clinical investigation plan and good clinical practice. This training shall be verified and where necessary arranged by the sponsor and documented appropriately. 2.8.   The clinical investigation report, signed by the investigator, shall contain a critical evaluation of all the data collected during the clinical investigation, and shall include any negative findings. CHAPTER II DOCUMENTATION REGARDING THE APPLICATION FOR CLINICAL INVESTIGATION For investigational devices covered by Article 62, the sponsor shall draw up and submit the application in accordance with Article 70 accompanied by the following documents: 1.   Application form The application form shall be duly filled in, containing information regarding: 1.1. name, address and contact details of the sponsor and, if applicable, name, address and contact details of its contact person or legal representative in accordance with Article 62(2) established in the Union; 1.2. if different from those in Section 1.1, name, address and contact details of the manufacturer of the device intended for clinical investigation and, if applicable, of its authorised representative; 1.3. title of the clinical investigation; 1.4. status of the clinical investigation application (i.e. first submission, resubmission, significant amendment); 1.5. details and/or reference to the clinical evaluation plan; 1.6. If the application is a resubmission with regard to a device for which an application has been already submitted, the date or dates and reference number or numbers of the earlier application or in the case of significant amendment, reference to the original application. The sponsor shall identify all of the changes from the previous application together with a rationale for those changes, in particular, whether any changes have been made to address conclusions of previous competent authority or ethics committee reviews; 1.7. if the application is submitted in parallel with an application for a clinical trial in accordance with Regulation (EU) No 536/2014, reference to the official registration number of the clinical trial; 1.8. identification of the Member States and third countries in which the clinical investigation is to be conducted as part of a multicentre or multinational study at the time of application; 1.9. a brief description of the investigational device, its classification and other information necessary for the identification of the device and device type; 1.10. information as to whether the device incorporates a medicinal substance, including a human blood or plasma derivative or whether it is manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives; 1.11. summary of the clinical investigation plan including the objective or objectives of the clinical investigation, the number and gender of subjects, criteria for subject selection, whether there are subjects under 18 years of age, design of the investigation such as controlled and/or randomised studies, planned dates of commencement and of completion of the clinical investigation; 1.12. if applicable, information regarding a comparator device, its classification and other information necessary for the identification of the comparator device; 1.13. evidence from the sponsor that the clinical investigator and the investigational site are capable of conducting the clinical investigation in accordance with the clinical investigation plan; 1.14. details of the anticipated start date and duration of the investigation; 1.15. details to identify the notified body, if already involved at the stage of application for a clinical investigation; 1.16. confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application; and 1.17. the statement referred to in Section 4.1. 2.   Investigator's Brochure The investigator's brochure (IB) shall contain the clinical and non-clinical information on the investigational device that is relevant for the investigation and available at the time of application. Any updates to the IB or other relevant information that is newly available shall be brought to the attention of the investigators in a timely manner. The IB shall be clearly identified and contain in particular the following information: 2.1. Identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule pursuant to Annex VIII, design and manufacturing of the device and reference to previous and similar generations of the device. 2.2. Manufacturer's instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements, as well as, to the extent that such information is available, information to be placed on the label, and instructions for use to be provided with the device when placed on the market. In addition, information relating to any relevant training required. 2.3. Pre-clinical evaluation based on relevant pre-clinical testing and experimental data, in particular regarding in-design calculations, in vitro tests, ex vivo tests, animal tests, mechanical or electrical tests, reliability tests, sterilisation validation, software verification and validation, performance tests, evaluation of biocompatibility and biological safety, as applicable. 2.4. Existing clinical data, in particular: — from relevant scientific literature available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of the device and/or of equivalent or similar devices; — other relevant clinical data available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of equivalent or similar devices of the same manufacturer, including length of time on the market and a review of performance, clinical benefit and safety-related issues and any corrective actions taken. 2.5. Summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks, any undesirable effects, contraindications and warnings. 2.6. In the case of devices that incorporate a medicinal substance, including a human blood or plasma derivative or devices manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives, detailed information on the medicinal substance or on the tissues, cells or their derivatives, and on the compliance with the relevant general safety and performance requirements and the specific risk management in relation to the substance or tissues, cells or their derivatives, as well as evidence for the added value of incorporation of such constituents in relation to the clinical benefit and/or safety of the device. 2.7. A list detailing the fulfilment of the relevant general safety and performance requirements set out in Annex I, including the standards and CS applied, in full or in part, as well as a description of the solutions for fulfilling the relevant general safety and performance requirements, in so far as those standards and CS have not or have only been partly fulfilled or are lacking. 2.8. A detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation and in particular information on any deviation from normal clinical practice. 3.   Clinical Investigation Plan The clinical investigation plan (CIP) shall set out the rationale, objectives, design methodology, monitoring, conduct, record-keeping and the method of analysis for the clinical investigation. It shall contain in particular the information as laid down in this Annex. If part of this information is submitted in a separate document, it shall be referenced in the CIP. 3.1.   General 3.1.1.   Single identification number of the clinical investigation, as referred to in Article 70(1). 3.1.2.   Identification of the sponsor — name, address and contact details of the sponsor and, where applicable, the name, address and contact details of the sponsor's contact person or legal representative in accordance with Article 62(2) established in the Union. 3.1.3.   Information on the principal investigator at each investigational site, the coordinating investigator for the investigation, the address details for each investigational site and the emergency contact details for the principal investigator at each site. The roles, responsibilities and qualifications of the various kinds of investigators shall be specified in the CIP. 3.1.4.   A brief description of how the clinical investigation is financed and a brief description of the agreement between the sponsor and the site. 3.1.5.   Overall synopsis of the clinical investigation, in an official Union language determined by the Member State concerned. 3.2.   Identification and description of the device, including its intended purpose, its manufacturer, its traceability, the target population, materials coming into contact with the human body, the medical or surgical procedures involved in its use and the necessary training and experience for its use, background literature review, the current state of the art in clinical care in the relevant field of application and the proposed benefits of the new device. 3.3.   Risks and clinical benefits of the device to be examined, with justification of the corresponding expected clinical outcomes in the clinical investigation plan. 3.4.   Description of the relevance of the clinical investigation in the context of the state of the art of clinical practice. 3.5.   Objectives and hypotheses of the clinical investigation. 3.6.   Design of the clinical investigation with evidence of its scientific robustness and validity. 3.6.1.   General information such as type of investigation with rationale for choosing it, for its endpoints and for its variables as set out in the clinical evaluation plan. 3.6.2.   Information on the investigational device, on any comparator and on any other device or medication to be used in the clinical investigation. 3.6.3.   Information on subjects, selection criteria, size of investigation population, representativeness of investigation population in relation to target population and, if applicable, information on vulnerable subjects involved such as children, pregnant women, immuno-compromised or, elderly subjects. 3.6.4.   Details of measures to be taken to minimise bias, such as randomisation, and management of potential confounding factors. 3.6.5.   Description of the clinical procedures and diagnostic methods relating to the clinical investigation and in particular highlighting any deviation from normal clinical practice. 3.6.6.   Monitoring plan. 3.7.   Statistical considerations, with justification, including a power calculation for the sample size, if applicable. 3.8.   Data management. 3.9.   Information about any amendments to the CIP. 3.10.   Policy regarding follow-up and management of any deviations from the CIP at the investigational site and clear prohibition of use of waivers from the CIP. 3.11.   Accountability regarding the device, in particular control of access to the device, follow-up in relation to the device used in the clinical investigation and the return of unused, expired or malfunctioning devices. 3.12.   Statement of compliance with the recognised ethical principles for medical research involving humans, and the principles of good clinical practice in the field of clinical investigations of devices, as well as with the applicable regulatory requirements. 3.13.   Description of the Informed consent process. 3.14.   Safety reporting, including definitions of adverse events and serious adverse events, device deficiencies, procedures and timelines for reporting. 3.15.   Criteria and procedures for follow-up of subjects following the end, temporary halt or early termination of an investigation, for follow-up of subjects who have withdrawn their consent and procedures for subjects lost to follow-up. Such procedures shall for implantable devices, cover as a minimum traceability. 3.16.   A description of the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where such additional care is necessary because of the subjects' participation in the clinical investigation and where it differs from that normally expected for the medical condition in question. 3.17.   Policy as regards the establishment of the clinical investigation report and publication of results in accordance with the legal requirements and the ethical principles referred to in Section 1 of Chapter I. 3.18.   List of the technical and functional features of the device, with specific mention of those covered by the investigation. 3.19.   Bibliography. 4.   Other information 4.1.   A signed statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject. 4.2.   Where applicable according to national law, copy of the opinion or opinions of the ethics committee or committees concerned. Where according to national law the opinion or opinions of the ethics committee or committees is not required at the time of the submission of the application, a copy of the opinion or opinions shall be submitted as soon as available. 4.3.   Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 69 and the corresponding national law. 4.4.   Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document. 4.5.   Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data, in particular: — organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed; — a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects; and — a description of measures that will be implemented in case of a data security breach in order to mitigate the possible adverse effects. 4.6.   Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports, shall, upon request, be submitted to the competent authority reviewing an application. CHAPTER III OTHER OBLIGATIONS OF THE SPONSOR 1.   The sponsor shall undertake to keep available for the competent national authorities any documentation necessary to provide evidence for the documentation referred to in Chapter II of this Annex. If the sponsor is not the natural or legal person responsible for the manufacture of the investigational device, that obligation may be fulfilled by that person on behalf of the sponsor. 2.   The Sponsor shall have an agreement in place to ensure that any serious adverse events or any other event as referred to in Article 80(2) are reported by the investigator or investigators to the sponsor in a timely manner. 3.   The documentation mentioned in this Annex shall be kept for a period of at least 10 years after the clinical investigation with the device in question has ended, or, in the event that the device is subsequently placed on the market, at least 10 years after the last device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Each Member State shall require that this documentation is kept at the disposal of the competent authorities for the period referred to in the first subparagraph in case the sponsor, or its contact person or legal representative as referred to in Article 62(2) established within its territory, goes bankrupt or ceases its activity prior to the end of this period. 4.   The Sponsor shall appoint a monitor that is independent from the investigational site to ensure that the investigation is conducted in accordance with the CIP, the principles of good clinical practice and this Regulation. 5.   The Sponsor shall complete the follow-up of investigation subjects. 6.   The Sponsor shall provide evidence that the investigation is being conducted in line with good clinical practice, for instance through internal or external inspection. 7.   The Sponsor shall prepare a clinical investigation report which includes at least the following: — Cover/introductory page or pages indicating the title of the investigation, the investigational device, the single identification number, the CIP number and the details with signatures of the coordinating investigators and the principal investigators from each investigational site. — Details of the author and date of the report. — A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations. — Investigational device description, in particular clearly defined intended purpose. — A summary of the clinical investigation plan covering objectives, design, ethical aspects, monitoring and quality measures, selection criteria, target patient populations, sample size, treatment schedules, follow-up duration, concomitant treatments, statistical plan, including hypothesis, sample size calculation and analysis methods, as well as a justification. — Results of the clinical investigation covering, with rationale and justification, subject demographics, analysis of results related to chosen endpoints, details of subgroup analysis, as well as compliance with the CIP, and covering follow-up of missing data and of patients withdrawing from the clinical investigation, or lost to follow-up. — Summary of serious adverse events, adverse device effects, device deficiencies and any relevant corrective actions. — Discussion and overall conclusions covering safety and performance results, assessment of risks and clinical benefits, discussion of clinical relevance in accordance with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device, limitations of the investigation. ANNEX XVI LIST OF GROUPS OF PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE REFERRED TO IN ARTICLE 1(2) 1. Contact lenses or other items intended to be introduced into or onto the eye. 2. Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings. 3. Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing. 4. Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. 5. High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment. 6. Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.

Guidance-on-Article-15-MDR-IVDR-Person-responsible-for-Regulatory-Compliance.pdf.txt

This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 1 MDCG 2019- 7 Guidance on Article 15 of the Medical Device Regulation (MDR) and in vitro Diagnostic Device Regulation (IVDR) regarding a ‘person responsible for regulatory compliance’ (PRRC) Manufacturers1 (paragraph 1) “Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom -made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. ” Clarification on qualifications It shall be noted that : - For the purpose of fulfilling the requirement laid down in point “ a” of Article 15 (1), any qualification acquired outside the EU, including any university diplomas or certificates, should have been recognised by an EU Member State as equivalent to the EU corresponding qualification. 1 Enterprises which employ at least 50 persons and whose annual turnover and/or annual balance sheet total exceeds EUR 10 million (Commission Recommendation 2003/361/Ε C of 6 May 2003) . 2 - Professional experience in regulatory a ffairs or in quality management systems relating to medical devices should be related to the EU requirements in the field . Meaning of “within their organisation” The person responsible for regulatory compliance (PRRC) appointed would need to be an employee of the organisation. Organisations with more than one legal manufacturer Organisations with more than one legal manufacturer under the parent company would need to ensure that each legal manufacturer has its own PRRC.2 Can the PRRC be located out side the EU? As to the location of the PRRC, it is important that a close linkage, of a permanent and continuous nature, is established between the PRRC and the manufacturing activities. For this reason, for manufacturers located outside the EU, it must be assumed that the PRRC should also be located outside the EU. On the other hand, for manufacturers located in the EU, it must be assumed that the PRRC should also be located in the EU. Micro and small manufacturers3 (paragraph 2) “Micro and small enterpri ses within the meaning of Commission Recommendation 2003/361/EC shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal .” Meaning of “permanently and continuously at their disposal” The micro or small enterprise may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the manufacturer can de monstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation, with which the manufacturer has established a contract lay ing down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? For micro or small enterpr ises located in the EU, it must be assumed that any person to be permanent ly and continuously at their disposal should be also located in the EU . 2 In the context of Article 15, the obligation for having available within the organisation at least one PRRC refers to the individual legal manufacturer. 3 Enterprises which employ fewer than 50 persons and whose annual turnover and/or annual balance sheet total does not exceed EUR 10 million (Commission Recommendation 2003/361/ΕC of 6 May 2003) . 3 Authorised representatives (paragraph 6) “Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the followi ng qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. ” Meaning of “permanently and continuously at their disposal” The authorised representative may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the authorised representative can demonstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation with which the authorised representative has established e a contract laying down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? Taking into account that the Authorised Representative is located in the EU, it must be assumed that any person to be permanently and continuously at its disposal should be also located in the EU . Roles and responsibilities of the person r esponsible for regulatory compliance within a manufacturer (paragraph 3) For the purpose of this position paper, the roles and responsibilities of a PRRC have been cross -referred to the roles and responsibilities of a manufacturer, as stated in Article 10 of the MDR and IVDR. This paper does not interpret the roles and responsibilities of a PRRC. We recommend that any guidance on post -market surveillance, vigilance, clinical investigations and performance studies, created at a European level, should cross -refer to Article 15, paragraph 3 to provide guidance on what a PRRC of a manufacturer would be expected to do in these areas. 4 “The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the dev ices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; ” Manufacturers “of devices, other than investigational [performance study] devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device” (Article 10(9) of the MDR and Article 10(8) of the IVDR). “(b) the technical documentation and the EU declaration of conformity are drawn up and kept up- to-date; ” Manufacturers “[of devices other than custom -made devices] shall draw up and keep up to date technical documentation for those devices” (Article 10(4) of the MDR and IVDR) and “shall draw up an EU declaration of conformity” (Article 10(6) of the MDR and Article 10(5) of the IVDR). “(c) the post -market surveillance obligations are complied with in accordance with Article 10(10) [Article 10(9) of the IVDR]; ” Manufacturers “of devices shall implement and keep up to date the post -market surveillance system” (Article 10(10) of the MDR and Article 10(9) of the IVDR). “(d) the reporting obligations ref erred to in Articles 87 to 91 [Article 82 and 86 of the IVDR] are fulfilled; ” Manufacturers “shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88” (Article 10(13) of the MDR and Article 10(12) of the IVDR). “(e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV [Section 4.1 of Annex XIV of the IVDR] is issued. ” Manufacturers shall ensure that “a signed statement by the natural or legal person responsible for the manufacture of the investigational device [for performance study] that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigati on [performance study] and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.” 5 Roles and responsibilities of the person responsible for regulatory compliance within an authorised represent ative (paragraph 3) The PRRC of an AR should be responsible for ensuring that the tasks of an AR as specified in the given mandate, in accordance with Article 11(3), are fulfilled. . Can one individual be the PRRC for a manufacturer and its authorised representative? The person responsible for regulatory compliance for an authorised representative and for an 'outside EU' manufacturer cannot be the same person. There is a clear desire within the Regulations for the authorised representative to be adding an additional level of scrutiny and ensure that the supervision and control of the manufacture of devices, and the relevant post -market surveillance and vigilance activities are adequately effected. If the two roles were conducted by the same person, the additional level of scrutiny would be undermined. For the same reason, the PRRC of a micro or small enterprise and the PRRC of the authorised representative of that same enterprise shall not belong to the same external organisation.

md_mfr_stepbystep.pdf.txt

Implementation Model for Medical Devices Regulation Step by Step Guide MEDICAL DEVICES CHANGE OF LEGISLATION 1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the MDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (MDR Classes I, IIa, IIb and III) and confirm conformity assessment routes for existing and future products Check the new definition of MD, particularly with respect to its expanded scope. This also applies to products covered in Annex XVI Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 61) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market clinical follow-up plan (PMCF, Annex XIV Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for medical devices under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know! Internal market, Industry, Entrepreneurship and SMEs2Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs for the possible upgrade of risk class of MDs and for the new procedures for conformity assessment as well as the costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the MDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, resource requirements and a steering group, and ensure overall responsibility for MDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transitional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through MDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (clinical evaluation, technical documentation, relation with other economic operators, Unique Device Identification, labelling, registration, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for MDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the MDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the MDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ET-03-18-103-EN-N ISBN: 978-92-79-89702-3 DOI: 10.2873/66341

MDCG 2019-8 v2 Implant guidance Card.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-8 v2 MDCG 2019-8 v2 Guidance document Implant Card relating to the application of Article 18 Regulation (EU) 2017/745 of the European Pa rliament and of the Council of 5 April 2017 on medical devices March 2020 This document has been endorsed b y the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed o f representatives of all Member States and it is chaired by a representative of the European Co mmission. The document is not a European Commission document and it canno t be regarded as reflecting the official position of the European Commission. Any views express ed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices: Guidance document Implant Card relating to the app lication of Article 18 Regulati on (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medic al devices List of Content 1. Scope ............................................................................................................... 4 2. Purposes of the Implant Card ..................................................................... 4 3. Legal consideration on Implant Card design ........................................... 4 4. Information to be provided by the manufacturer on the Implant Card and information to be added by the health institution ........................... 5 5. Use of symbols .............................................................................................. 6 6. Language requirements on specific fields ................................................ 7 7. Benefits of an informativ e instruction leaflet ........................................... 7 8. Implant Card for implantable systems ...................................................... 7 Annex I examples of principle designs of Implant Cards and leaflets ....... 8 1. Scope This document provides guidance for Memb er States, concerned industry and other stakeholders on a blueprint of an implant card (IC) required by the MDR (Regulation (EU) 2017/745). It describes the intended use, cont ent and information to be provided by the manufacturer together on the IC and a definition of fields to be completed by the implanting healthcare institutions or healthcare provider s according to national law in Member States. Whereas the intended purpose and most of the da ta elements of the IC are already defined in Article 18 of the MDR, this document contains the description of other data elements which must be completed by the healthcare institution or healthcare provider and which must be considered by the individual Member State wh en implementing Article 18 MDR as required 1. 2. Purposes of the Implant Card The aim of introducing an IC has been to achieve three main objectives: 1. Enable the patient to identify the impl anted devices and to get access to other information related to the implanted device (e.g. via EUDAMED, and other websites). 2. Enable patients to identify themselves as persons requiring special care in relevant situations e.g. security checks. 3. Enabling e.g. emergency clinical staff or fi rst responder to be informed about special care/needs for relevant patients in case of emergency situations. 3. Legal consideration on Implant Card design Article 18 MDR describes the requirements rega rding the IC which shall be provided by the manufacturer together with the device. Wherea s Article 18 para 1a) describes the information which shall be provided by the manufacturer on the IC, Article 18 pa r a 2 l a y s d o w n t h e obligation of Member States to require health in stitutions to provide the IC to the concerned patient. In accordance with Article 18, 1a) the manufact urer should provide th e following information on the IC (preferably on the card itself or, alternatively, as stickers to be placed by the clinician):  Device name;  Serial number, lot number;  Unique device identification (UDI);  Name, address and the website of manufacturer;  Device type. 2 Article 18, 2 lays down that Member States shall require health institutions (or healthcare providers) inter alia to make available the IC to the relevant patient. The IC should bear their 1 This guidance doesn’t include the patient information described in Ar ticle 18 para 1 (b-d) which might be provided by the manufacturer by any means that allow rapid access to that information and that shall be stated in the language(s) determined by the concerned Member State. 2 In Article 18 1a) of the MDR, the term “device model” is used. However, this term which is not defined in the MDR, is part of the UDI-DI related info r m a t i o n t o b e p r o v i d e d t o E U D A M E D . T o a v o i d duplication and in the context of the intended purpos e of the IC (to be used in situations requiring special care or in emergency situations), it is cons idered that reference to device model in the MDR for the purpose of the IC shall be read as reference to device type, like “pacemaker”, “hip implant”, etc. When the European Medical device nomenclature is made available, a “standardised” set of terms of this nomenclature should be recommended for use in relation to the field “device type”. identity . For this purpose, the IC provided togeth er with the device should contain blank fields which shall be filled out by the health institution or healthcare provider, respectively. Since the establishment of (and the logistics behind) many different national IC designs is very expensive and of no additional benefit, Member States should ensure that, in the context of national implementation of Article 18 of the MD R, only the following information is required to be provided by the health institution or healthcare provider on the IC (together with the information provided by the manufacturer). Accordingly, a European or international blueprint for an IC which supports the purposes described in Article 18, 2 should contain the following blank fields: 1. Name of the patient or patient ID; 2. Name and address of the health institution or healthcare provider who performed the implantation; 3. Date of implantation. In order to be fit for the purposes described in Article 18, the outer dimensions of the IC should be the same as those of credit cards, ATM cards or ID cards (85.60 mm × 53.98 mm /3 3 ⁄8 × 2 1⁄8 inches) and with a radius of 2.88–3.48 mm 3. 4. Information to be provided by the manufacturer on the Implant Card and information to be adde d by the health institution The manufacturer shall provide the following necessary information: 1. Device name; 2. Device type; 3. Serial number or, where app licable, lot or batch number; 4. Unique device identification (UDI); the UDI as AIDC4 format and the UDI-DI as HRI5 5. Name and address of the manufacturer of the medical device; 6. Website of the manufacturer of the medical device. The text provided on the IC and on the instru ction for completing the IC by the healthcare institution or healthcare provider must be legible and at least 2 millimetres high. ‘Text’ includes any: number, letter, symbol, or letter or number in a symbol. In addition, the manufacturer shou ld design the IC in a way that the following blank fields to be filled out by the implanting healthcare institution or healthcare provider are available: 1. Name of the patient or patient ID; 2. Name and address of the healthcare inst itution which performed the implantation; 3. Date of implantation. 3 Dimensions to conform to the standard ISO/IEC 7810 ID-1. 4 AIDC - Automatic identification and data capture format (e.g. linear or 2D-Barcodes) 5 HRI - Human readable interpretation 5. Use of symbols To avoid national versions of the IC , the use of symbols is advisable. The following list contains symbols which have either been validated by users and have been submitted and accepted for inclusion in an upco ming international standard or already exist in the ISO database (Online Browsing Platform). The explanation of symbols on the IC should be provided in a leaflet (see section 7) or on the back of the IC, if space allows. Article 18(1) lays down that the information provided in the IC shall be stated in the language(s) determined by the concerned Member State. List of symbols recommended for use on the IC6: Patient Name or patient ID Date of implantation Name and Address of the implanting healthcare institution/provide r Name and Address of the manufacturer Information website for patients Device Name7 Serial Number Lot Number/Batch Code 6 The symbols for patient name or patient ID, name and ad dress of the implanting healthcare institution/provider, date of implantation, name and address of the manufacturer, serial number, lot number/batch code are already available and published in existing ISO standards. The symbols for device name, patient information website and UDI have been validated by users according to the ISO 15223-2 process. Note that the symbols listed here to indicate the following terms: ‘Device Name’, ‘Patient Name or Pati ent ID’, ‘Date of Implantation’, ‘Name and address of the implanting healthcare institution/provider’ on the implant card, are used in the ISO context to indicate ‘Medical Device’, ‘Patient Identification’, ‘Date’, ‘Health Care Center or Doctor’. 7 Please note that in the ISO context, the ‘MD’ symbol is used to identify that the product in question is a medical device. On the implant card, this symbol is used to indicate the device name. UDI as AIDC format UDI-DI information in a HRI format should be introduced by the wording “UDI-DI”. 6. Language requirements on specific fields Despite the nearly complete list of symbols for fields on the IC, there is currently no symbol available for the required field “Device Type”. The lack of a symbol and the purpose of this field makes it necessary that the information on the device type must be provided in the language accepted/required by the concerned Member State. There are several possibilities available to provid e this information in the necessary languages, e.g. the information is already printed on the IC in the different languages or stickers are provided with the IC and the healthcare professional selects the right one etc. 7. Benefits of an informati ve instruction leaflet8 As mentioned above (section 5), there is a need to provide, together with the IC, instructions on how to complete the IC and to explain the us ed symbols. This information shall be stated in the language(s) determined by the concerned Member State. For this reason, the use of a leaflet, containing the relevant information, to be provided together with the IC and the implantable device, is the recommended solution. As part of the risk management, the manufacturer has to investigate, by means of an ergonomic analysis or ergonomic usability test procedure, if the provided instructions are sufficient to enable the health professional to complete the IC correctly. The instructions must reflect the solution chosen by the manufacturer (e .g. pre-printed IC, blank IC with sticker(s) to be added, mixture of both). Special considerat ions might be needed when providing a system IC or an IC for a separate implantable compon ent, when there is not yet a common practice (standard) established. 8. Implant Card for implantable systems If an implantable device contains implantable components which might be replaced by other (or the same) components, for example in case of a later revision, the manufacturers should consider the use of a System IC. In Annex I to this guide an example is provided. W a y s c o u l d b e e x p l o r e d b y r e l e v a n t s t a k e h o l d e r s t o d e v e l o p c o m m o n r u l e s o n h o w t h e necessary information to be placed on the Sy stem IC is delivered with the replaceable component and how health professionals could en sure t hat the System I C is appropriately updated, when necessary. 8 This leaflet should not be confused with any possible vector of information referred to in points “b”, “c” and “d” of Article 18(1) of the MDR. UDI Annex I examples of principle designs of Implant Cards and leaf lets GENERAL NOTE: All examples contained in this Annex are to be intended as illustrative examples only.9 The basic shape of the IC shall be designed in compliance with ISO/IEC 7810 ID-1 (credit card form). The following pictures provide exam ples for individual device ICs. Example 1: Front – Not to scale (handwritten text on pre-printed content) Back – Not to scale (blank – serial printed content in production) 9 Please note that this includes translations (into languages other than English) shown in Examples throughout Annex 1, which are machine translated and not intended to be read as official translations into EU languages. International Implant Card https://www.genericmed.com/patientimplantinfo John Smith 27/05/2021 ABC Healthcare Center 123 Medical Parkway, Cork, Ireland Dr. H.C. Professional PM-5503 Pacer Advanced UDI-DI: (01)01865494261654 SN79856214 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Example 2: Back – Not to scale (blank – batch/lot printed content in production) PM-5503 Pacer Advanced UDI-DI: (01)03584124658462 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com AO.582122 Example 3 (suggested design of a foldable System IC): To be able to represent medical device syst ems in one IC, the IC shall be available in collapsible form. ABC Healthcare CenterInternational Implant Card www.genericmed.com/patientimplantinfo John Smith 27/05/2021 123 Medical Parkway Dr. H.C. Professional Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Cork, Ireland PM-5503 Pacer Advanced Pacemaker UDI-DI: (01)85412654285216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com PL-55-4 Pacer Lead Pro Pacemaker Lead UDI-DI: (01)89654213882154 SN86223214 Examples of IC Leaflet Front 1 (no stickers – preferred option) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. PM-5503 Pacer Advanced (01)8541265428 5216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 www.genericmed.com/patientimplantinfo Front 2 (sticker only for device type information) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare instit ution. To be filled by the healthcare institution/provider. 5. Add sticker with device type in required language. Stickers (to be detached and placed on the righ t place at the IC according to the numbers) PM-5503 Pacer Advanced (01)85412654285216 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 SN65695452 www.genericmed.com/patientimplantinfo 5 Front 3 (stickers) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. 4. Manufacturer’s information website. 5. Device type in required language. 6. Device name. 7. UDI-DI Code (HRI). 8. UDI code (AIDC format). 9. Serial number. 10. Name and address of the manufacturer of the implanted medical device. NOTE: Fields 4-10 might be filled with stickers (though this is not the preferred solution) Stickers (to be detached and plac ed on the right place at the IC according to the numbers) 5, 6 9 8 7 2 081019001 002 4 10 4 Back Explanation/ transl ation of symbols Patient Name or patient ID, Име на пациента , Jméno pacienta, Patientens navn, Patientenname, Όνομα ασθενούς , Nombre del paciente, Patsiendi nimi, Potilaan nimi, Nom du patient, Ime i prezime bolesnika, Imi ę i nazwisko pacjenta, A beteg neve, Nome del paziente, Paciento vardas ir pavard ė, Pacienta v ārds, uzvārds, Naam patiënt Pasientens navn, A beteg neve, Nome do doente, Nume pacient, Meno pacienta, Ime bolnika, Patientens namn Name and Address of the implanting healthcare institution/provide r , établissement sanitaire, centro de salud, struttura sanitaria, Gesundheitseinrichtung, gezondheidszorginstelling, placówka słu żby zdrowia, здравно заведение, veselības aprūpes iestāde, εγκατάσταση για την υγεία Date of Implantation , Дата на имплантиране, Datum implantace, Implanteringsdato, Implantationsdatum, Ημερομηνία εμφύτευσης, Fecha de implantación, Implanteerimiskuupäev, Implantointipäivämäärä, Date d’implantation, Datum implantacije, Beültetés dátuma, Data dell'impianto, Implantavimo data, Implant ēšanas datums, Implantatiedatum, Data wszczepienia , Data do implante, Data implant ării, Dátum implantácie, Datum vsaditve Device Name, Nazwa urz ądzenia medy cznego, Název zdravotnických prost ředků, Medicinsk enhed, Name des Medizinprodukts, Nombre del dispositivo médico, Nom du dispositif médical, Orvosi eszköz neve, Namn på medicinsk enhet, Ime medicinske naprave Nome do dispositivo médico κατασκευαστής, Producent, Fabrikant, Produttore, Fabricante, Fa bricant, manufacturer, Hersteller Information website for patients , Webová stránka s informacemi pro pacienta, Informationswebsite for patienten, Webseite mit Informationen für Patienten, Sitio web con información para el paciente, Site d'in formations pour le patient, Információs honlap betegek számára, Sito web con le informazioni per i pazienti, Website met informatie voor patiënten, Strona internetowa z informacjami dla pacjenta Translation of serial number in required languages. Translation of LOT number in required languages. Explanation of unique device identi fier (UDI) in required languages. Place to attach the Implant card

md_guidance-manufacturers_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019 -15 rev1 MDCG 2019 -15 rev.1 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES December 2019 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this doc ument are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 2 MDCG 2019 -15 revision 1 changes MDR postponement dates: from 2020 to 2021 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 3 Contents List of acronyms ................................ ................................ ................................ ................................ .... 4 Foreword ................................ ................................ ................................ ................................ ................ 5 Introduction ................................ ................................ ................................ ................................ ........... 5 Definitions ................................ ................................ ................................ ................................ .............. 8 Placing on the market of Class I medical devices: The necessary steps ................................ ......... 11 0) Integrate MDR in the Quality Management System (QMS). ................................ .................. 11 1) Confirm product as a medical device ................................ ................................ ........................ 11 2) Confirm product as a Class I medical device ................................ ................................ ............ 11 3) Procedures before placing on the market ................................ ................................ .................. 12 a) Meet the general safety and performance requirements ................................ ....................... 12 b) Conduct clinical evaluation ................................ ................................ ................................ ... 12 c) Prepare technical documentation ................................ ................................ .......................... 14 d) Request Notified Body involvement ................................ ................................ ..................... 16 e) Prepare Instructions for Use and Labelling ................................ ................................ ........... 16 4) Check compliance with general obligations for manufacturers ................................ ................ 17 5) Draw -up the EU Declaration of Conformity ................................ ................................ ............. 18 6) Affix the CE marking ................................ ................................ ................................ ................ 18 7) Registration of devices and manufacturers in Eudamed ................................ ........................... 19 8) Post Market Surveillance (PMS) ................................ ................................ ............................... 20 a) Review experience gained from Post -Market Surveillance ................................ .................. 20 b) Vigilance ................................ ................................ ................................ ............................... 20 c) Non conforming products ................................ ................................ ................................ ..... 22 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 4 List of acronyms MDD – Medical Devices Directive MDR – Medical Devices Regulation FSCA – Field Safety Corrective Action FSN - Field Safety Notice UDI - Unique Device Identifier SRN - Single Registration Number NB - Notified Body ISO - International Organization for Standardization IEC - International Electrotechnical Commission CA – Competent Authority PPE – Personal Protective Equipment QMS - Quality Management System Im – Class I devices with measuring function Is – Class I sterile devices Ir – Class I reusable surgical instruments DI – Device Identifier Eudamed - European database on medical devices MD - Medical Device CS - Common Specification PMS – Post Market Surveillance IFU – Instructions for use PMCF - Post Market Clinical Follow -up Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 5 Foreword These guidance notes do not aim to be a definitive interpretation of Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices (MDR) and are intended for guidance purposes only. Introduction The purpose of this document is to provide guidance to manufacturers of Class I medical devices (other than custom made devices) who place on the Union market medical devices (from now on referred to as devices) under their name or trade mark, to help them meet the provi sions of the MDR. This guidance should also be applicable for situations when an importer, distributor or any other legal person assumes the obligations incumbent on manufacturers, as per Article 16 (1), while not covering the exception indicated by Artic le 16 (2). The MDR has changed the scope of the medical device legislation and it now extends its application to all economic operators in the supply chain (manufacturer, authorised representative, importer and distributor) as well as a broadened range of products such as those specifically intended for the cleaning, disinfection or sterilization of devices (Article 2 (1)) and products without an intended medical purpose (such as certain aesthetic products, as indicated in Annex XVI of the MDR). In addition , more emphasis is placed on a life -cycle approach to safety, backed up by clinical data and new requirements such as transparency and traceability1. Before placing a device on the market, the manufacturer will affix the CE mark in accordance with Annex V and draw up the EU declaration of conformity, including all the information required by Annex IV. Prior to that, the manufacturer will demonstrate conformity with the MDR and compliance with the applicable general safety and performance requirements laid o ut in Annex I. In order to accomplish the abovementioned tasks, the manufacturer will carry out the following:  Put in place a quality management system and a system for risk management according to Article 10(2) and 10(9).  Conduct a clinical evaluation i n accordance with Article 61, as established in Article 10(3) and Annex XV.  Conduct a conformity assessment according to Article 52(7). In specific cases ( sterile devices, devices with measuring function, reusable surgical instruments ) defined in the referred Article, the manufacturer will request the involvement of a Notified Body (NB).  Draw up and keep up -to-date technical documentation related to devices as set out in Annexes II and III, in accordance with Article 10(4).  Draw up an EU declaration of conformity in accordance with Article 19.  Submit the required information to the electronic system for registration of economic operators (Eudamed) and comply with the registration obligation. The manufacturer will use the Single Regis tration Number (SRN) when applying to a NB for conformity assessment, if applicable and for further accessing Eudamed2 in order to fulfil its obligations related to registration of the devices.  Register the device in Eudamed assigning the Basic UDI -DI to t he device, as defined in Part C of Annex VI, and provide this to the UDI database together with the other core data elements referred in Part B of Annex VI related to that device.  Assign to the device and, if applicable, to all higher levels of packaging, a UDI which will allow identification and traceability. 1 More information can be found at https://ec.europa.eu/health/md_sector/overview 2 Regarding all references to Eudamed in this document, please be advised that for the purposes of this guidance, obligations s trictly related to Eudamed will only apply when it is fully functional and any u pdates will be published on the EU Commission webpage. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 6  Ensure that the device is accompanied by the information needed to identify it and its manufacturer, and any safety and performance information relevant to the user, or any other person, as appropria te (Article 10(11)). This information, set out according to Section 23 of Annex I, must be provided in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label w ill be indelible, easily legible and clearly comprehensible to the intended user or patient.  Implement a post -market surveillance system in accordance with Article 83 (Article 10(10)) proportional to the risk class and appropriate for the type of device, this includes additional aspects to be taken into account in case of devices placed on the market in sterile condition, with a measuring function or that are reusable surgical instruments. This system will be an integral part of the manufacturer's quality management system based on a post -market surveillance plan (Article 84) , which will be part of the technical documentation specified in Annex III.  Implement a system for recording and reporting incidents and field safety corrective actions as described in Articles 87 and 88 (Article 10(13)).  Put measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC3, without prejudice to more protective measures under national law. These measures will be proportional to the risk class, type of device and the size of the enterprise (Article 10(16)). Further detail on the aforementioned list of obligations is provided in the chapter “Placing Class I medical devices on the market ”. For devices placed on the market in a sterile condition, with a measuring function or which are reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI which require a NB assessment, limited t o critical aspects such as those concerning sterile condition, metrological requirements and the reuse of the device, as relevant, according with Article 52 (7 a, b and c). 3 Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of t he Member States concerning liability for defective products Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 7 Figure 1. Illustration of the conformity procedures for the assessment of Class I devices with and without NB involvement. For big and medium size enterprises, the manufacturer will have available within their organization at least one person responsible for regulatory compliance4, as established by Article 15. Micro and small enterprises5 are required to have such person permanently and continuously at their disposal. A manufacturer with a registered place of business outside the Union will designate a sole authorised representative, at least per each gener ic device group, according to a written mandate. Such a mandate will establish the tasks to be performed by the authorised representative. To enable the fulfilment of these tasks, the manufacturer ensures that the authorised representative has the necessar y documentation permanently available and up -to date. The mandate will require the authorised representative to perform at least the tasks described in Article 11(3), however the manufacturer cannot delegate its obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). In case of the change of authorised representative, Article 12 establishes the minimum content of agreement to be addressed between the manufacturer, where practicable the outgoing authorised representative, a nd the incoming authorised representative. Upon request, the manufacturer will provide all the information and documentation necessary to demonstrate conformity of the device to competent authorities and cooperate with them on any corrective action. If th e manufacturer does not cooperate or does not provide the requested information or documentation, the competent authority (CA) can adopt restrictive measures. The manufacturer should periodically verify whether implementing and delegated acts, common speci fications, technical standards and guidelines might be available on the European Commission website6. Such documents might for example cover specific parts of legislation (e.g. classification of 4 See the relevant MDCG guidance on Article 15 of MDR and IVDR regarding a "person responsible for regulatory compliance" (PRRC) 5 See Commission Recommendation 2003/361/EC 6 https://ec.europa.eu/health/md_sector/overview Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 8 medical devices, clinical evaluation) or specific requirement s regarding certain medical device technologies (e.g. software, 3D printing ) that can also be applicable for Class I devices. During the transitional period, manufacturers might be tempted to refer to guidance documents developed under the Directive 93/42/ EC. However, the old guidance documents, unless otherwise updated in line with the MDR, may have only some limited indicative value under the MDR. For the purpose of the MDR, only the text of the Regulation is valid in law and sets out requirements not reflected in the old guidance. Hence, the MDR alone can be relied upon as a legal basis . Definitions For the complete list of definitions refer to Article 2 of the MDR. This is an excerpt of some definitions. Accessory for a medical device - means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s) (Article 2(2)) . Authorised representative - means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under the MDR (Arti cle 2(32)). The designation of an authorised repre sentative will be in compliance with Article 11 and effective at least for all devices o f the same generic device group (Article 11(2)) . Adverse event - means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, inc luding an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device (Article 2(57)) . Benefit -risk determination - means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer (Article 2(24)) . Class I medical devices with measuring function - are considered Class I medical devices which measure physiological parameters or anatomical parameter or energy, respectively, or volume of medicinal products, body liquids or other substances administered to or removed from the body and display or indicate its value in a unit of measurement (example: urine bags, non -active thermometers, measuring spoons). Note: According to section 15.2 of Annex I, measurements made by devices with a measuring function will be expressed in legal un its7. CE marking of conformity or CE marking - means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in the MDR and other applicable Union harmonisation legislation providing for its affix ing (Article 2(43)) . Note: CE marking will be made in accordance with Annex V. Clinical evaluation - means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify th e safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. (Article 2(44)). Clinical data - means information concerning safety or performance that is generated from the use of a device and is sourced fr om the following:  clinical investigation(s) of the device concerned, 7 In conformance to the provisions of Council Directive 80/181/EEC Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 9  clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,  reports published in peer re viewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,  clinically relevant information coming from post -market surveillance, in particular the post - market clinical follow -up. (Article 2(48)) Conformity Assessment – The process demonstrating whether the requirements of the MDR relating to a device have been fulfilled. (Article 2(40)). This process depends on the medical device classification, according to the procedures described in the MDR, in particular Article 52 (7) applicable for class I devices. Distributor - means any natural or legal person in the supply chain, other than the manufacturer or the importer that makes a device available on the market, up until the point of putting into service (Article 2(34)) . Economic operator - means a manufacturer, an authorised representative, an importer, a distributor or the person referre d to in Article 22(1) and 22(3) (Article 2(35)) . Field safety corrective action - means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market (Article 2(68)) . Field safety notice - means a com munication sent by a manufacturer to users or customers in relation to a field safety corrective action (Article 2(69)) . Harmonised standard - means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) N° 1025/20128, (as referred on the Article 2(70)) – means a European standard adopted on the basis of a request made by the Commission for the application of Union harmonisation legislation. Importer - means any natural or legal person established within the Union that places a devic e from a third country on the Union market (Article 2(33)). Intended purpose/intended use - means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (Article 2(12)). Instructions for use - means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use, and of any precautions to be taken (Article 2(14)). Label - means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices (Article 2(13)). Medical device - means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: ‒ diagnosis, prevention, m onitoring, prediction, prognosis, treatment or alleviation of disease, ‒ diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, ‒ investigation, replacement or modification of the anatomy or of a physiological or path ological process or state, ‒ providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, 8 Regulation (EU) No 1025/2012 of the European Parliament and of the Council , of 25 October 2012 , on European standardization Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 10 and which does not achieve its principal intended action by pharmacological, immuno logical or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: ‒ devices for the control or support of conception; ‒ products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (Article 2(1)) Manufacturer - means a natural or legal person who manufactures or fully refur bishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark ; (Article 2(30)). Notified Body - means a conformity assessment body designated in accordance with the MDR (Article 2(42)). Placing on the market - means the first making available of a device, other than an investigational device, on the Union market (Article 2(28)). Post-market surveillance - means all activities carried out by manufacturers in cooperation with other economic op erators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediate ly apply any necessary corrective or preventive actions (Article 2(60)). Risk - means the combination of the probability of occurrence of harm and the severity of that harm (Article 2(23)). Serious incident - means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; ((Article 2( 65)) Serious public health threat - means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time (Article 2(66)) . Unique Device Identifier (UDI) - means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market (Article 2(15)). User - means any healthcare professional or lay person who uses a device (Article 2(37)). Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 11 Placing Class I medical devices on the market: The necessary steps Manufacturers that intend to place Class I medical devices on the market must guarantee compliance with all the requirements below. Please note that some of the described requirements are inter -dependent and can be performed in a differe nt order than the one presented. For Class I devices already placed on the market in accordance with the MDD, the manufacturer will conduct a gap analysis in order to guarantee that all the necessary requirements outlined below are fully completed at the d ate of the application of MDR. 0) Integrate MDR in the Quality Management System (QMS). The applicable provisions of the MDR will be integrated into the QMS of the manufacturer. This will allow the correct assessment/decision to be made and the proper documented evidence to be created, ensuring compliance with the following requirements. 1) Confirm product as a medical device Confirm that the product qualifies as a medical device as defined in Article 2(1) in accordance with its intended purpose and principal mode of action. If the manufacturer assigns several different intended purposes to their product, not all of which fall under the scope of the MDR, such a product qualifies as a medical device only with respect to those intended medical purposes which are covered by Article 2(1). This is applicable, for instance, for the case of examination gloves that are intended by the manufacturer to be used to protect the patient (medical purpose - MD) and also to protect the healthcare professional (protecti on purpose – PPE9). In that case the relevant requirements of both legislations will be applicable. In the case of accessories to medical devices, despite not being medical devices per se, they are covered by MDR provisions and fall under the term “device” in the meaning of the MDR. However, accessories to devices covered by the MDR by virtue of its Annex XVI are not covered by the MDR. For borderline products where such a determination could be difficult, please consult primarily the information10 available on the European Commission website. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 2) Confirm product as a Class I medical device Consult Annex VIII of the MDR to confirm that the product is correc tly classified as Class I. It should be noted that some Class I devices according to MDD will be reclassified under the MDR considering the new classification rules of that annex, this is the case for most software (rule 11) and devices that are composed o f substances or of combination of substances (rule 21) . For devices that were reclassified from Class I to higher risk classes by application of the MDR, the present guideline cannot be applied. The application of the classification rules will be governe d by the intended purpose of the device and 9 Directive 89/686/EEC is repealed with effect from 21 April 2018 by Regulation (EU) 2016/425 10 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 12 their inherent risks linked to the duration of use, part of the body, whether it is active or not, whether it is invasive or non -invasive. If more than one rule according to Annex VIII applies to the intended pur poses of the device, the highest classification applies to the device, i.e. it must be classified on the basis of the most critical specified use. For classification issues, please primarily consult the information11 available on the European Commission web site. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 3) Procedures before placing on the market a) Meet the general safety and performance requirements The devices will meet the general safety and per formance requirements set out in Annex I of the MDR which apply to them, taking into account the purposes intended by their manufacturers. Particular attention will be given to devices that are also machinery, within the meaning of Article 2(2), point (a) , Machinery Directive 2006/42/EC12, where the relevant requirements of that directive will also be covered given their specificity (according to Article 1(12)). The manufacturer will establish and implement a risk management system, which will allow for the identification and analysis of the hazards associated with each device, estimation and evaluation of the associated risks, elimination or control of residual risks and evaluation of the adopted measures based on the information collected from the post -market surveillance system. The risk management will be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. To carry out this process the manufacturer can find solutions in common sp ecifications, or in harmonised standards, published in the Official Journal of the European Union, or in other referential materials. Where a harmonised standard exists but the manufacturer is following other referential, the application of that referentia l should guarantee at least the same level of safety and performance. Conformity with the relevant harmonized standards will provide presumption of conformity with the requirements of the MDR covered by those standards or parts thereof. Where common speci fications are available the manufacturer is obliged to follow them unless they can duly justify that they have adopted a solution at least with the same level of safety and performance. The risk management, clinical evaluation processes and PMS will be inter-dependent and will be periodically updated. b) Conduct clinical evaluation All devices, regardless of risk classification, require a clinical evaluation as part of the technical documentation requirements of the MD R13. The manufacturer will specify and justify the level of clinical evidence necessary to demonstrate 11 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en%20 12 Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24) 13 For further, see Annex II of the MDR Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 13 conformity with the relevant general safety and performance requirements described in Annex I. That level of clinical evidence will be appropriate in view of the characteristics of the device and its intended purpose. In order to do that, manufacturers will plan, conduct and document a clinical evaluation in accordance with Article 61 and Part A of Annex XIV. Guidance on the process of conducting clinical eval uation is also available on the Commission website.14 Conformity to Annex I requirements can only be assumed when the following items are aligned with each other:  Risk management;  The information materials supplied by the manufacturer, including: o labelling , o instructions for use (where required), o available promotional materials, o any accompanying documents foreseen by the manufacturer;  The clinical evaluation (the device description used for the clinical evaluation, other contents of the clinical evaluati on report);  The available clinical data (such as results of clinical investigations, publications, Post Market Surveillance studies, clinical registries, etc.). The MDR reinforces the need to consider the following aspects when carrying out a clinical eval uation: • Consideration of available alternative treatment options is required as part of clinical evaluation for the MDR15. Whilst the existence of better alternative treatment options does not influence the compliance of the device with the MDR, the manufacturer needs to be able to justify the clinical benefit of using their device if alternatives are available. • The incorpo ration of clinical data obtained throughout the life cycle of the device from the manufacturers post -market clinical follow -up plan and post -market surveillance plan to update the clinic al evaluation and documentation16. • The acceptability of the benefit -risk ratio must be based upon sufficient clinical data and will be continuously monitored and reassessed from clinical data collected through the post - mark et surveillance phase. The post -market surveillance plan should incorporate suitable indicators and thr eshold values to be used in this reassessment 17. If available clinical data are not sufficient to demonstrate compliance with the MDR, further clinical data will be obtained or generated by clinical investigations. For devices which are currently certifie d with respect to the Directive 93/42/EC, and for which the available clinical data are not sufficient to demonstrate compliance with MDR, additional clinical data may be obtained by post -market clinical follow -up studies of the device. Sometimes, even dat a from the general post -market follow -up might suffice to close the gap18. Note : if a clinical investigation is required, then the Member State requires advance notification of the proposal and the provisions of Article 62 and Annex XV will be applicable. 14 https://ec.europa.eu/health/md_sector/new_regulations/guidance_en 15 MDR, Article 61(3)(c) 16 MDR, Article 61(11) 17 MDR, Article 61(1) and Annex III 1.1b 18 An MDCG guidance is intended to be published on this matter including ‘sufficient clinical da ta’ in 2020 and will be availabl e at the EU Commission webpage Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 14 In duly justified and substantiated cases, some Class I devices manufacturers may exceptionally demonstrate that the conformity with general safety and performance requirements based on clinical data is not deemed appropriate. Such a justification by the m anufacturer must be based upon an evaluation of evidence in accordance with Article 61(10). The clinical evaluation, risk management processes and PMS will be inter -dependent and will be periodically updated. c) Prepare technical documentation The manufactur er will draw up and keep up to date the technical documentation that demonstrates the conformity of their devices with the technical requirements of the MDR. This technical documentation must be prepared according to Annex II and III and prior to drawing u p the EU declaration of conformity. The technical documentation and, if applicable, its summary, will be drawn up and presented by the manufacturer in a clear, organised, readily searchable and unambiguous manner. The manufacturer must make the technical d ocumentation available to the CA, the authorised representative (when applicable) and NB (when applicable). The technical documentation will be prepared following review of the general safety and performance requirements and relevant technical provisions o f the MDR and, if applicable, of the Machinery Directive19 and will cover all the relevant aspects from Annex II and III, such as: - Rationale for the qualification as a medical device and the risk class attributed. - Description and specification - A general d escription of the device, including its intended purpose and intended users/patient population and, if applicable, accessories and variants of the product (for example trade names, model numbers, references, sizes). In addition , the Basic UDI-DI as per Par t C of Annex VI will be provided. - Technical Specifications of the device - Specifications including details of raw materials, drawings of components and/or master patterns and any quality control procedures. - Information to be supplied by the manufacturer - Labels on the device and packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions and instruction for use (if applicable), in the languages determined by the Member States where the device is envisaged to be sold. - Reference to previous generations of the device and to similar devices - Provide an overview of previous generation(s) of the device and similar devices available on the market as ap plicable - Design and manufacturing information – Information that allows the understanding of the design and manufacturing of a device, including the results of qualifications tests and design calculations relevant to the intended use of the product, includ ing connections to other devices in order for it to operate as intended. If the manufacturer can provide information showing that a safe design has been established for a number of years and that product has been performing as intended during that time suc h information is likely to be sufficient to cover this 19 According to Article 1 (12) Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 15 requirement. The identification of all sites, suppliers and sub -contractors, where design and manufacturing activities are performed will also be included. - General safety and performance requirements – information for the demonstration of conformity with the general safety and performance requirements, set out in Annex I. In order to do this, the manufacturer will refer to all the methods and solutions used for conformity demonstration with each safety and performance requirement, including harmonised standards and/or common specifications (CS). The same applies for the requirements contained in the Machinery Directive. - Demonstration of conformity with the requirements set out in Annex I should typically be presented in the form of a checklist. This should list all requirements referred to in Annex I and specify: (1) the applicability of each requirement to the device, (2) the solution adopted by the man ufacturer to comply with each applicable requirement, (3) the reference to any possible CS or harmonized standards applied in full or in part and (4) the reference to where to find evidence of the solution adopted in the technical documentation. Manufacturers wil l list the relevant harmonised standards (concerning for example sterilisation, labelling and information to be supplied with the device, biocompatibility, specific groups of products) which have been applied in full or in part. If harmonised standards hav e not been applied in full, additional data will be required and provided detailing remaining solutions adopted to meet the concerned requirements. Information on standards harmonised under the MDR will be made available in the Official Journal of the Euro pean Union. Changes on the harmonised standards used to demonstrate the conformity of device will be adequately taken into account in a timely manner. Please note that no standard harmonized under the Directive 93/42/EC, has ever covered all the requirements of the Annex I to that Directive. Hence, it is not likely that any one standard harmonized under the MDR will cover all the requirements of the Anne x I to the MDR. The scope of coverage is indicated in the so -called Annex Z to the European “EN” standard. The scope of coverage is never to be found in the ISO or IEC standard text. - Benefit -risk analysis (sections 1 and 8 of Annex I) and Risk management ( section 3 of Annex I). - Pre-clinical and Clinical evaluation data – Information to be provided on the results from pre - clinical and clinical evaluation. - The post -market surveillance system - The technical documentation on post -market surveillance to be dr awn up by the manufacturer in accordance with Articles 83 to 85 will be presented in a clear, organized, readily searchable and unambiguous manner. It shall address and cover the elements of point 1.1 of Annex III. The plan will cover the post -market clini cal follow up plan as referred to in part B of Annex XIV or a justification as to why it is not applicable. The PMS report of article 85 shall be part of the technical documentation on post -market surveillance. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 16 - Records - Manufacturers will keep the techn ical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market (Article 10(8)). Availability of documentation – In case of request by the CA, the manufacturer will provide the required technical documentation in an official Union language determined by the Member State concerned (Article 10(14)). d) Request Notified Body involvement In the case of devices placed on the market in sterile condition, having a measuring function or being reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI of MDR. This requires the involvement of a NB. In all other cases the intervention of a NB is not required for Class I devices. If involvement of the NB is needed it is limited: - In the case of devices placed on the market in sterile condition, to the aspects of manufacture concerned with securing and maintaining sterile conditions; - In the case of devices with a measuring function, to the aspects of man ufacture concerned with the conformity of the devices with the metrological requirements; - In the case of reusable surgical instruments20, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance a nd functional testing and the related instructions for use. Manufacturers can choose any NB designated according to the MDR for the relevant codes and corresponding types of devices as established by Regulation (EU) 2017/2185 (code MDS 1005 for “Devices in sterile condition”, code MDS 1006 for “Reusable surgical instruments” and code MDS 1010 for “Devices with a measuring function”) . The list of designated NBs is available in the NANDO database at the following link: http://ec.europa.eu/growth/tools -databases/nando/ Please note that notification under the Directive 93/42/EC, become s void after the application of the MDR on the 26 May 202 1. Hence, it is necessary to consult the NANDO database for the MDR. e) Prepare Instructions for Use and Labelling Each device must be accompanied by any safety and performance information needed to use it safely and to identify the device as well as the manufacturer and/or the authorised representative, taking account of the training and knowledge of the potential users. This information comprises the label, device packaging and the data in the instructions for use. By way of derogation to the general principles, no instructions for use are required for Class I de vices if they can be used properly and safely without such instruction. An exception is most likely posed for Class Ir devices as reprocessing (cleaning and sterilization) will require an instruction. The requirements regarding the information to be suppl ied with the device will be found in Annex I, Chapter III (23). In the labelling and instructions for use as well as in promotional materials of the device, the manufacturer may not (Article 7): 20 Please also note that involvement of a Notified Body in the case of reusable surgical instruments is a new requirement under the MDR, which did not exist under the MDD. Manufacturers of such products are advised to take this into consideration for their pl ans to meet the provisions of the MDR before its application on the 26 May 202 1. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 17 - Ascribe functions and properties to the device which the devi ce does not have; - Create a false impression regarding treatment or diagnosis, functions or properties which the device does not have; - Fail to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; - Suggest uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. National language requirements must be taken into account in relation to the labelling and instructions for use. Versions of labelling and IFU ( in each of the relevant national languages) will be included in the technical documentation. Note : According to Article 16(2), a distributor or importer may provide a translation of the information provided according to Section 23 of Annex I. The manufacturer will be informed about the intended translation and receive a copy 28 days prior to the date of making the device available in the respective country. It is advisable to perform a review of the translation, as a w rong or misleading translation can cause harm to patients or others, leading to possible liability of the manufacturer. Where appropriate, the information supplied by the manufacturer will take the form of internationally recognised symbols. Any symbol or identification colour used will conform to harmonised standards or common specifications (CS). In areas for which no harmonised standards or CS exist, the symbols and colours will be described in the documentation supplied with the device. The label should have the indication that the product is a “medical device”. 4) Check compliance with general obligations for manufacturers Before placing a device on the market, the manufacturer will make sure to comply with the general obligations for manufacturers as est ablished in Article 10. Special attention will be given to the establishment of an appropriate QMS that will ensure compliance with the MDR in the most effective manner, for example by means of an internal audit. The QMS will be documented, implemented, m aintained, kept up to date and continually improved and will cover at least the following aspects: a) a strategy for regulatory compliance; b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; c) responsibility of the management; d) resource management, including selection and control of suppliers and sub -contractors; e) risk management; f) clinical evaluation, including post market clinical follow -up (PMCF); g) product realisation, including planning, design, development, production and service provision; h) verification of the UDI assignments; i) setting -up, implementation and ma intenance of a post -market surveillance system; j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; k) processes for reporting of serious incidents and field safety corrective ac tions in the context of vigilance; l) management of corrective and preventive actions and verification of their effectiveness; m) processes for monitoring and measurement of output, data analysis and product improvement. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 18 The QMS will be established at least in parallel, if not prior to chapter 3 a) and 3 b) as described in this guidance note. Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Therefore, manufacturers sha ll, in a manner that is proportionate to the risk class, type of device and size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to mor e protective measures under national law. 5) Draw -up the EU Declaration of Conformity The EU declaration of conformity, referred to in Article 19, is the procedure whereby the manufacturer, who fulfils the obligations imposed by Article 52(7), declares that the devices concerned fulfil the requirements of the MDR which apply to them. The declaration of conformity will contain as a minimum all information referred to in Annex IV and will be available to the CA. The manufacturer will continuously update the EU declaration of conformity and will translate it into an official union language or languages required by Member States in which the device is made available. If, in addition to the MDR, a device is covered by other Union legislation which also requires an EU declaration of conformity, the manufacturers will elaborate a single EU declaration of conformity where all the Union legislation applied to the product are referred to. By drawing up the EU declaration of conformity the manufacturer assumes the respon sibility for the regulatory compliance of the device with all Union legislation applicable to it. Before affixing a CE mark, for class Ir, Im and Is devices, the manufacturer will have an EC certificate issued by NB according to the Annex IX, Chapter I and III, or to Annex XI, Part A. 6) Affix the CE marking All Class I medical devices placed on the mar ket will bear the CE marking of conformity, which will be affixed in a visible, legible and indelible form on the device or on its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE markin g shall be affixed to the packaging. The CE marking shall also appear on the instructions for use, as well as on any sales packaging. In the case of Class I medical devices placed on the market in a sterile condition and/or devices with measuring function and/or reusable surgical instruments, the CE marking will be accompanied by the identification number of the relevant NB. It is prohibited to affix marks which are likely to mislead third parties with regard to the meaning of the CE marking. Other additio nal marks may be affixed to the device, to the packaging or the instructions for use, but must not impair the visibility or legibility of the CE marking. The CE marking format will be in compliance with Annex V. Where the device is very small the minimum d imensions of the CE mark may be waived. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 19 7) Registration of devices and manufacturers in Eudamed Before placing a device on the market, the manufacturer of a Class I medical device will register the device in Eudamed. In order to register the device, the manufacturer will submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already been registered in accordance with Article 31. In cases where the conformity ass essment procedure requires the involvement of a NB pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI will be provided to that electronic system before applying to the NB. After having verified the data about the manufac turer, the CA will validate it in Eudamed and the manufacturer will obtain a SRN from said electronic system. The manufacturer will use the SRN when applying to a NB for conformity assessment and for accessing Eudamed in order to fulfil its obligations und er Article 29. Note: Authorised representatives and importers are also required to register to get an SRN in order to access Eudamed and provide data, as appropriate The registration of a device in Eudamed by the manufacturer includes:  Assignment of a UDI -DI (with a Basic UDI -DI) as defined in Part C of Annex VI to the device (in accordance with the rules of the issuing entity referred to in Article 27(2) and introduction of the UDI -DI (with a Basic UDI -DI) to the UDI database together with the other core d ata elements referred to in Part B of Annex VI related to that device.  Entering, or if already provided, verifying in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and thereafter keeping the information updated. If the manufacturer has its devices designed or manufactured by another legal or natural person, the information on the identity of that person will be part of the information (Section 2.13 of Part A of Annex VI) to be submitted to Eudamed before the registration of the device. Note 1 – The Unique Device Identification system will allow the identification and facilitate the traceability of devices (as referred on Article 27). [Special attention will be given to point 11 of Article 27]. Note 2 – The Basic UDI -DI as defined in Part C of Annex VI is the primary identifier of a device model. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity21. Note 3 – For Class I devices placed on the market according to MDD, afte r the date of application of MDR manufacturers will have in consideration the guidance documents applicable to legacy devices timelines22 and registration in Eudamed23. 21 For more information on the Basic UDI -DI, please refer to https://ec.europa.eu/docsroom/documents/28667 22 See at EU Commission webpage the relevant guidance on timelines for registration of device data elements in EUDAMED23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED 23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 20 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 21 All devices including legacy devices of the manufacturer portfolio which are placed on the market or put into service will have to be registered in Eudamed. However, until Eudamed is fully functional the manufacturer of a Class I medical device, or, where the manufacturer has no place of business in the EU, its authorised representative must inform the CA of the country in which they have their registered place of business and provide a description of the device that is sufficient to identify it. The manufacturer or its authorised representative will contact their relevant CA for the required procedures and forms required for such notifications. A fee might be applicable. 8) Post Market Surveillance (PMS) After placing the Class I device on the market, the manufacturer will follow the next PMS steps: a) Review experience gained from Post -Market Sur veillance The manufacturer will put in place the required post market surveillance (PMS) system and actively keep this PMS up to date in accordance with Article 83 of MDR. This includes actively and regularly collecting the user experience from devices on the market, reviewing these and ensuring timely implementation of any necessary corrective action, taking account of the nature and risks in relation to the product. In addition, there should be an evaluation of whether the intended benefits are achieved a nd whether the benefit -risk profile stays positive. The manufacturer will involve the distributors of the device and where applicable, the authorised representative and importers of the device in this system, in order to obtain the relevant information from the market. This system will be part of the QMS, and be supported by the manufacturer’s PMS plan, which must address a range of information (Annex III), such as information from the vigilance context, information from trending and trend reporting, inf ormation and data on any undesirable side -effects, information from reports, complaints and incidents, provided by users and economic operators, related to the device. Moreover, the manufacturer will gather and assess the relevant information such as techn ical literature, databases, registers review and public information for the device itself as well as for similar devices already present on the market. A PMS report will be prepared according to Article 85, summarizing the results and conclusions of the analysis of all of the data from the market. This report will be updated when necessary, for example the intended benefits are not achieved or there is a change in the benefit -risk balance. The report can be requested by the CA at any time. Data gathered from PMS system must be used to actively update the clinical evaluation, benefit -risk determination, improve risk management, as well as other technical documentation on a regular basis. b) Vigilance The manufacturer is responsible for reporting all serious incidents and field safety corrective actions (FSCA) to the relevant CAs, according to Article 87 (1) of the MDR. After serious incident notification, the manufacturer is obliged to make investigations, according to Article 89, which will include a risk assessment of the incident. If needed, a FSCA will be implemented in order to reduce the risk associated with the use of the device. The manufacturer will involve the distributors of the device and, where applicable, the authorised representative and import ers in the system, in order to obtain the information needed from the market, especially for FSCA and issued field safety notices (FSN) to ensure that required actions are followed and completed in a timely manner. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 22 When Eudamed is available, serious incide nts and FSCAs will be submitted via this electronic system only. Manufacturers will report any serious incident immediately after they have established the causal relationship between that incident and their device or that such a causal relationship is re asonably possible. The timeframe to report serious incidents must not exceed the following upper limits:  In the event of a serious public health threat, a report will be submitted not later than 2 days after becoming aware of the threat. (Article 87 (4))  In the event of death or an unanticipated deterioration in a person’s state of health a report will be submitted not later than 10 days after becoming aware of the serious incident. (Article 87 (5))  In all other cases not later than 15 days after becoming aware of the serious incident (Article 87 (3)) Where necessary to ensure timely reporting of serious incidents, the manufacturer may submit an initial report that is incomplete followed up by a complete report. If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report. Serious incidents will be reported only to the competent authority of the country in which the serious incident occurred via Eu damed. The manufacturer will provide a final report to that competent authority via Eudamed setting out its findings from the investigation. The report will set out conclusions and - where relevant - indicate corrective actions to be taken. When the compet ent authority notifies a manufacturer of a suspected serious incident, communicated to the competent authority by a healthcare professional, patient or user, the manufacturer is obliged to:  submit a report of this serious incident to the notifying competen t authority via Eudamed within the timeframes described above;  submit an explanatory statement, to the competent authority, if the manufacturer believes the suspected serious incident does not fulfil the reporting criteria. In case the competent authority disagrees with the explanatory statement provided by the manufacturer a report of the serious incident may be required to be provided to the competent authority that does not agree via Eudamed by the manufacturer. If a FSCA is undertaken, manufacturers wil l without unnecessary delay report the field safety corrective action via Eudamed in advance of the carrying out of the FSCA unless urgency demands the manufacturer to undertake the actions immediately. Manufacturers will ensure that the information relate d to the FSCA is brought without delay to the attention of users of the device in question by means of a FSN. Except in cases of urgency, the content of the draft FSN will be submitted to the evaluating competent authority or to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice will be consistent in all Member States. Manufacturers will also report the FSN(s) to Eudamed. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 23 The FSN w ill allow the correct identification of the manufacturer ( by including the, if issued, SRN), the device or devices affected (by including the relevant UDIs) and the FSN will explain, in a clear manner, without understating the level of risk, the reasons fo r the FSCA. This includes a clear reference to the device deficiency and the associated risks for patients, users or other persons and will clearly indicate all action to be taken by the users. Manufacturers will report by the means of a trend report to Eudamed any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side -effects, when it could have a significant impact on the benefit -risk analysis and which have led o r may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. Manufacturers will, if they exist, follow national provisions in the field of vigilance specifically in but not limited to the case of field safety corrective actions:  The allowed languages used to communicate with users by means of the Field Safety Notice. Manufacturers are asked to check if templates exist (on European Commission website) on any of the reporta ble forms and make sure that all the necessary information according to these templates is provided. This will be only applicable until Eudamed is available. Manufacturers should keep concerned economic operators informed of reported serious incidents and FSCA activities. c) Non-conforming products If a manufacturer has reasons to believe that a device which they have placed on the market or put into service is not in conformity with the MDR they will immediately take the necessary corrective action to bring t hat device into conformity, to withdraw it or to recall it, as appropriate. The manufacturer will inform the distributors of the device in question and, if applicable, the authorised representative and importers. If the device presents a serious risk, the manufacturer will immediately inform the competent authorities of the Member States in which the manufacturer made the device available and, where applicable, the notified body that issued a certificate for the device, in particular, of the non -compliance and of any corrective action taken.

mdcg_2019_3_rev1_cecp_en.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 1 of 4 MDCG 2019 -3 Rev. 1 Interpretation of Article 54(2)b April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 2 of 4 MDCG 2019 -3 Rev. 1 changes Addendum on procedural aspects New Interpretation of Article 54(2)b Article 54(2) of the MDR lays down three criteria that exempt devices from the pre - market clinical evaluation consultation procedure with the involvement of expert panels. In particular that article states that: “The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not ad versely affect the benefit -risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device”. Interpretation of point (b) of Article 54(2) is unclear, notably in relation to the application of the word “marketed”. In fact, while in point “a” the co -legislator explicitly indicates that the certificates referred to are those issued under the new Regulation, in point “b” there is no indication of whether a “device already marketed” refers to devices already marketed under the Directi ves or the Regulations. This has raised questions from the public and from Member States. As we are about to launch the procedures for the establishment of expert panels, clarification of this issue is extremely urgent, notably due to its impact on the fu ture workload of panels and hence on relevant budget and workload estimations. The following considerations seem to indicate that the expression “device already marketed” cannot be intended to refer to a device already marketed uniquely under the new Regu lation :  If the co -legislators had decided to restrict the application of point “b” to devices marketed uniquely under the MDR, they would have explicitly stated so, as they did for point “a”;  Article 54, together with other Articles (such as Article 61(6) and Article 120(3)), was written at the end of the negotiation process with a view to smoothen the Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 3 of 4 implementation of the new Regulation. Therefore the interpretation of the exemption should be understood in line with the spirit and intention of the co - legislators. It has to be noted that, in respect to devices that have been marketed already under the relevant Directives, the word “modification” shall be meant as limited only to those modifications needed in order to comply with the new legal requiremen ts introduced by the MDR1 2. Addendum - Procedural aspects Together with the application to be lodged under the applicable conformity assessment procedure, the manufacturer will provide the notified body with:  a statement that it has marketed the device in question for the same intended purpose under the relevant Directive,  copy of the last issued certificate(s) together with the certificate history, and  a description of the modifications introduced to comply with the MDR As part of its technical documen tation assessment according to the MDR, the notified body will verify that the “modifications”, as referred to in the main document, do not adversely affect the benefit -risk ratio. In particular, the notified body will verify:  that the device in question h ad a valid certificate under the Directives,  in case the certificate has been withdrawn, suspended3 or expired, if there is an impact on compliance with the general safety and performance requirements, and  that there is no pending assessment of changes fo r the device or outstanding non-compliance. In addition, the notified body will verify the description of modifications provided and assess if these modifications are limited only to those needed in order to comply with the new legal requirements introdu ced by the MDR. Limitations of the intended purpose of the device should not trigger the consultation procedure in accordance to Art. 54. 1 These devices will anyhow be subject to all applicable new MDR requirements, including those ones related to the clinical evaluation, and will need to be assessed by notified bodies against these new (and higher) requirements. This aspect together with the increased notified bodies’ oversight foreseen under MDR should guarantee a high standard of safety for these products. 2 From a practical perspective, u nder the scenario where those products had to be subject to clinical evaluation consultation procedure with the involvement of expert panels, as a result of the application of criteria set in Annex IX 5c, in most if not all of the cases, the panel would de cide not to give an opinion. Therefore , a very significant additional workload and financial burden would be created for an extremely limited added value. 3 Certificates for which the rationale for withdrawal or suspension is linked to lack of complian ce with essential requirements may adversely affect the benefit -risk ratio of the device and will require a clinical evaluation consultation procedure. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 4 of 4 In case that any of the abovementioned conditions are not fulfilled the notified body will follow the consultation procedure in accordance to Art. 54. The assessment of the above conditions will be documented by the notified body in accordance with Section 4.6 of Annex VII in the clinical evaluation assessment report that will be made available to competent authorities in accordance with Art. 54 (1) and (3). Clarifications in respect to the applicability of Art. 54(2)b with regard to devices already marketed under the MDR are to be provided in a separate guidance.

mdcg_2019_11_guidance_qualification_classification_software.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-11 MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR October 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 1 of 28 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR Guidance on Qualification and Classification of Software October 201 9 Page 2 of 28 Table of Contents 1. Scope and purpose of this document 3 2. Definitions and abbreviations 3 3. Qualification 6 3.1. Introduction to qualification criteria 6 3.2. Medical Device Software (MDSW) 7 3.3. ‘Software driving or influencing the use of a medical device’ 8 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device 10 4. Classification of MDSW per MDR 2017/745 12 4.1. Implementing Rules 12 4.2. Classification Rules 12 5. Classification and implemen ting rules per IVDR 2017/746 15 5.1. Implementing Rules: 15 5.2. Classification Rules: 15 6. Considerations on placing on the market and conformity asse ssment of MDSW 16 6.1. Option 1: as a medical device in its own right 16 6.2. Option 2: as an integral component/part of a device 17 7. Modules 17 8. Consideration of changes to an MDSW 18 9. Annex I: Illustrative examples of qualifica tion of software used in the healthcare environment 18 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 24 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 26 12. Annex IV – Classification examples 27 Page 3 of 28 1. Scope and purpose of this document This document, which primarily targets medical software manufacturers, defines the criteria for the qualification of software falling within the scope of the new medical devices regulations1 and provides guidance on the application of classification criteria for software under Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR.2 The guidance also provides information related to placing on the market. The classification criteria (classification rules) are set out in Annex VIII of the Medical Devices Regulation (EU) 2017/745 (MDR) and Annex VIII of the In vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR). The criteria specified in this document shall also apply to applications (commonly referred to as apps), may they be operating on a mobile phone, in the cloud or on other platforms. 2. Definitions and abbreviations Intended purpose : According to Regulation (EU) 2017/745 – MDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation;3 According to Regulation (EU) 2017/746 – IVDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements or as specified by the manufacturer in the performance evaluation; 4 Accessory: According to Regulation (EU) 2017/745 – MDR, “Acc essory for a medical device” means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); 5 According to Regulation (EU) 2017/746 – IVDR, “Accessory for an in vitro diagnostic medical device” means an article which, whilst not being itself an in vitro diagnostic medical device, is intended by its manufacturer to be used together with one or several particular in vitro diagnostic medical device(s) to specifically enable the in vitro diagnostic medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the in vitro diagnostic medical device(s) in terms of its/their intended purpose(s);6 Note: Software accessory may be driving or influencing the use of a medical device. Note: Manufacturers must describe in the technical documentation accessories of a medical device or an in vitro diagnostic medical device which are intended to be used in combination with it; and in case 1 The use of “The Medical Devices Regulations” from here on out refers to both Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR. 2 It shall be noted that the term “standalone software” which was used in the text of the medical device directives, is no longer used in the context of the Medical Device Regulation. The rationale of the change is that software should be qualified and classified depending on its intended purpose uniquely, regardless of its location. 3 Article 2(12) of Regulation (EU) 2017/745 – MDR 4 Article 2(12) of Regulation (EU) 2017/746 – IVDR 5 Article 2(2) of Regulation (EU) 2017/745 – MDR 6 Article 2(4) of Regulation (EU) 2017/746 – IVDR Page 4 of 28 of medical devices they must include in the instructions for use information allowing the selection of the corresponding software and accessories.7 Placing on the market: According to Regulation (EU) 2017/745 – MDR, “Placing on the market” means the first making available of a device, other than an investigational device, on the Union market; 8 According to Regulation (EU) 2017/746 – IVDR, “Placing on the market” means the first making available of a device, other than a device for performance study, on the Union market;9 Putting into service: According to Regulation (EU) 2017/745 – MDR, “Put ting into service” means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose;10 According to Regulation (EU) 2017/746 – IVDR, “Putti ng into service” means the stage at which a device, other than a device for performance study, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; 11 Medical device : “medical device” means any instrument, apparatus, appliance, software , implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, - investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, - providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: - devices for the control or support of conception; - products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point.12 Active medical device: “active device” means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; 13 7 Article 32.2(c), Annex I, Chapter III Section 23.4(f), Annex II Section 1.1(h) of Regulation (EU) 2017/745 – MDRArticle 29.2(c) and Annex II Section 1.1(m) of Regulation (EU) 2017/746 – IVDR 8 Article 2(28) of Regulation (EU) 2017/745 – MDR 9 Article 2(21) of Regulation (EU) 2017/746 – IVDR 10 Article 2(29) of Regulation (EU) 2017/745 – MDR 11 Article 2(22) of Regulation (EU) 2017/746 – IVDR 12 Article 2(1) of Regulation (EU) 2017/745 – MDR 13 Article 2(4) of Regulation (EU) 2017/745 – MDR Page 5 of 28 In vitro diagnostic medical device: “In vitro diagnostic medical device” means any medical device which is a reagent, reagent product, calibrator, control material, kit, instru ment, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following: - concerning a physiological or pathological process or state; - concerning congenital physical or mental impairments; - concerning the predisposition to a medical condition or a disease; - to determine the safety and compatibility with potential recipients; - to predict treatment response or reactions; - to define or monitoring therapeutic measures. Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;14 Software: For the purpose of this guidance, “software” is defined as a set of instructions that processes input data and creates output data. Input data : Any data provided to software in order to obtain ou tput data after computation of this data can be considered as input data. Input data examples (non-exhaustive): - Data given through the use of a human data-input device such as a keyboard, mouse, stylus, or touch screen; - Data given through speech recognition; - Digital document: formatted for general purpose such as Word file or pdf file or jpeg image, formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document. Note that digital documents have to be differentiated from software able to read such documents; - Data received from/transmitted by devices. Output data : Any data produced by a software can be considered as an output data. Output data examples (non- exhaustive): - Screen display data (such as layout with number, characters, picture, graphics, etc.); - Print data (such as layout with number, characters, picture, graphics, etc.); - Audio data; - Digital document (formatted for a general purpose such as Word file or pdf file or jpeg image, or formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document). - Haptic buzzing as an alternative to audio sound Software driving or influencing the use of a device Software which is intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: (a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device (b) or supply output related to the (hardware) functioning of that device Note: Software driving or influencing the use of a (hardware) medical device may be qualified as an accessory for a (hardware) medical device. 14 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 6 of 28 Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination, for a purpose as specified in the definition of a “medical device” in the medical devices regulation15 or in vitro diagnostic medical devices regulation.16 3. Qualification 3.1. Introduction to qualification criteria The purpose of this section is to clarify what software is in itself subject to the medical devices regulations. Software must have a medical purpose on its own to be qualified as a medical device software (MDSW). It should be noted that the intended purpose as described by the manufacturer of the software is relevant for the qualification and classification of any device. In order to be qualified as medical device software, the product must first fulfil the definition of software according to this guidance and the definiti on of a medical device according to Article 2(1) of Regulation (EU) 2017/745 – MDR. To be qualified as an in vitro diagnostic medical device software, the product must additionally fulfil the definition of an in vitro diagnostic medical device according to Article 2(2) of Regulati on (EU) 2017/746 – IVDR. Where a given product does not fall under the definition of a medical device, or is excluded by the scope of the Medical Devices Regulations, other Community and/or national legislation may be applicable. Software that does not meet th e definition of a medical device or an in vitro diagnostic medical device (i.e. software that is not MDSW) but is intended by the manufacturer to be an accessory for a medical device, or an in vitro diagnostic medical device, falls respectively under the scope of the Regulation (EU) 2017/745 – MDR or Regulation (EU) 2017/746 – IVDR. Software can directly control a (hardware) medical device (e.g. radiotherapy treatment software), can provide immediate decision-triggering information (e .g. blood glucose meter software), or can provide support for healthcare professionals (e.g. ECG interpretation software). It is important to clarify that not all software used within healthcare is qualified as a medical device. For example, “Simple search”, which refers to the retrieval of records by matching record metadata against record search criteria or to the retrieval of information does not qualify as medical device software (e.g. library functions). However, software which is intended to process, an alyse, create or modify medical information may be qualified as a medical device software if the creation or modification of that information is governed by a medical intended purpose. For example, the software which alters the representation of data for a medical purpose would qualify as a medical device software. (e.g. “searching image for findings that support a clinical hypothesis as to th e diagnosis or evolution of therapy” or “software which locally amplifies the contrast of the finding on an image display so that it serves as a decision support or suggests an action to be taken by the user”). However, altering the representation of data for embellishment/cosmetic or compatibility purposes does not readily qualify the software as medical device software. Software intended for non-medical purposes (excludi ng MDR Annex XVI devices), such as invoicing or staff planning, does not qualify as a medical device software. These software do not fall under the Medical Devices Regulations. 15 Article 2(1) of Regulation (EU) 2017/745 – MDR 16 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 7 of 28 A task such as e-mailing, web or voice messaging, data parsing, word processing, and back-up is by itself not considered as having a medical purpose. Additionally, software may run on different operating systems or in virtual environments. These operating systems or virtual environments do not impact the qualification criteria. It must be highlighted that the risk of harm to patients, users of the software, or any other person, related to the use of the software within healthcare, including a possible malfunction is not a criterion on whether the software qualifies as a medical device. 3.2. Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination , for a purpose as specified in the definition of a “medical device” in the MDR or IVDR, regardless of whether the software is independent or driving or influencing the use of a device. Note 1: MDSW may be independent , by having its own intended medical purpose and thus meeting the definition of a medical device or in vitro diagnostic medical device on its own (i.e. alone ) MDSW that uses maternal parameters such as ag e, concentration of serum markers and information obtained through foetal ultrasound examination for evaluating the risk of trisomy 21. MDSW that receives measurements from transrectal ultrasound findings, age, and in vitro diagnostic instruments and calculates a patient’s risk of developing prostate cancer. Mass Spectrometry MDSW intended to analyse LC-MS/MS data to be used for microorganism identification and detection of antibiotic resistance. MDSW smartwatch app, which is intended to send alarm notifications to the user and/or health practitioner when it recognises irregular heartbeats for the purpose of detecting cardiac arrhythmia. Note 2: If the software drives or influences a (hardware) medical device and also has a medical purpose, then it is qualified as a MDSW Melanoma image analysis software intended to drive a near-infrared laser light scanner. MDSW intended to measure and transmit blood glucose levels, calculate insulin dose required and drive the insulin pump to administer the calculated dosage (closed loop insulin delivery system). Note 3: Software may be qualified as MDSW regardless of its location (e.g. operating in the cloud, on a computer, on a mobile phone, or as an additional functionality on a hardware medical device). MDSW that is intended to operate a point of care test from a remote location. Note 4: MDSW may be intended to be used by healthcare professionals or laypersons (e.g. patients or other users).17, 18 MDSW that provides insulin dose recommendations to a patient regardless of the method of delivery of the prescribed dose, whether via an insulin pump, insulin pen or insulin syringe. 17 Where MDSW is intended to be used by a lay person, the manufacturer shall apply safety and performance requirements outlined in MDR Annex I. 22 and 23.4 (w); or IVDR Annex I. 9.4 and 20.4.2. 18 MDSW which can be considered as an IVD for self-testing shall be considered as a device intended to be used by laypersons. Page 8 of 28 Manufacturers must ensure that all regulatory requirements for placing on the market and conformity assessment have been fulfilled. As set out in Article 7 of MDR and IVDR, this also entails that any claims, relating to the intended medical purpose of their MDSW are supported by clinical evidence. If this is not the case, the software would not meet the requirements of the regulations and therefore may not be CE marked as a medical device, nor present said claims. 3.3. ‘Software driving or influencing the use of a medical device’ Is software intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device b) or supply output related to the (hardware) functioning of that device Note: Software that is driving or influencing the use of a medical device is covered by the medical devices regulations either as a part/component of a device or as an accessory for a medical device. (refer to Figure 2, box 2). Software that is intended to be used to operate a clinical chemistry analyser. Software with built-in electronic controls for IVD quality control procedures. These quality control procedures are intended to provide users with assurance that the device is performing within specifications. Decision steps for qualification of software as MDSW (Figure 1) Decision step 1 : if the product is software according to Section 2 (Definitions and Abbreviations) of this guidance, then it may be a medical device software, proceed to decision step 2; if the product is not software according to the definition of this guidance, then it is not covered by this guidance but may still be covered by the Medical Devices Regulations. Decision step 2 : if the product is an MDR Annex XVI device, or is an accessory for a medical device19, or is software driving or influencing the use of a medical device, then it must be considered as part of that device in its regulatory process or independently if it is an accessory. If it is not, proceed to decision step 3. Decision step 3 : if the software does perform an action on data, or performs an action beyond storage, archival, communication20, simple search, lossless compression (i.e. using a compression procedure that allows the exact reconstruction of the original data) then it may be a medical device software (Refer to section 3.1 for more guidance on these software functions) proceed to step 4. Decision step 4 : is the action for the benefit of individual patients? Examples of software which are not considered as being for the benefit of individual patients are those which are intended only to aggregate population data, provide generic diagnostic or treatment pathways (not directed to individual patients), scientific literature, medical atlases, models and templates as well as software intended only for epidemiological studies or registers. Decision step 5: Is the software medical device software (MDSW) according to the definition of this guidance? 19 According to Article 2(2) of the Medical Devices Regulation or In Vitro Diagnostic Medical Devices Regulation. 20 Communication: The flow of information from one point, known as the source, to another, the receiver; Source: IEEE 610.10-1994. Page 9 of 28 Page 10 of 28 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device Medical Device Software (MDSW) fulfilling the definition of an in vitro diagnostic medical device falls under the in vitro diagnostic medical devices Regulation (EU) 2017/746. Provided that MDSW is intended specifically by its manufacturer to be used together with an in vitro diagnostic medical device to enable it to be used in accordance with its in tended purpose, this MDSW falls under the scope of the in vitro diagnostic medical devices regulation and shall be treated as an In Vitro Diagnostic MDSW (IVD MDSW) in its own right. In cases when software is driving or influencing the use of a (hardware) device, the software should be considered as falling under the respective regulation of the driven or influenced (hardware) device. Software that analyses and interprets the optical density delivered by an ELISA reader, line or spot pattern of a blot. Such software takes raw data outputs and use clinical algorithms for diagnostic and/or prognostic purposes, in which case it qualifies as IVD MDSW. Decision steps for qualification of MDSW as either a medical device or an in vitro diagnostic medical device (Figure 2) Decision Step 1: Does the Medical Device Software (MDSW) provide information within the scope of the in vitro diagnostic medical device definition? MDSW which provides information according to Re gulation (EU) 2017/746 – IVDR Article 2(2) (a) to (f) should qualify as In Vitro Diagnostic Medical Device Software (IVD MDSW) (a) concerning a physiological or pathological process or state (by investigation of this process or state); or (b) concerning congenital physical or mental impairments (c) concerning the predisposition to a medical condition or a disease; (d) to determine the safety and compatibility with potential recipients; (e) to predict treatment response or reactions; (f) to define or monitoring therapeutic measures. A MDSW which falls under the definition set out in EU Article 2 (1) of Regulation (EU) 2017/745 – MDR should qualify as Medical Device Software (MD MDSW). In specific, the following considerations should apply on the prov ision of information by software on: (g) diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease (h) diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, (i) investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, (j) control or support of conception; (k) products specifically intended for the cleaning, disinfection or sterilization of devices as referred to in Article 1(4) and Annex XVI products. Decision Step 2 : Does the MDSW create information based on data obtained by in vitro diagnostic medical devices only? If the information provided is based on data obtained solely from in vitro diagnostic medical devices, then the software is an in vitro diagnostic medical device and is therefore an IVD MDSW. If the data analysed is obtained from a combination of both in vitro diagnostic medical devices and medical devices, proceed to step 3. Page 11 of 28 Decision Step 3 : Is the intended purpose substantially driven by data sources coming from in vitro diagnostic medical devices? If yes, then the appli cable legislation is Regulation (EU) 2017/746. If the intended purpose is substantially driven by data sources coming from medical devices, then the applicable legislation is Regulation (EU) 2017/745. In the condition where the intended purpose of the MDSW output data fulfils both the medical device and in vitro diagnostic medical device definitions set out in the MDR and IVDR (refer to Decision Step 2), a weighting of the data sources based on the significance of the information21 in relation to fulfilling the intended purpose should be conducted to aid the manufacturer in determining which regulation to apply. Annex II of this guidance offers some prescrip tive examples of how such a weighting may be performed. 21 A qualitative approach is intended to drive the weighting of data. The weighing aims to assess the contribution of each data towards achieving the result. Page 12 of 28 4. Classification of MDSW per MDR 2017/745 4.1. Implementing Rules All implementing rules in Annex VIII of Regulation (EU) 2017/745 shall be considered. Special considerations on Implementing Rule 3.3 and 3.5: The first sentence of implementing rule 3.3 of Annex VIII clarifies the regime applicable to software driving or influencing the use of a device: ‘Software, which drives or influences the use of a device, shall fall within the same class as the device’ The second sentence of implementing rule 3.3 of Annex VIII clarifies that the regime applicable to Independent MDSW: ‘If software is independent of any other device, it shall be classified in its own right’ This rule should also be considered at least as an orientation for finding the correct (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. Therefore, Medical Device Software that both achieves its own intended purpose and also drives or influences the use of a (hardware) device for a medical purpose is classified on its own, based on the intended purpose achieved. In such a case, however, the risk class shall not be lower than the risk class of the hardware medical device. Implementing rule 3.5 of Annex VIII is relevant for all devices and states that ‘If several rules, or if, within the same rule, seve ral sub-rules, apply to the same device based on the device’s intended purpose, the strictest rule and sub-rule resulting in higher classification will apply’ Melanoma image analysis software intended to be used with a near-infrared laser light scanner , which is considered class IIa per Rule 10. The software “drives or influences the use of” the near- infrared laser light scanner as it is intended to take control of the scanner by letting it execute proprietary multi-exposure programs for the detection of melanoma. As such, implementing rule 3.3 applies. However, Rule 11 would also apply based on the intended medical purpose of the software e.g. cancer diagnosis. The MDSW would be classified as class III based on Rule 11 (see section Classification Rules) and per implementing rule 3.5 of Annex VIII. 4.2. Classification Rules Rules 9, 10 and 12 mainly categorise the risks related to the exchange of energy/substances between the body and diagnostic or therapeutic active devices, taking into account the different healthcare situations (condition of patients). MDSW, in the majority of cases, does not (directly) relate to such risks. It relates to the consequences of indirect harm from failure to provide correct information. Therefore, in line with Recital 5 of the Medical Device Regulation and international guidance from the IMDRF (International Medical Device Regulators Forum)22, Rule 11 was introduced into the MDR and is intended to address the risks related to the information provided by an active device, such as MDSW. Rule 11, in particular, describes and categorises the significance of the information provided by the active device to the healthcare decision (patient management) in combination with the healthcare situation (patient condition). As software is defined as an active device, for the classification of active (hardware) devices, which also includes MDSW providing information for patient management, Rules 9, 10, 11, 12, 13, 15 and 22 IMDRF is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundational work of the Global Harmonization Task Force on Medical Devices (GHTF) and aims to accelerate international medical device regulatory harmonization and convergence. Page 13 of 28 22 of Annex VIII MDR 2017/ 745 should be considered. In line with implementation rule 3.5, the strictest rule or sub-rule should hence apply. MDSW should be classified in the same way, rega rdless of the software's location or the type of interconnection between the software and a (hardware) device. 4.2.1. Rule 11 – Software for decisions with diagnosis or therapeutic purposes or software intended to monitor physiological processes Rule 11 states: Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: death or an irreversible deterioration of a person's state of health, in which case it is in class III; or a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. The text of Rule 11 can be divided into what are essentially three sub-rules that are applied depending on the intended use/purpose of the MDSW: 11a: (3 first paragraphs of Rule 11) intended to provide information which is used to take decisions with diagnostic or therapeutic purposes; 11b: (Paragraph 4 of Rule 11) intended to monitor physiological processes or parameters; 11c: (Paragraph 5 of Rule 11) all other uses. Sub-rule 11a): The wording “intended to provide information which is used to take decisions with diagnosis or therapeutic purposes” describes, in very general terms, the “mode of action” which is characteristic of all MDSW. Therefore, this sub-rule is generall y applicable to all MDSW (excluding those MDSW that have no medical purpose). Sub-rule 11a), states that MDSW (which is intende d to provide information which is used to take decisions with diagnosis or therapeutic purposes) is classified as class IIa. There are two exceptions from sub-rule 11a) that ar e mainly intended to apply a risk classification based on the significance of the provided information and the potential impact of an (incorrect) decision made using information from the MDSW.23 Accordingly, MDSW that is intended to provide information which is used to take decisions with diagnosis and therapeutic purposes, is at a higher risk class where such decisions, if based on incorrect information from the MDSW, are reasonably likely to have an impact that may cause: i. death or an irreversible deterioration of a person's state of health, in which case it is in class III; ii. serious deterioration of a person's state of health or surgical intervention, in which case it is classified as class IIb. 23 Compare IMDRF/SaMD WG/N12FINAL:2014 which states that there are two major factors that provide adequate description of the intended use of software: A. - Significance of the information provided by the software to the healthcare decision and B. - State of the healthcare situation or patient condition. Page 14 of 28 The MDR contains several references to “serious deterioration of a person’s state of health” and “surgical intervention”, notably in the vigilance or clinical investigation context. Further horizontal guidance could be provided in the future and will be available at: https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en Rule 11 was also introduced to mirror the regulatory guidance developed at international level and notably in the context of the International Medi cal Device Regulators Forum (IMDRF). The IMDRF framework for risk categorisation of software as a medical device (SaMD) (“IMDRF Risk Framework”) categorises the risk of software based on the combination of the significance of the information provided by the software to the healthcare decision and the healthcare situation or patient condition. IMDRF also developed a table for assisting operators in identifying the appropriate risk category for their own product. Such a table could provide operators placing MDSW on the EU market with some useful indications on the risk class applicable to their products as a result of the application of Rule 11 of the MDR. For this purpose, a table is provided in Annex III to this document which lists the IMDRF risk categories and the possible corresponding MDR risk classes accor ding to Rule 11 of the MDR. It must be noted that this table does not take into account MDSW which is Class I. Sub-rule 11b): MDSW that is intended to monitor physiological processes will, under most circumstances, provide “information which is used to take decisions with diagnosis or therapeutic purposes and hence fall under sub-rule 11a. Sub-rule 11b) should therefore be considered as a specific rule for MDSW intended only for monitoring purposes. Sub-rule 11b) was introduced to ensure that MDSW which has the same intended purpose as (hardware) devices which would fall under rule 10, third indent, are in the same risk class. However, this sub rule applies to MDSW intended to be used for monitoring any/all physiological processes and not just vital physiological processes (equivalent to rule 10, third indent). Vital physiological processes and parameters include, for example, respiration, heart rate, cerebral functions, blood gases, blood pressure and body temperature. Sub-rule 11c): Sub-rule 11c) implies that all other MDSW is classified as class I. 4.2.2. Rule 12 – Active devices intended to administer and/or remove substances As software devices cannot physically administer and/or remove substances, please refer to the implementation rule 3.3 of Annex VIII for MDSW covered by this rule. 4.2.3. Rule 13 – All other active devices Taking into consideration all implementing and classification rules applicable to active devices, if no other rule applies, all other active devices are class I. 24 4.2.4. Rule 15 - Devices used for contraception Rule 15 applies to devices used for contraception or prevention of the transmission of sexually transmitted diseases. Software used for contraception will be classified as class IIb. 24 Specific implementation or classification rules for active Annex XVI devices (which might also include software) are expected to be provided together with the relevant Common Specifications for those devices. Page 15 of 28 4.2.5. Rule 22 – Closed loop systems Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. See also implementing rule 3.3 fo r MDSW covered by this rule. Further horizontal Guidance on the application of MD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . This is expected to provide useful orientation in relation to the application of non-software specific classification rules. 5. Classification and implementing rules per IVDR 2017/746 5.1. Implementing Rules: All implementing rules in Annex VIII of Regulation (EU) 2017/746 shall be considered. Special considerations on Implementing Rule 1.4 and 1.9: Implementing rule 1.4 is only applicable for software which drives or influences the use of an in vitro diagnostic medical device. This rule should also be considered at least as an orientation for finding the right (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. According to the second sentence of implementing rule 1.4 , if the software is independent of any other device, it shall be classified in its own right. Examples for applying this implementing rule under the in vitro diagnostic medical devices regulation:  Software that is exclusively intended to drive or influence the use of an instrument intended by the manufacturer specifically to be used for in vitro diagnostic procedures is classified in the same class as the instrument.  A software that is intended to operate (driving) a C-reactive protein (CRP) measuring analyser from a remote location is classified in the same class as the analyser i.e. if the analyser is a classified as class A then the software operating the analyser falls into Class A.  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring; this is an independent IVD MDSW and is classified on its own. Implementing rule 1.9 states that if several classification rules apply to the same device based on the devices’ intended purpose, the rule resulting in higher classification will apply. To classify In Vitro Diagnostic Medical Device Software (IVD MDSW) which is independent of any other device, see the MDCG Guidance on Classification of IVDs when available at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . 5.2. Classification Rules: In determining the proper classification of MDSW under the IVDR, the manufacturer shall consider all classification and implementing rules of Annex VIII of the IVD Regulation (EU) 2017/746. As spelled out by Implementing Rule 1.1 of Annex VIII of Regulation (EU) 2017/746, the application of the classification rules shall be governed by the intended purpose of the MDSW. Page 16 of 28 Guidance on the application of the IVD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en25 Examples for the classification of MDSW under the IVDR:  Software intended to be installed on a fully automated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA, intended to screen for and diagnose diabetes and monitor diabetic patients, should be in class C per Rule 3(k).  Software within a PAP stain automated cervical cytology screening system, intended to classify the PAP cervical smear as either normal or suspicious, should be in class C per Rule 3(h).  Software for the interpretatio n of automated readings of line immunoassay for the confirmation and determination of antibodie s to HIV-1, HIV-1 group O and HIV-2 in human serum and plasma, should be in class D per Rule 1.  Software that uses maternal parameters such as age, concentration of serum markers and information obtained through foetal ultrasound ex amination for evaluating the risk of trisomy 21, should be in class C per Rule 3(l). Classification examples in Annex IV are provided for guidance purposes and aim to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules must also be considered. 6. Considerations on placing on the market and conformity assessment of MDSW The type of interconnection between the MDSW and the device (e.g. embedded systems, wires, Wi-Fi, Bluetooth) does not affect the qualification of the software as a device under the MDR and IVDR (e.g. whether the software is incorporated in a device or is at a different location). However, MDSW can be placed on the market in two different ways: as a medical device or in-vitro diagnostic medical device in its own right or as an integral component or part of a hardware device. 6.1. Option 1: as a medical d evice in its own right MDSW may be placed on the market or put into service in its own right.  MDSW intended to be installed on a fully aut omated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW app that provides a 10-year risk of cardiovascular disease from data input by a lay user.  MDSW app that calculates anticoagulant dosage fo r patients in oral anticoagulant therapy, from INR test results input by IVD instrume nts and other manually entered patient data.  MDSW app that analyses digital images of stained HEp-2 cell substrates from a microscope, for detecting antinuclear antibody (ANA) patterns to guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. Conformity assessment: 25 Please note that at the time of the adoption of this document, the referenced Guidance on the application of IVDR classification and implementing rules was under finalisation. Page 17 of 28 MDSW placed on the market as a device or put into service in its own right shall undergo an appropriate regulatory process that shall take into consideration the qualification, classification and intended purpose of the MDSW. 6.2. Option 2: as an integral component/part of a device MDSW may be placed on the market or put into service as an integral component/part of a device.  MDSW contained within a blood gas analyser that enables a user to run tests on the instrument.  MDSW that is part of a handheld hardware device intended for near-patient testing (POCT: point of care testing) for the determinat ion of the blood glucose concentration.  A fully automated enzyme-linked immunosorb ent assay (ELISA) analyser, composed of hardware and MDSW, intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW that is part of a pulse oximeter intended to digitally filter the noise from low perfusion performance and motion artefacts, to calculate the ratio of red light/infrared light and to use a lookup table based on Beer-Lambert law to convert the ratio into the oxygen saturation in a person’s blood (SpO2). Conformity assessment: MDSW that is placed on the market or put into se rvice solely as an integral component/part of a (hardware) device may not have to undergo its own regulatory process. 26 In this case, the MDSW shall be assessed through the regulatory process applied to the device as a whole, as it is placed on the market. Applying the classification rules to these hardware devices, which is de-facto a combination of the hardware device and the MDSW, requires careful consideration of the intended purpose of the MDSW. This must also be analysed when later changes to the MDSW are done. Note: MDSW could be independent under both scenarios described in 6.1 and 6.2, despite the presentation in which it is placed on the market. 7. Modules Some medical device software may be segregated into a number of applications where each of these applications is correlated with a module. Some of these modules have a medical purpose, some not. Such modules may be intended to cover many needs, e.g.:  Collect and maintain administrative patient data;  Keep on file the medical history of the patient;  Invoicing and other accounting functions;  Provide a link to the social security system for reimbursement;  Provide a link to drug prescription systems (with possible link to drug dispensing outlets);  Provide expert system assistance for medical decision making (e.g. radiotherapy dose planner). 26 Note: MDSW that is intended specifically to replace a part or com ponent of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation (see Article 23.2 (2)). Page 18 of 28 This raises the issue as to whether the whole product can be CE marked when not all applications have a medical purpose. Computer programmes used in healthcare can have applications which consist of both medical device and non-medical device modules. The modules which are subject to the Medical Devices Regulations (figure 1 and 2) must comply with the requirements of the medical device regulations and must carry the CE marking. The non-medical device modules are not subject to the requirements for medical devices. It is the obligation of the manufacturer to identify the boundaries and the interfaces of the different modules. The boundaries of the modules which are subject to the medical device regulations should be clearly identified by the manufacturer based on the intended use. If the modules which are subject to the medical device regulations are intended for use in combination with other modules of the whole software stru cture, other devices or equipment, the whole combination, including the connection system, must be safe and must not impair the specified performances of the modules which are subject to the medical device regulations. 27 8. Consideration of changes to an MDSW Manufacturers shall evaluate the potential impact of any changes to the function, intended use, essential design, and manufacturing characteristics on the software’s qualification as MDSW and its classification (including the classification of the combination of the MDSW with another medical device). It is to be noted that a change to or the addition of functionality to a software may lead it to be qualified as MDSW, or a revision of the classificati on of the MDSW. Similarly, a module that is added to a software might be qualified as a MDSW on its own. When determining the risk class of a combinati on of a modified MDSW and a medical device, the intended purpose and functionality of that (new) combination must be considered. Note: For all MDSW, the manufacturer shall ensure safety and performance throughout the lifecycle of the software, through a continuous process of clinical and/or performance evaluation and risk management. 9. Annex I: Illustrative examples of qualification of software used in the healthcare environment Software for a medical purpose is rapidly evolving. Thus, the list of examples provided below is not exhaustive. The examples have been drafted in light of today’s state of the art, in order to give the reader a better understanding of the application of the principles set out in the guideline. The Manual on borderline and classification in the Community regulatory framework for medical devices contains many examples related to qualification of software and apps, under the current 27 i.e. general safety and performance requirements 14.1 of EU MDR 2017/745 and 13.1 of EU IVDR 2017/746 Page 19 of 28 Directives28. The Manual is currently under revision for adaptation to MDRs. In light of the technological progress, further examples will be regularly published in both the Manual and in this guidance. a) Hospital Information Systems Hospital Information Systems mean, in this context, systems that support the process of patient management. Typically they are intended for patient admission, for scheduling patient appointments, for insurance and billing purposes. These Hospital Information Systems are not qualified as medical devices. However, they may be used with additional modules, as described hereafter. These modules might be qualified in their own right as medical devices. b) Decision Support Software In general, these are computer based tools which combine general medical information databases and algorithms with patient-specific data. They are intended to provide healthcare professionals and/or users with recommendations for diagnosis, prognosis, monitoring and treatment of individual patients. Based on Figure 1, they are qualified as medical devices.  Radiotherapy treatment planning systems 29 are intended to calculate the dosage of ionizing irradiation to be applied to a specific patient . They are considered to control, monitor or directly influence the source of ionizing radiation and are qualified as medical devices.  Drug planning systems (e.g. chemotherapy) are intended to calculate the drug dosage to be administered to a specific patient and therefore are qualified as medical devices.  Computer Aided Detection systems are intended to provide information that may suggest or exclude medical conditions are qualified as medical devices (MDSW). For example, such systems would be able to automatically analyse x-ray images or interpret ECGs. c) Information Systems Information Systems that are intended only to transfer, store, convert, format, archive data are not qualified as medical devices in themselves. However, they may be used with additional modules which maybe qualified in their own right as medical devices (MDSW). c.1.) Electronic Patient Record Systems Electronic patient record systems are intended to store and transfer electronic patient records. They archive all kinds of documents and data related to a specific patient. The electronic patient records should not be qualified as a medical device, i.e. an electronic patient record that simply replaces a patient’s paper file does not meet the definition of a medical device. The modules used with electronic patient record system modules that might be qualified in their own right as medical devices (MDSW) are for example:  An image viewer with functionality for diagnosis based on digital images;  A medication module 28 http://ec.europa.eu/DocsRoom/documents/12867/a ttachments/1/translations/en/renditions/native 29 See EN 62083 “Requirements for the safety and radiotherapy treatment planning systems” Page 20 of 28 c.1.1.) Clinical Information Systems – CIS / Patient Data Manag ement Systems – PDMS A CIS/PDMS is a software-based system primarily intended to store and transfer patient information generated in association with the patient’s intensive care treatment (e.g. intensive care units). Usually the system contains information such as patient identification, vital intensive care parameters and other documented clinical observations. These CIS/PDMS are not qualified as medical devices. Modules that are intended to provide additional information that contributes to diagnosis, therapy and follow-up (e.g. generate alarms) are qualified as medical devices. c.1.2.) Pre-hospital Electrocardiograph (ECG) System A system for managing pre-hospital ECG is a software-based system intended for ambulance services to store and transfer information from patients to a doctor at remote location. Usually the system contains information about patient identification, vital parameters and other documented clinical observations. These Pre-hospital Electrocardiograph (ECG) Systems are not qualified as medical devices. Modules that create and provide new patient treatment information to the paramedics or to the doctor at a remote location to start the patient’s treatment while the patient is being transported are qualified as medical devices. c.1.3.) Picture Archive Communication System (PACS) The Manual on Borderline and Classification in th e Community Regulatory Framework for Medical Devices addresses the qualification of PACS. 30 The transposition of this Directive Guidance to the Regulations is currently underway and will be published at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en d) Communication Systems The healthcare sector uses communication systems (e.g. email systems, mobile telecommunication systems, video communication systems, paging, etc.) to transfer electronic information. Different types of messages are sent such as prescription, referrals, images, patient records, etc. Most of the communication systems handle types of messages other than medical information. This communication system is intended for general purpos es, and is used for transferring both medical and non-medical information. Communication systems are normally based on software for general purposes, and do not fall within the definition of a medical device. Communication system modules might be used with other modules that might be qualified in their own right as medical devices (MDSW). A software module generating alarms based on th e monitoring and analysis of patient specific physiological parameters is qualified as a medical device (MDSW). d.1) Telemedicine systems Telemedicine Systems are intended to allow monitoring and/or delivery of healthcare to patients at locations remote from where the healthcare professional is located. 30 https://ec.europa.eu/docsroom/documents/35582/attachments/1/translations/en/renditions/native Page 21 of 28 d.1.1.) Telesurgery Telesurgery is intended to conduct a surgical procedure from a remote location. Virtual reality technology may be used to support a remote surgeon to control a surgical robot performing the surgical procedure. Telesurgery systems should be qualified as medical devices according to Figure 2 of this document. Remote control software used in combination with telesurgery robots is a software that drives or influences the use of a medical device. Communication modules themselves are not medical devices. Other modules that are intended to influence the su rgery procedure are qualified as medical devices (MDSW). e) Web systems for monitoring of data A web system for the monitoring of clinical data typically interacts with a medical device (e.g. implanted devices or homecare devices), and uses a transmitter to send the information over the internet, a landline telephone or a mobile network. The information is collected and stored on a web server usually run by an external party who is generally the manufacturer of the system. The information can be reached by authorized health professionals or the patient through an internet connection.  Monitoring of performance of medical devices: Modules that are intended to monitor the medical performance of medical devices fall under the medical device regulations. This includes the clinical performance and failures that could affect medical performance of the device. One example of such a product is a web system for monitoring of active implants such as pacemakers or Intra Cardiac Defibrillators (ICDs).  Monitoring of non-medical performance of medical devices Modules that are intended to perform administrative monitoring of non-medical performance of medical devices do not necessarily fall under the scope of the medical devices regulations. Software for the monitoring of medical devices in hospital systems for the purpose of maintenance and repair. f) In vitro diagnostic medical device software f.1.) Laboratory Information Systems (LIS) and Work Area Managers (WAM) Laboratory Information System (LIS) and Work Area Managers (WAM) mean, in this context, systems that support the process from patient sample to patient result. Typically, they have pre- analytical functions for ordering, sorting and distribution of test samples. The main task is the management and validation of incoming information obtained from in vitro diagnostic medical device analysers connected to the system, such as calibration, quality control, product expiry and feedback (e.g. retesting of samples needed) through interconnections with various analytical instruments (technical and clinical validation). Finally the post-analytical process allows communication of laboratory results, statistics and optional reporting to external databases. The software normally supports the following functions:  Ordering of laboratory tests, samples with labels and sorting;  Technical and clinical validation, connection to analytic instruments;  Laboratory results and reports on paper, fax or electronic records that can be directly returned to e.g. the ordering clinic’s patient record;  Analytical instruments can be interfaced with Hospital Information Systems (HIS), Electronic Patient Record Systems, Infectious control databases, etc. Page 22 of 28 Note : software intended to modify the representation of available in vitro diagnostic medical device results is not considered an in vitro diagnostic medical device, e.g. basic operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function of time, and/or a comparison of the result to the limits of acceptance set by the user. The results are available, readable and understandable without the intervention of the software. Laboratory Information Systems (LIS) and Work Area Managers (WAM) are not qualified as medical devices in themselves. However, they may be used with additional modules. These modules might be qualified in their own right as medical devices. A module whose intended purpose is to assess the criticality of tests required and to perform automatic reprioritisation of the order based on patient data is qualified as a MDSW. f.2.) Expert system MDSW which is intended to provide information within the scope of the in vitro diagnostic medical devices definition by capturing and analysing together one or multiple results obtained for one patient by means of in vitro examination of body samples (possibly combined with information from medical devices and non-medical devices).  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring;  MDSW that uses an algorithm to characterise viral resistances to various drugs, based on a nucleotide sequence generated by genotyping assays. This software serves to generate new information (virus resistance profile) from avai lable information on the genotype of the virus;  MDSW intended to be used in microbiology for the identification of clinical isolates and/or the detection of antimicrobial resistances. Refer to Figure 2 of this guidance if data is obtained from both in vitro diagnostic medical devices and medical devices. f.3.) Interpretation of raw data In the case where MDSW is necessary to render raw data, readable for the user, obtained from an in vitro diagnostic medical device by means of in vitro examination of body samples, this MDSW is to be considered driving or influencing the use of the in vitro diagnostic medical device when it is specifically intended to be used together with this in vitro diagnostic medical device to enable it to be used in accordance with its intended purpose. MDSW intended for the analysis and interpretatio n of enzyme-linked immunosorbent assay (ELISA) reader optical density results, line patterns or spot patterns of a blot. f.4.) Home care monitoring, wired or mobile Software intended for archiving patient result s or for transferring results obtained from in vitro diagnostic medical devices from the home environment to the healthcare provider is not an in vitro diagnostic medical device. The results are available, readable and understandable by the user without the intervention of the software. f.5.) Image Management System (IMS) An IMS is a software-based system primarily intended to be networked with digital pathology systems, e.g., whole slide scanners, scanning microscopes, as well as LIS. It does not contain controls for the direct operation of the digital pathology syst ems, and is intended to access, display, annotate, manage, store, archive and share collections of digitised patient images. IMS may be configured to Page 23 of 28 provide limited or extensive capabilities to further visualise or analyse patient images acquired from networked digital pathology systems. An IMS only used for viewing, archiving and transmitting images are not considered medical devices in themselves. However, these IMS may be used with additional modules that might be qualified in their own right as medical devices (MDSW). IMS that incorporate functions to support post-processing of images for diagnostics purposes, e.g., image processing functions which alter image data or complex quantitative functions to aid in diagnosis, are qualified as MDSW. Page 24 of 28 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 Figure 1 - Example 1: A software module which runs on an in vitro diagnostic medical device instrument and tracks how the laboratory is performing in real-time on key operational metrics such as test volumes, turnaround times, pending tests, and quality control. Its intent is to improve a laboratory’s operations by providing real-time monitoring of performance metrics that can drive change management and continuous improvement initiatives within the lab. The software is configurable so that customers can choose the metrics on which they would like to focus. Qualification: Step 1 is concluded with a “yes” as the software is a product which uses a set of instructions (or algorithm) to process input data and create output data. Step 2 determines that the software is not an MDR Annex XVI device, nor is it an accessory for a medical device, nor a software driving or influencing the use of a medical device. Step 3 is answered “yes” since the software is doing more than storage, archival, communication or simple search of information. Step 4 is answered “no” as the software does not perform this action for the benefit of individual patients. The conclusion is that the software does not fall under the Medical Devices Regulations. This is appropriate since the software is intended to be a Laboratory Information Systems (LIS), which is not considered a medical device. Figure 2 - Example 2: MDSW intended to generate a risk score in order to trigger care processes to help reduce ICU transfers, readmissions, adverse events and length of stay. The risk score by default includes respiratory rate, heart rate, blood pressure and Sp O2, but a user can configure it to include other parameters, including in vitro diagnostic medical device results. Qualification: In decision Step 1, the MDSW can be understood to meet criteria (a), (f) and (h), it is therefore answered “yes”. Step 2 is answered with a “No” as an in vitr o diagnostic medical device result may be included in the in the calculation. Step 3 directs the significance of the medical device derived information as driving the intended purpose, re sulting in the qualification of the software as an MD MDSW (as the data received from the in vitro diagnostic medical device is not deemed decisive for the overall calculation result (output) achieved by the MDSW) Figure 2 - Example 3: A MDSW algorithm intended to provide information on the statistical predisposition for Down syndrome (Trisomy 21) and Edwards syndrome (Trisomy 18) in the first and second trimesters of pregnancy. 31 The MDSW analyses input data from various in vitro diagnostic medical device assays32 as well as, ultrasound measurements of the nasal bone or neck fold. The MDSW provides clinicians/obstetricians with a risk factor score for a foetus’s likelihood of having genetic mutations in the first or second trimester of pregnancy. The risk score suggests whether or not additional diagnostic testing is needed to confirm the genetic mutations of Trisomy 21, Trisomy 18. 33 Qualification: Step 1 can be answered “yes” as the software bears a medical purpose and fulfils the definition of MDSW. The MDSW meets criteria (c) as it provides information according to the in vitro 31 The software can also detect neural tube defects (NTD) in the second trimester as well as the risk for Patau’s syndrome (Trisomy 13). 32 AFP (LKAP, L2KAP), Unconjugated Estriol (LKUE3, L2KUE3), hCG (LKCG, L2KCG), free β-hCG (LKFB, L2KFB), PAPP A (LKPC, L2KPC) 33 or neural tube defects and Trisomy 13 Page 25 of 28 diagnostic medical devices definition. Decision step 2 is answered “no” as an imaging measurement is included in the calculation. Step 3 is answered “yes” as the intended purpose is substantially driven by in vitro diagnostic medical device data resulting in the qualification of the software as an IVD MDSW (as the data received from the in vitro diagnostic medical devices (markers) are deemed decisive for the overall calculation result (output) achieved by the MDSW). Figure 2- Example 4: A bioinformatics MDSW intended to analyse digi tal Next Generation Sequencing (NGS) raw data coming from sequenced patient’s cancer genomes. It allows the detection and visualisation of somatic genome alterations (such as substitutions, small insertions and deletions (indels), copy number alterations, and genomic rearrangements) across a selected number of genes. Additionally, it is also capable of determining genomic signatures* (such as microsatellite instability [MSI] and/or tumour mutational burden [TMB]). The types of somatic genome alterations and genomic signatures detected depend on the test chosen. The MDSW assists the user in identifying and visualising genomic alterations and is intended to identify somatic genome alterations to support diagnosis and treatment decisions. Qualification: Decision step 1 is concluded with a “yes” as the MDSW is intended for analysing congenital data to provide information on the predisposition to a medical condition or disease, thus meeting criteria (b) and (c) laid out in the decision step. As the MDSW processes data coming only from in vitro diagnostic medical devices into the calculation, then the software is qualified as an IVD MDSW according to Step 2. Page 26 of 28 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 34 The table below, which is intended for illustrative purposes only, may provide operators placing MDSW on the EU market with some useful indicative orientation on the risk class applicable to their products as a result of the application of Rule 11 a of the MDR. Note: MDR 2017/745 Sub-rule 11(a), point i., referr ing above to MDR class III, aligns with IMDRF risk category IV . Sub-rule 11(a), point ii.,, referring above to MDR class IIb, aligns with IMDRF risk category III products mentioned in section 7.2 of the mentioned IMDRF document. The IMDRF risk category II and IMDRF risk category I products are classified as MDR class IIa as per Rule 11. This table does not take into account MDSW which is Class I. Significance of Information provided by the MDSW to a healthcare situation related to diagnosis/therapy State of Healthcare situation or patient condition High Treat or diagnose ~ IMDRF 5.1.1 Medium Drives clinical management ~ IMDRF 5.1.2 Low Informs clinical management (everything else) Critical situation or patient condition ~ IMDRF 5.2.1 Class III Category IV.i Class IIb Category III.i Class IIa Category II.i Serious situation or patient condition ~ IMDRF 5.2.2 Class IIb Category III.ii Class IIa Category II.ii Class IIa Category I.ii Non-serious situation or patient condition (everything else) Class IIa Category II.iii Class IIa Category I.iii Class IIa Category I.i Table 1: Classification Guidance on Rule 11 34 Annex III and IV are not relevant for IVD MDSW. See sec tion 4.2 in order to classify IVD MDSW. MDCG Guidance on Classification of IVDs should also be considered. Page 27 of 28 12. Annex IV – Classification examples The examples are provided for guidance purposes only, to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules might also be considered. Moreover, the proposed classification reflects the specific intended purpose, or the healthcare context or situation, in which the device is used as described in the example itself. Any change to the intended purpose or the healthcare context/situation in which that same device is used might result in a different risk class.  MDSW intended to perform diagnosis by means of image analysis for making treatment decisions in patients with acute stroke should be classified as class III under Rule 11(a) - IMDRF Risk Category IV.i as the healthcare situation (stroke) is critical and the significance of the information is “treat or diagnose”.  Cognitive therapy MDSW that includes a diagnostic function which is intended to feed back to the software to determine follow-up therapy , e.g. software adapts treatment of depression based on diagnostic feedback, should be in class III per Rule 22 . When a specialist determines the necessary cognitive therapy base d on the outcome provided by the MDSW, the MDSW would be classified as class IIa per Rule 11(a). - IMDRF Risk Category II.ii as the healthcare situation is serious and the significance of the information is to “drive clinical management”.  Medical devices including MDSW intended to be used for continuous surveillance of vital physiological processes in anaesthesia, intensive care or emergency care should be classified as class IIb per (Rule 11(b)) .  Medical devices, including MDSW intended to monitor physiological processes that are not considered to be vital, and devices intended to be used to obtain readings of vital physiological signals in routine check-ups incl uding monitoring at home should be classified as class IIa (Rule 11(b)).  A mobile app intended to analyse a user’s he artbeat, detect abnormalities and inform a physician accordingly should be classified as class IIb per Rule 11(a) , if the information provided by the software is intended to guide the physician in the diagnosis. - IMDRF Risk Category III.i as the information drives clinical management.  Diagnostic MDSW intended for scoring depression based on inputted data on a patient’s symptoms (e.g. mood, anxiety) should be classified as class IIb under Rule 11(a) , - (IMDRF Risk Category III.ii) as the healthcare situation (depression) is serious and the significance of the information is “diagnosis”).  Ambulatory respiratory ventilation systems MD SW intended for long-term use (e.g. at home) that alert the user/operator to any disconnection or deviation to the programmed respiratory volume should be classified as class IIb per Rule 9 .  Active devices, such as electronic thermometers and stethoscopes, which include MDSW intended for direct diagnosis may be classified as class IIa per Rule 10 , third indent since body temperature and heart rate are considered decisive information for diagnosis (implementing rule 3.7), where the nature of the variations of these parameters would not result in immediate danger to the patient.  MDSW intended to rank therapeutic suggestions for a health care professional based on patient history, imaging test results, and patient characteristics, for example, MDSW that lists and ranks all available chemotherapy options for BRCA-positive individuals, should be classified as class IIa per Rule 11(a) Page 28 of 28 - IMDRF Risk Category II.i as it informs clinical management for cancer, a critical disease.  MDSW app intended to support conception by calculating the user’s fertility status based on a validated statistical algorithm. The user inputs health data including basal body temperature (BBT) and menstruation days to track and predict ovulation. The fertility status of the current day is reflected by one of three indicator lights: red (fertile), green (infertile) or yellow (learning phase/cycle fluctuation). This MDSW app should be classified as class I per Rule 11c.

md_mfr_factsheet.pdf.txt

Factsheet for Manufacturers of Medical Devices What you need to know!MEDICAL DEVICES CHANGE OF LEGISLATION This Factsheet is aimed at manufacturers of medical devices. For a general overview of the impact of the In-Vitro Medical Devices Regulation (IVDR) on manufacturers see the Factsheet for manufacturers of in-vitro diagnostic medical devices. Refer - ences to Annexes and Articles in this factsheet refer to the MDR (2017/745/EU). The new Medical Devices Regulation (2017/745/EU) (MDR) and the In-vitro Diagnostic Medical Devices Regulation (2017/746/EU) (IVDR) bring EU legislation into line with technical advances, chang - es in medical science, and progress in law making. The new Regulations will create a robust, transparent, and sustainable regulatory framework, recognised internationally, that improves clinical safety and creates fair market access for manufacturers. In contrast to Directives, Regulations do not need to be transposed into national law. The MDR and the IVDR will therefore reduce the risks of discrepancies in inter - pretation across the EU market. Transitional periods are planned to smooth the application of the new Regulations. However, you should bear in mind that con - sultants, in-house professionals, and Notified Bodies will all get busier as the deadline draws closer. Act now to be ready on time! Medical Devices Regulation (MDR) background The MDR will replace the existing Medical Devices Directive (93/42/EEC) (MDD) and the Active Implantable Medical Devices Directive (90/385/EEC) (AIMDD). The MDR was published in May 2017, marking the start of a three-year period of transition from the MDD and the AIMDD. During the transitional period the MDR will come into force gradually, start - ing with the provisions related to the designation of Notified Bodies and the ability of manufacturers to apply for new certificates under the MDR. The transitional period will end on 26 May 2020, the “Date of Application” (DoA) of the Regulation. From that date the MDR will apply fully. 1 Internal market, Industry, Entrepreneurship and SMEs Ref. Ares(2018)3873669 - 20/07/20182To avoid market disruption and allow a smooth transition from the Directives to the Regulation, several transitional provisions are in place (Article 120). Some devices with certificates issued under the Directives (AIMDD/MDD certificates) may continue to be placed on the market until 27 May 20241, and made avail - able until 27 May 20252 . During the transition phase, products certified under the Direc - tives and products certified under the Regulation will coexist on the market. Both will have equal status under the law, and no discrimination in public tenders may take place. What has changed? In terms of their impacts on manufacturers and products, the Directives and the MDR largely share the same basic regulatory requirements. No existing requirements have been removed, but the MDR adds new requirements. Compared to the current Directives, the MDR places more em - phasis on a life-cycle approach to safety, backed up by clinical data. The MDR brings more stringent requirements for the designation of Notified Bodies, with increased control and monitoring by the national competent authorities and the Commission. The MDR reclassifies certain devices and has a wider scope. For instance, the MDR explicitly covers all devices for cleaning, sterilising or disinfecting other medical devices (Article 2.1); re - processed single-use medical devices (Article 17)3; and certain devices with no intended medical purpose (Annex XVI). The MDR also covers internet sales of medical devices and med - ical devices used for diagnostic or therapeutic services offered at a distance (Article 6). The MDR introduces a clinical evaluation consultation procedure for some Class IIb devices and for implantable Class III devices by an independent expert panel (Article 54). A new Unique Device Identification system (Article 27) will significantly enhance the traceability and the effectiveness of post-market safety-related activities. The MDR will also provide increased transparency, with infor - mation on devices and studies being made public. The new Eu - ropean Database for Medical Devices – Eudamed – will play a central role in making data available and increasing both the quantity and quality of data (Article 33). 1 For definition see Article 2 paragraph 282 2 For definition see Article 2 paragraph 27 3 Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 4 EEA: European Economic Area What does this mean in practice? Scope (Article 1) The scope of the MDR has broadened, so as a manufacturer you must check your product portfolios to find out whether more of your devices fall within the scope of the Regulation compared to the Directives. Pay attention to products listed in Annex XVI, which will be covered by the Regulation once the respective Im - plementing Regulation setting out common specifications has been adopted. The list of products excluded from the scope can be found in paragraph 6. Some products that combined a medi - cal device and an in-vitro diagnostic device or a medicinal prod - uct follow specific rules (see paragraphs 7, 8, 9). It is now explicit that devices and services sold online fall under the scope of this Regulation (Article 6). Definitions (Article 2) The definition of a medical device has been slightly modified and there are more definitions of terms in the Regulation than in the Directives, in order to ensure a common understanding at EU level. Examples include: Unique Device Identifier (Definition 15), clinical data (Definition 48), clinical evidence (Definition 51), and serious incident (Definition 65). Obligations of manufacturers The obligations of the different actors and their relations are now clearly stated in the Regulation. According to Article 10, manufacturers shall have systems for risk management (paragraph 2) and quality management (paragraph 9); conduct clinical evaluations (paragraph 3); com - pile technical documentation (paragraph 4); and apply a confor - mity assessment procedure (paragraph 6). Manufacturers are also responsible for their devices once they are on the market (paragraphs 12, 13, 14). They must have systems in place to cover their financial responsibility for harm caused by defective devices (paragraph 16). Every manufacturer shall have a named person responsible for regulatory compliance (Article 15). Manufacturers of some implantable devices will have to provide an implant card for the patient (Article 18). Once they have completed all these obligations, manufacturers shall draw up a declaration of conformity (Article 19) and apply CE marking to their devices (Article 20). Manufacturers outside the EU/EEA shall have a contract with an authorised representative inside the EU/EEA4 (Article 11).3The obligations of authorised representatives (Article 11), importers (Article 13) and distributors (Article 14) are also clearly described. Risk classes of devices As a manufacturer you must check your portfolio of products to determine whether some of your devices will be reclassified or will need to be scrutinised by a Notified Body. Determining the risk class of a medical device is essential in specifying the steps required for CE marking (Article 51), especially in terms of the choice of conformity assessment procedure and clinical requirements. The MDR sets out 22 rules for determining risk classes (Annex VIII), compared to 18 rules under the Directive. You should pay special attention to rules regarding: invasive devices, surgically invasive devices and implantable devices (Section 5: Rules 5 to 8); active devices (Section 6: Rules 9 to 13, for example, soft - ware now falls under Rule 11); devices utilising tissues and cells (Rule 18); devices incorporating nanomaterials (Rule 19); and devices composed of substances (Rule 21). Notified Bodies (Chapter IV) Notified Bodies have to be designated under the new Regula - tion. They will be required to meet more stringent criteria, par - ticularly in terms of clinical competence. Notified Bodies can apply to be designated from 26 November 2017. The process of designation, which might take 12 months or more, involves assessors from different national and European authorities. This means that the first Notified Bodies designated under the new Regulation might be available by the end of 2018. The database of Notified Bodies (NANDO) can be found here. http://ec.europa.eu/growth/tools-databases/nando/ As a manufacturer you must verify whether your Notified Body will be designated under the new Regulation and whether the scope of its designation will cover all your products. You must also start working with your Notified Body to plan the timing of certification for your product portfolio, taking into account the availability of your Notified Body, the need for additional data on devices and the transitional provisions in the new Regulation. Device identification A system of unique device identifiers (UDIs) will enhance the identification (Article 27) and traceability (Article 25) of MDs. This is a completely new feature of the Regulation. Each MD – and as applicable, each package – will have a UDI composed of two parts: a device identifier (UDI-DI) specific to a device, and a production identifier (UDI-PI) to identify the unit producing the device.Manufacturers are responsible for entering the necessary data on the European database (Eudamed), which includes the UDI database, and for keeping it up to date. Conformity assessment (Chapter V Section 2) The assessment of the conformity of a device for CE marking varies according to the risk class and specific features of certain devices (Article 52). The intervention of a Notified Body is need - ed for all Class IIa, IIb and III devices, as well as some specific Class I devices (see paragraphs 7a5, b6, and c7). The different routes of assessment according to the class of the device are described in Article 52 and the Annexes IX, X, XI. In some cases manufacturers have some choice regarding the conformity as - sessment route. For certain Class III and Class IIb devices there is a new clinical evaluation consultation procedure to be carried out by an inde - pendent expert panel, based on the clinical evaluation assess - ment report of the Notified Body (Article 54). Annex I specifies the general safety and performance require - ments, while Annexes II and III specify the makeup of the tech - nical documentation. The scope of the Quality Management System (Article 10 para - graph 9) now includes clinical evaluation and post-marketing clinical follow-up (PMCF). A clinical evaluation plan must pre - cede the clinical evaluation itself (Annex XIV, Part A). Common specifications defining additional requirements may be put in place for certain devices (Article 9). Clinical requirements (Chapter VI) The new Regulation reinforces the requirements for clinical evaluation (Article 61), introducing some of the biggest changes compared to the previous regime. As under the Directives, it includes the collection of clinical data already available in the literature as well as the setting up of any necessary clinical investigations. The concept of equiva - lence with other devices for which clinical data already exists can still be used, but only in a limited number of situations, and the new rules are tighter (Article 61 paragraphs 4, 5, 6). Article 62 and Annex XV set out the new and more precise re - quirements for clinical investigations. With only certain excep - tions, implantable and Class III medical devices must now go through clinical investigations. For all Class III devices, and for Class IIb devices intended to administer a medicinal product (or remove it from the body), the manufacturer has the option to consult a group of European experts to obtain an upstream review of its intended clinical de - velopment strategy (Article 61 paragraph 2). 5 “Devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions”. 6 “Devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements”. 7 “Reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use”.4Summary of safety and clinical performance (Article 32) For Class III and implantable devices, manufacturers shall draw up a summary of their safety and clinical performance in a form that intended users (and patients, if relevant) can understand. This summary will form part of the technical documentation sent to the Notified Body Timing your transition to the new Regulation As a manufacturer, the timing of your transition to the MDR is up to you. From 26 May 2020, all new certificates will have to be delivered according to the Regulation. The certificates delivered under the Directives can be valid until their date of validity for a maximum of four years (27 May 20248 at the latest). However, in the latter case, the requirements of the new Regulation relating to post-mar - ket surveillance, market surveillance, vigilance, and the registration of economic operators and devices shall apply from the Date of Application (Article 120 paragraph 3). Class I devices (other than those that have a valid certificate under the Directive) will have to conform to the new Regulation from 26 May 2020. Class I (except sterile devices, devices with a measuring func - tion and reusable surgical instruments) and Class IIa might be easiest to start with. Classes IIb and III will be more challenging because of the more stringent requirements for clinical data. As a manufacturer, you can start now by making sure that: 1. all your products are classified appropriately; 2. all product documentation and evidence of compliance will be available in a timely fashion and conforms with the MDR; and 3. you have the necessary systems in place to handle clinical evaluation, quality management, post-market surveillance, and liability for defective devices. More information For more information on any of the above topics, please refer to the Medical Devices section on the DG GROW website. https://ec.europa.eu/growth/sectors/medical-devices_en Frequently asked questions Below you can find an extract from the FAQs of the Competent Authorities for Medical Devices. For a complete list, see: http://www.camd-europe.eu/sites/default/files/media/docu - ments/FAQ_MDR_180117_V1.0.pdf . When does the Medical Devices Regulation (MDR) apply? The MDR (EU) 2017/745 will apply from 26 May 2020 – the “Date of Application” (DoA). Some provisions of the MDR will come into force earlier (e.g. regarding Notified Bodies and the Medical Device Coordination Group). Some will apply later (e.g. regarding UDI labelling). When do the existing Directive cease to apply? In general, Directives 90/385/EEC and 93/42/EEC will be repealed on 26 May 2020 (the DoA). However, there are some exceptions, such as: • for the continued marketing of devices that comply with the Directives (see below); and • to serve as a backup in case Eudamed is not fully functional by the DoA. What is the applicable legislation up to 26 May 2020? Until the Date of Application, the laws and regulations adopted by Member States in accordance with the Directives will contin - ue to apply. However, there are some exceptions. Is it possible to place devices on the market that are compliant with the MDR prior to the DoA? Yes, you may certainly place MDR-compliant devices on the market before the end of the transitional period. This applies to devices in all risk classes, and includes, for example, cus - tom-made devices, systems and procedure packs. However, devices subject to the “clinical evaluation consultation procedure”, which covers certain devices in Classes IIb and III, may not be placed on the market before the Medical Device Coordination Group (MDCG) and the expert panels have been established. Depending on the risk class of the device, conformity assess - ment may involve an appropriate Notified Body. This require - ment may create further delays before such devices can be marketed due to the delays in the availability of appropriate Notified Bodies for all technologies. 8 There are some exceptions described in Article 120 paragraph 25As a manufacturer, which obligations of the Regulation do I need to fulfil in order to place compliant devices on the market before the DoA? You should meet as many obligations as possible, bearing in mind that the complete MDR infrastructure, including Eudamed, is unlikely to be complete before the Date of Application. Both the device and the manufacturer must comply with the MDR. You should assess the conformity of your device – a pro - cess that may require the involvement of a Notified Body. Other important points include: • Clinical evaluation • Risk management • Quality Management System (QMS) • Post-market surveillance • Technical documentation and other reports • Liability for defective devices. Until Eudamed is fully operational, some parts of the Directives will have to substitute for the corresponding requirements of the Regulation. These include the registration of devices and economic operators. A person responsible for regulatory compliance needs to be available but not necessarily registered until Eudamed is operational. Do certificates issued by Notified Bodies under the existing Directives remain valid after the DoA? Yes, AIMDD/MDD certificates will generally remain valid un - til their indicated expiry dates. This applies to all the certifi - cates commonly issued by Notified Bodies, including the EC Design- Examination Certificates, Certificates of Conformity, EC Type Examination Certificates, the EC Certificate Full Quality Assurance System, and the EC Certificate Production Quality Assurance.However, all certificates issued after 25 May 2017 will be void at the latest by 27 May 2024. After this date there will be no more valid AIMDD/MDD certificates. Is it possible to have valid MDR and AIMDD/MDD certificates in parallel until 27 May 2024? Yes. Can manufacturers still place on the market/put into service Directive-compliant devices after the end of the transition period? Yes, under certain conditions there will be an option to con - tinue placing on the market/putting into service devices that comply with the Directives until their existing certificates ex - pire. This may avoid the immediate need for a new certificate under the MDR. To use this option, all the existing certificates will have to be val - id (including, for example, the QMS), the purpose and nature of the device must not change, and you must follow the new MDR rules for registration, surveillance and vigilance. What is the “sell-off” provision about? The “sell-off” provision is intended to limit the time during which devices that are compliant with the Directives and have already been placed on the market may be made available. Any devices that are still within the supply chain and that have not reached their final user as being ready for use, for example a hospital, on 27 May 2025 are no longer marketable and must be withdrawn. Once a Directive-compliant device has been made available to the final user by the deadline, the further making available of this device is not subject to/covered by the Regulation. © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89634-7 DOI: 10.2873/614436 ET-03-18-102-EN-N

cnd_general_principles_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 13 The CND Nomenclature ‘Classificazione Nazionale Dispositivi medici’ Table of Contents 1. Background and General Principles ................................ ................................ ................................ ...... 2 2. The CND structure ................................ ................................ ................................ ................................ .. 4 Anatomic Categories – by anatomical area of use: ................................ ................................ ................... 6 Functional Categories – by intended use or clinical method: ................................ ................................ .... 6 Special Categories – by other criteria: ................................ ................................ ................................ ....... 6 Groups: the second hierarchical level ................................ ................................ ................................ ........ 7 Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) ........... 7 3. External links ................................ ................................ ................................ ................................ ........... 8 The purpose of this document is to provide information regarding the basic principles and the structure of the Italian “Classificazione Nazionale Dispositivi medici” (CND) . In March 2019, an d according to the criteri a set out by the Medical Device Coordination Group1 (MDCG) , the CND was selected as the basis for the future European M edical Device Nomenclature (EMDN ). The EMDN will support the functi oning of EUDAMED as stated by the MDCG and in accordance with Articles 23 of Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 2 of 13 1. Background and General Principles2 In 2005, the Italian Ministry of Health set out that the CND would be the official Italian medical device classification and nomenclature. Since then, t he CND has been implemented not only in Italy, but also in Portugal and Greece. About 15.000 manufacturers3 from various countries have used the CND for the registration of medical devices and in vitro diagnostic medical devices in the Italian database. The distribution of manufacturers of medical devices and in vitro diagnostic medical devices per countr y is reported below in Figure 1. Fig. 1 Distribution of manufacturers of medical devices per countr y The CND nomenclature is one of the tools used in the governance of the medical device sector and is characteri sed by its refined and hierarchical structure . It aims to support the improvement of patient safety and the quality of health systems by enabling information to be communicated in a standard ised manner . Updates and maintenance of CND: 2 The principles and rules presented thereafter are the ones historically established/followed when building the CND nomenclature u p to the last update in 2018. This is without prejudice to the new rules that will govern the EMDN which will be established by th e MDCG. 3 Source NSIS: data updated on 10 August 2019 31,6% 15,2% 10,2% 9,8% 3,9% 3,6% 2,7% 2,5% 2,0% 18,5% 0,0%5,0%10,0%15,0%20,0%25,0%30,0%35,0%Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 3 of 13 The construction of the CND , its subsequent updates and maintenance have been based on three fundamental principles. A) Participative approach: For the update and maintenance of a qualitative nomenclature, highly differentiated and qualified expertise is required. As the medical device sector is acknowledged for its heterogeneity and complex ity, a broad participation of all stakeholders (economic operators and healthcare professional from NHS - at all levels of its organisation ) is essential. B) Qualified validation of proposals : Nomenclature and Classification proposals are technically validated based on assessment s of actual need . Factors taken into consideration are:  other existing nomenclature and classification systems available at international level  consumption and expense information  assessment with sector experts from the different disciplines C) Formal adoption and free public availability: The CND system , which represents the basis of the whole information system on medical devices is formally approved and thus constitutes an offici al reference, freely available to all stakeholders. More information on previous updates of the CND up to 2018 can be found in Annex I of this document. The following pr oducts are currently not included in the CND :  Medicinal products  Cosmetics products  Human blood and its derivatives;  Organs, tissues and cells of human origin, products including human tissues and cells and products derived therefrom.  Organs, tissues and cells of animal origin except medical devices manufactured using animal devitalized tissues o r devitalized products derived from animal tissue.  Individual Protection Devices Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 4 of 13 2. he CND structure The CND is characterised by its alphanumeric structure that is established in a multi -level hierarchical tree . It clusters medical devices in three main levels:  Category: the first hierarchical level  Group: the second hierarchical level  Type: the third hierarchical level (which if necessary, expands into several levels of detail (1°, 2°, 3°, 4° e 5°)) Each medical device is classified by an alphanumeric code consisting of a letter referring to the “Category”, a couple of numbers referring to the “Group” and a series of other couples of numbers referring to the “Type” (whose amount depends on the level o f detail) up to a maximum of 7 levels . Each level isidentified by: •an alphanumeric code (max 13 digits ) A ## ## ## ## ## ## Level 1: C ategoriesLevel 2: GroupsLevel from 3 to 7: TypesMedical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 5 of 13 Categories: the first hierarchical level The first hierarchical level of the CND is defined as a “Category”. There are 22 categories, each identif ied by a letter of the alphabet: Each “Category ” includes devices regulated under Directive 93/42/EEC, 90/385/EEC or 98/79/EC or following a dedicated prescription from reimbursement rules in Italy. These “categories” are used for the same specific apparatus, anatomical district or organ or as a replace ment of them (anatomical categories), or devices characterised by similar use, intended use or clinical m ethod (functional categories). Considering these criteria and the ramified tree structure with different detail level, the following Anatomic (8), Fun ctional (9) and Special (5) Categories have been defined: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 6 of 13 Anatomic Categories – by anatomic al area of use: • B – HEMATOLOGY AND HEMOTRANSFUSION DEVICES • C – CARDIOCIRCULATORY DEVICES • F – DYALISIS DEVICES • G – GASTROINTESTINAL DEVICES • N – DEVICES FOR NERVOUS AND MEDULLAR SYSTEMS • Q – DENTAL, OPHTALMOLOGIC AND ENT DEVICES • R – RESPIRATORY SISTEM AND ANAESTHESIA DEVICES • U –UROGENITAL APPARATUS DEVICES Functional Categories – by intended use or clinical method: • A – DEVICES FOR ADMINISTRATION, COLLECTING AND PICKING • D – DISINFECTANTS, ANTISEPTICS AND P ROTEOLYTICS FOR MEDICAL DEVICES (regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • H – SUTURE DEVICES • K – ENDOTHERAPY AND ELECTROSURGICAL DEVICES • L – REUSABLE SURGICAL INSTRUMENT S • M – DEVICES FOR GENERIC AND SPECIALISTIC MEDICATION • S – STERILIZATION DEVICES • T – PROTECTION DEVICES AND INCONTINENCE AIDS ( regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • V – MEDICAL DEVICES - VARIOUS Special Categories – by other criteria : • J – ACTIVE -IMPLANTABLE DEVICES : MDs regulated by Directive 385/90 EEC • P – IMPLANTABLE PROSTHETIC DEVICES AND OSTEOSYNTHESIS DEVICES : non-active implantable MDs • Y – SUPPORTS OR TECHNICAL AIDS FOR DISABLED PERSONS • W – IN VITRO DIAGNOSTIC DEVICES MDs regulated by Directive 98/79 EEC • Z – MEDICAL EQUIPMENT AND RELATED ACCESSORIES AND MATERIALS Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 7 of 13 Groups : the second hierarchical level The second hierarchical level s are called “Group s”. There are 146 anatomical/functional Medical Devices Gr oups 4, which represent the various differentiations that distinguish devices contained in the Categories. They are identified by two -digit nu mbers from 01 to 99 for each Category. Number “90” identifies the gr oups of devices having various characteristics that are not related to existing gro ups. Number “99” “Altri – Others” is reserved to medical d evices that are not included in already existing Groups and will be categori sed in later updates. Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) The “Type” represents the third hierarchical level . If necessary, it expands into several level s of detail (1°, 2°, 3°, 4° and 5°). The group of every type includes medical devices characteri sed by a high affinity of use, intended use or s imilar clinical method. In case of doubt, the peculiar characteristics of the medical device under examination should be considered for a proper collocation or search proces s (i.e. the anatomic -functional characteristics and/or the intended use declared by the manufacture r). As explained, the term “ot hers” marked with the code “99 ”on the first detail level is suitable for devices not included i n existing types. The “99” types will be submitted for later updates. Th e code reserved to the generic term “others” must be used by users only if it is not possible to classify the medical device in existing typologies . This type is subject to continuous checks and monitoring. Regarding accessories, e very accessory follows the CND classification code of the medical device that it is associated with , according to the intended use given by the manufacturer . If an accessory can be used with multiple medical devices belonging to several group s, it must be placed in the prevalent type. 4 Updated as of the Italian Ministerial Decree of 13 March 2018. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 8 of 13 3. External links For more information, please consult the Italian Ministry website at: http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=328&area=dispositivi - medici&menu=classificazione The fo llowing documents may also be of use :  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 ( PDF format)  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 (XLSX format)  English translation of National Classification of Medical Devices Codes (as modified by Minister ial Decree 13.03.2018 -pdf, format).  English translation of National Classification of Medical Devices Codes (as modified by Ministerial Decree 13.03.2018 -XLSX format).  Search code and description of the CND  Search in alphabetical order Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 9 of 13 Annex I – CND updates up to 2018 The periodical updating process of the CND was schematically subdivided into four main phases:  Phase 1: Collection of proposals This phase is open to all stakeholders who submit proposals for the definition of new classifications or for the revision of existing ones.  Phase 2: Preliminary technical evaluation and elaboration of the proposal. The MoH MD Technical Team (MDTT) analyses th e collected proposals, the existing systems and the contents of the medical devices database to identify elements useful for classification.  Phase 3: “Widespread validation” of the proposal. The proposal is formally evaluated in three steps: A) the regional levels of the NHS involving clinical professionals in technical sessions B) Technical Health Committee - medical devices section of the Ministry of Health C) State - Regions Conference  Phase 4: Formal adoption of the proposal Finally, the proposal is approved by formal MoH act and published on the Italian Official journal as well as the website of the Italian MoH Most of the inputs adopted for updating purposes are listed below:  The analysis of the terminal typologies "90" and "99": Implemented and consolidated, it originates from the analysis of information within the Italian databank and consider s data from all the medical device s registered and classified in the CND terminal types with code " 90" ( - various) and "99" ( - other) of specific categories or groups identified. In fact, the classification system had already foreseen ab origine that medical devices that are not placed in a specific “typology” are classified in the generic typologies in dicated with the codes 90 and 99.  Manufacturer requests: When a manufacturer is unable to classify a medical device in an appropriate way inside the CND terminal level, a specific request for the introduction of a new CND class is required, with a communic ation to the MoH of a rationale and the technical characteristics and / or intended use that differentiate the device from the specific terminal classes already represented in the CND.  The analysis of CND coming from vigilance system: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 10 of 13 Market surveillance and the vigilance system are part of the institutional activities of the MOH. The lack of classificatory level can emerge in order to identify products that need particular attention for public health. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 11 of 13  The analysis of consumption by the NHS: The revision of the CND made through the processing of the consumption data of the Monitoring Database is based on identification of medical devices with great economic relevance or price variability.  The analysis coming from HTA Report s: Health Technology Assessment documents are periodically published by the Ministry of Health. These reports are considered when evaluating the revision of the CND. The following principles were considered in the revision of the CND:  the number of levels in the CND structure can be inc reased up to a maximum of seven, by coherently applying the homogeneity of the classification rules and of the coding system defined for the first CND structure.  for the definition of a new CND branch the number of manufacturers manufacturing the medical devices that will be placed in the new typology of the CND should be more than 1;  significant characteristics of medical devices detected by NHS professionals should be evaluated  the proposal of relocation of medical devices placed in class 90 or 99 should be consistent.  for the definition of a new CND branch significant differences of price between similar medical devices could be considered if necessary:  for the definition of a new CND branch an assessments related to the use of medical devices is conside red (quantity and number of users in NHS); For each update proposal of the CND, the information associated to the devices registered in the Italian database were analysed and, if necessary, the information detect ed by the “Consumption Monitoring Database” were processed. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 12 of 13 Annex II – CND VERSIONS Art. No. 57 of the Italian Law n° 289 of the 27 December 2002 stated the requirement of the establishment of a Commission on Medical Devices (CUD) as a technical advisory board to the Ministry of H ealth. The CUD has the task of defining and updating the repertoire of medical devices and classifying all medical devices in specific classes and sub -classes. The CUD d efined the first version of the Classificazione Nazionale dei Dispositivi Medici (CND) on July 2005 (Italian Ministerial Decree of 22 Sept .2005). In Vitro Diagnostic Medical Devices (regulated by European Directive No. 98/79 EEC and Italian Legislative De cree No. 332/2000) were not included in the first version of the Classification , although they belong to a class of Medical Devices. The Italian Financial Law of 2006 (Law No. 266 of the year 2005, art. 1, par. 409) established that the CND has to be appr oved by a decree of the Minister of Health in agreement with the State - Regions Conference. The CUD considered it appropriate to review and update the CND with the inclusion of in vitro diagnostic medical devices before proceeding with the State -Regions Con ference . Therefore, on 20 February 2007 , and after a revision of the classification, the Health Minister decreed the approval of the Classificazione Nazionale dei Dispositivi Medici (CND) drawn up by the CUD. The classification refers to the medical device s regulated by Italian legislative decrees N°. 507/92, N°. 46/97, N°. 332/2000 and subsequent amendments. In 28 March2013, the Italian D.P.R. n.44, replaced the Commission on Medical Devices (CUD) with the Technical Committee section F on medical devices. The Classification represented the first step towards the establishment of the Italian Repertoire of the Medical Devices. According to the art. N° 2 of The Italian Financial Law No. 266, the Technical Committee section F (previously CUD) , review the CND a nd make the necessary changes and updates. Every update is approved by a Ministerial Decree: 1. Decree of the Italian Ministry of Health (13 Mar 2008) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in th e Official Gazette - GU No. 125 of 29/05/2008. Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_2_file.pdf Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 13 of 13 www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_3_file.xls 2. Decree of the Italian Ministry of Health (12 Feb 2010) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.119 of 24/05/2010. Links: http://www.salute.gov.it/imgs/C_1 7_pagineAree_328_listaFile_itemName_5_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_7_file.xls 3. Decree of the Italian Ministry of Heal th (7 Oct 2011) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.259 of 7/11/2011.Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_9_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_10 _file.xls 4. Decree of the Italian Ministry of Health (29 July 2013) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No. 258 of 04/11/2013). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_16_file.pdf www.sa lute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_17_file.xlsx 5. Decree of the Italian Ministry of Health (8 J une 2016 ) regarding Modification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, n. 242 del 15/10/2016). 6. Decree of the Italian Ministry of Health (13 march 2018) regarding Mod ification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, No. 116 del 21/05/2018). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_15_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_18_file.xlsx

mdcg_2019_2_gui_udi_dev_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 1 of 3 MDCG 201 9-2 Guidance on application of UDI rules to device -part of products referred to in Article 1(8), 1(9) and 1(10) of Regulation 745/2017 February 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 2 of 3 1. Scope Article 1(8),1(9), 1(10) of the Medical Device Regulation (EU) 2017/745 (MDR) set the basic criteria to determine whether and to what extent the relevant legislation on medical devices, medicinal products, human tissue and cells apply to certain products c ontaining a medical device part. In particular, “8. Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in poin t 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation. However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament an d of the Council, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 9. Any device which is intende d to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal produ ct. However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned.” 10. Any device which, when placed on the market or put into service, incorporates, as an integral part, non -viable tissues or cells of human origin or their de rivatives that have an action ancillary to that of the device shall be assessed and authorised in accordance with this Regulation. In that case, the provisions for donation, procurement and testing laid down in Directive 2004/23/EC shall apply. However, if the action of those tissues or cells or their derivatives is principal and not ancillary to that of the device and the product is not governed by Regulation (EC) No 1394/2007, the product shall be governed by Directive 2004/23/EC. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned”. Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 3 of 3 2. Application to UDI rules to the device part of products referred to in point 1 that are governed by the medical device Regulations EXAMPLES: - Catheters coated with heparin or an antibiotic - Soft tissue fillers incorporating local anaesthetics - Implantable infusion pump - Spacer devices for use with metered dose inhalers - Bone void filler with an antibiotic - Bone void filler with animal growth factors, where the action of the growth factors is demonstrated to be ancillary to that of the physical filler If a product referred to in point 1 is assessed and authorised in accordance with the Medical device regulations, the device part will be subject to all UDI -related obligations. 3. Application to UDI rules to the device part of combination products that do not fall under the medical device Regulations EXAMPLES: - Non-reusable autoinjectors containing a medicinal product as integral part - Nebulizers precharged with a specific medicinal product - Patches for transdermal drug delivery - Wound dressings impregnated with an antibiotic, where the primary intended purpose is to administer the antibioti c to the wound - Bone void filler with animal growth factors, where the action of the growth factors cannot be demonstrated to be ancillary to that of the physical filler In general terms, if a product referred to in point 1 is governed by the medicinal product or tissue and cell legislation, the device part is required to comply only with the relevant general safety and performance requirements set out in Annex I to the Regulation on medical devices. This cannot be interpreted as meaning that the relevant o bligations related to UDI, as laid down in Chapter III and Annex VI of the Regulation on medical devices, apply to the medical device part or the package of the relevant combination. For this reason, the medical device part is not mandatorily required to c omply with any UDI -related obligation. This also means that a UDI is not needed on the package that combines the medicinal product and the medical device1 2. 1 However, if the medical device part bears a UDI on its label, that should not be deemed as being in contrast with the applicable medical device legislation 2 For products such as prefilled syringes which are made on the b asis of a UDI direct part marked (MDR compliant) syringe it shall be noted that, while UDI rules do not apply to the device part of the integral product, the direct mark UDI on the syringe shall not be removed unless that mark compromises the safety and pe rformance of the integral product.

mdcg_2018_4_udi_core_spp_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 1 of 3 MDCG 2018 -4 Annex: UDI database Definitions/Descriptions and formats of the UDI core elements for systems or procedure packs October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission . The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 2 of 3 In accordance with Article 29(2) and Annex VI, Part B of the MDR, in the case of systems and procedure packs, the system or procedure pack producer shall provide to the UDI database the UDI -DI and all of the following information1: 1. quantity per package configuration (meaning the quantity of systems or procedure packs in a package, whenever applicable) 2. the Basic UDI -DI as referred to in Article 29 (MDR) and any additional UDI - DIs, 2a. Indication of s pecific medical purpose of the system or procedure pack 3. the manner in which the system or procedure pack is controlled (expiry date or manufacturing date, lot number, serial number), 5. name and address of the system or procedure pack producer (as indic ated on the label), 6. the SRN of the system or procedure pack producer 8. The medical device nomenclature code as provided for in Article 26 (MDR)2 9. risk class (to be intended as the highest risk class of the device components of the system or procedure pack), 10. if applicable, name or trade name, 11.A. name or, if applicable, system or procedure pack model associated with the BASIC UDI -DI in the statement drawn in accordance with Article 22.1 of the MDR 11.B. reference or catalogue number, or product n umber found on the system or procedure pack label or accompanying packaging to identify a system or procedure pack 13. additional product description, 14. if applicable, storage and/or handling conditions of the system or procedure pack (as indicated on th e label or in the instructions for use), 15. if applicable, additional trade names of the system/procedure pack, 18. labelled sterile (y/n) (meaning that the system or procedure pack in its entirety is labelled as sterile), 19. need for sterilisation before use (y/n) 22. URL for additional information, such as electronic instructions for use (optional), 23. if applicable, critical warnings or contra -indications 1 Please note that format and definition of all UDI data elements are provided at https://ec.europa.eu/docsroom/documents/28669 2 Applicability of this data element to systems and procedure packs is to be determined at the time of designation of the future EU nomenclature for medical devices (foreseen end of 2018/beginning 2019). Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 3 of 3 24. status of the system or procedure pack (on the market, no longer placed on the market, recalled, field safety corrective action initiated). Whenever a label is referred to, the label of the entire system/procedure pack shall be meant, in accordance with Article 22(5) of Regulation 745/2017. ,

faq_udi_en.pdf.txt

Introduction to the new UDI system and the obligations of operators The existing regulatory framework on medical devices dates back to the 1990s and consists of three Directives. Two new Regulations (Regulation (EU) 745/2017 on medical devices and Regulation (EU) 746/2017 on In Vitro diagnostic medical devices) were adopted in April 2017 and entered into force on 25 May 2017. The general application dates of the two Regulations are 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices, though different timelines apply for certain specific provisions. These Regulations introduce an EU identification sys - tem for medical devices based on a Unique Device Identifier (UDI). 1The UDI system will facilitate easier traceability of medical devices, significantly enhance the effectiveness of the post-mar - ket safety-related activities for devices and allow for better monitoring by competent authorities. It will also help to reduce medical errors and to fight against falsified devices. The use of the UDI system finally should also improve purchasing and waste disposal policies and stock-management by health institutions and other economic operators. 1 IMDRF/UDI WG/N7FINAL:2013 UDI Guidance Unique Device Identification (UDI) of Medical Device s 2 IMDRF/UDI WG/N48 FINAL: 2019 Unique Device Identification system (UDI system) Application Guide - DOCX (12.5Mb)The new system will be applied to all medical devices except custom-made and performance study/investigational devices and is substantially based on internationally recognised principles, notably by using definitions that are compatible with those used by major trade partners.1,2MEDICAL DEVICES CHANGE OF LEGISLATION What you need to know! Unique Device Identification (UDI) System under the EU medical devices Regulations 2017/745 and 2017/746European Commission Health and Food Safety 2Article 27 of Regulation (EU) 2017/745 (‘MDR’) and Article 24 of Regulation (EU) 2017/746 (‘IVDR’) lay down that the UDI system shall consist of: a. the production of a UDI that comprises a UDI device identifier (‘UDI-DI’) specific to a manufacturer and a device, providing access to the information, and a UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI; b. the placing of the UDI carrier on the label of the device or on its packaging or in case of reusable devices on the device itself (direct marking); c. the storage of the UDI by economic operators, health insti - tutions and healthcare professionals, in accordance with the conditions laid down in paragraphs 8 and 9, respectively, of the Articles; d. the establishment of an electronic database for Unique Device Identification (the ‘UDI database’), which is part of the Eudamed database, in accordance with Article 28 of MDR and Article 25 of IVDR. In accordance with the new rules, any manufacturer shall thus assign a unique UDI to a device and to all higher levels of packag - ing before placing that device on the market except custom-made medical devices and performance study/investigational devices. The UDI carrier shall be placed on the label of the device and on all higher levels of packaging and in case of reusable devices on the device itself (direct marking). The manufacturer shall also ensure that the information – related to the device in question - referred to in Part B and Part A, Section 2, of Annex VI of the relevant Regulation, is correctly submitted to the European Database on Medical Devices (Eudamed) as required by Article 27(3) of MDR and Article 24(3) of IVDR. The manufacturer shall also maintain unique UDIs for its devices. NOTE: Timelines related to those obligations are indicated under question 6 of this document. Within the EU, the manufacturer shall assign to their devices, together with a UDI, also a Basic UDI-DI, which is not yet required by other jurisdictions. The Basic UDI-DI is the main key in Eudamed and relevant documentation (e.g. certificates, declaration of conformity, technical documentation and summary of safety and clinical performance) and will also be the access key for device-related information entered in the database. UDI issuing entities designated by the European Commission operate a system for the assignment of UDI in the EU.3 3 Issuing entities have been designated on 6 June 2019 via the Commission Implementing Decision (EU) 2019/939 .Frequently Asked Questions and Answers 1. What is the UDI? The UDI is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific medical device on the market. The UDI is comprised of the UDI-DI and UDI-PI. The unique identifier may include information on the lot or serial number and be able to be applied anywhere in the world. The production of a UDI comprises the following: • A UDI device identifier (‘UDI-DI’) specific to a device, providing access to the information laid down in Part B of Annex VI. • A UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI. 2. What is the Basic UDI-DI? The Basic UDI-DI is the main access key for device-related information in the Eudamed database and it is referenced in relevant documentation [e.g. certificates (including certificate of free sale), EU declaration of conformity, technical documentation and summary of safety and (clinical) performance)]. It is intended to identify and connect devices with the same intended purpose, risk class and essential design and manufac - turing characteristics. It is independent/separate from the packaging/labelling of the device and it does not appear on any trade item. Any Basic UDI-DI shall identify the devices (group) covered by that Basic UDI-DI in a unique manner. MDCG 2018-1 v3 guidance provides additional information on Basic UDI-DI. 3. Which products are subject to the UDI system? The UDI system should apply to all devices, except custom-made and performance study/investigational devices.34. Who is responsible for placing the UDI carrier on the device itself, on the label and on the package of a device? The manufacturer is responsible for complying with all UDI related requirements. This includes the assignment of the UDI (and Basic UDI-DI), the UDI (and Basic UDI-DI) registration in the Eudamed database and the placement of the UDI carrier on the label of the device or on its packaging or, in case of reusable devices, on the device itself (direct marking). 4.1 What happens in the case of Article 16 of the MDR and IVDR? Which obligations do economic operators have regarding UDI when assuming obligation incumbent on manufacturers per Article 16 of the MDR and IVDR? Any distributor, importer or other natural or legal person that assumes the obligations incumbent on manufacturers in accord - ance with Article 16(1), assumes all the relevant responsibilities related to UDI, including UDI labelling. The distributor or importer carrying out the operations described in Article 16(2) (providing translation or repackaging of devices) shall ensure that: • the activities are performed by means and under conditions that in no way compromise the readability of the UDI carrier and its information identifying the actual device. • the specific procedures are part of the distributor’s or import - er’s quality management system. A dedicated guideline with additional information on this aspect is available at the MDCG 2018-6 guidance document . 5. What is the procedure for systems and procedure packs to undergo a UDI registration? Systems and procedure packs shall undergo a UDI registration, as described in Article 29(2) of MDR. Before placing on the market a system or procedure pack pursuant to Article 22(1) and (3), that is not a custom-made device, the system or procedure pack producer shall assign to the system or procedure pack, in compliance with the rules of the issuing entity, a Basic UDI-DI and shall provide it to the Eudamed database together with the other relevant core data elements listed in the MDCG 2018-4 guidance document .6. What is the mandatory deadline for a device to comply with the UDI requirements? The obligation for UDI assignment applies as from the date of application of the two new Regulations, i.e. 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices. The obligation for submission of UDI data in the EUDAMED database applies from 26 November 2022 for medical devices and 26 November 2023 for in vitro diagnostic medical devices (provided that EUDAMED is fully functional before the date of application of the respective Regulation; otherwise, this obligation applies 24 months after EUDAMED has become fully functional) However, manufacturers will be in a position to voluntarily comply with registration obligations as from 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices. It shall be noted that, provided that Eudamed is fully functional, at any time after 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices, the full registration of devices (Article 29 of MDR and Article 26 of IVDR) remains a pre-condition for the possible registration of their relevant serious incident in Eudamed. The MDCG 2019-4 guidance document provides more information on this subject. The obligation for placing the UDI carrier applies according to the following timelines: Device as per Regulation (EU) 2017/745 (MDR)Implantable devices and Class III devicesClass IIa and Class IIb devicesClass I devices Placing UDI-carriers on the labels of devices MDR Article 123(3)(f), Article 27(4)26 May 202126 May 202326 May 2025 Direct marking of the reusable devices MDR Article 123(3)(g), Article 27(4)26 May 202326 May 202526 May 2027 Device as per Regulation (EU) 2017/746 (IVDR)Class D IVDsClass C and B IVDsClass A IVDs Placing UDI-carriers on the labels of devices IVDR Article 113(3)(e), Article 24(4)26 May 202326 May 202526 May 2027 NOTE: Devices which are compliant with the Regulations may be placed on the market ahead of the general application date of 26 May 2021 (MDR) and 26 May 2022 (IVDR). For more information on this aspect, please consult FAQ - MDR Transitional Provisions and FAQ - IVDR Transitional Provisions .47. Are devices, which are compliant with the Medical Device Directives (MDD and AIMDD) and placed on the market after the applica - tion date of the Regulations (legacy devices), continue to be subject to UDI requirements? In order to facilitate the transition to the new system, the new Regulations give manufacturers the possibility to place products on the market after the general application dates of the new Regulations (and until 26 May 2024 at the latest) by virtue of valid Directive certificates.4 These legacy devices are not subject to UDI obligations but they should be registered in the Eudamed database. Timelines for registration as described under question 6 also apply to these products. More information on the operational aspects of the registration of legacy devices is available at the MDCG 2019-5 guidance document . 8. What is the role of the UDI issuing entities? Who designates them? The issuing entities operate a system for the assignment of UDIs. Following a call for applications launched at the end of 2018, the Commission has designated the following entities: a. GS1 AISBL b. Health Industry Business Communications Council (HIBCC) c. International Council for Commonality in Blood Banking Automation (ICCBBA) d. Informationsstelle für Arzneispezialitäten (IFA) GmbH For more information, please refer to the relevant implementing act designating the entities: Commission Implementing Decision (EU) 2019/939 of 6 June 2019 designating issuing entities designated to operate a system for the assignment of Unique Device Identifiers (UDIs) in the field of medical devices. 4 For additional information on the general conditions for legacy devices to be placed on the market after the general application dates of the new Regulations, see the MDR and IVDR transitional FAQs published by the CAMD Transitional Task-force 9. How should a UDI appear on the label or package of a device? The UDI Carrier [Automated Identification for Data Capture (AIDC) and human readable interpretation (HRI) representation of the UDI] shall be on the label or on the device itself and on all higher levels of device packaging. In the event of significant space constraints on the unit of use packaging, the UDI carrier may be placed on the next higher packaging level. Higher levels of packaging shall have their own unique UDI. Please note that shipping containers shall be exempted from the requirement. The UDI must appear in a plain-text version/human readable information (HRI) and in a form that uses AIDC technology. AIDC means any technology that conveys the unique device identifier or the device identifier of a device in a form that can be entered into an electronic patient record or another computer system via an automated process. The HRI consists of legible characters that can easily be read by people. If there are significant constraints limiting the use of both AIDC and HRI on the label, only the AIDC format shall be required to appear on the label. For devices intended to be used outside healthcare facilities, such as devices for home care, the HRI shall, however, appear on the label even if this results in there being no space for the AIDC. For other specific requirements related to the UDI carrier, please consult Section 4 of Annex VI Part C of the two Regulations. For single-use devices of classes I and IIa medical devices and class A and class B IVD medical devices packaged and labelled individually, the UDI carrier shall not be required to appear on the packaging but it shall appear on a higher level of packaging, e.g. a carton containing several (individually packaged) devices. However, when the healthcare provider is not expected to have access, in cases such as in home healthcare settings, to the higher level of device packaging, the UDI shall be placed on the packaging (of the individual device). For devices exclusively intended for retail point of sale, the UDI- PIs in AIDC shall not be required to appear on the point of sale packaging. If the UDI carrier is readily readable or, in the case of AIDC, scannable, through the device’s packaging, the placing of the UDI carrier on the packaging shall not be required.510. Are there any requirements for the PI (Production Identifier) information? If a lot number, serial number, software identification or expiry date appears on the label, it shall be part of the UDI-PI. If there is also a manufacturing date on the label, it does not need to be included in the UDI-PI. If there is only a manufacturing date on the label, this shall be used as the UDI-PI. The different types of UDI-PIs include serial number, lot number, software identification and manufacturing date and/or expiry date. The UDI-PI characteristics such as the lot or serial number shall be defined by the manufacturer. However: • For active implantable devices, the UDI-PI shall include at least the serial number; for other implantable devices, the serial number or lot number. • A configurable device UDI-PI shall be assigned to each indi - vidual configurable device. It is important to note that no UDI-PI information can be included in the UDI database. 11. What changes in the medical device would require a new UDI-DI? A new UDI-DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability. In particular, a new UDI-DI shall be required in the case of any change of the following elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilisation before use, quantity of devices provided in a package, critical warnings or contra-indications and CMR/Endocrine disruptors. A UDI-DI shall be associated with one and only one Basic UDI-DI. Additional information on this aspect is available at MDCG 2018-1 v3 guidance document .12. What are the obligations of economic operators and health institutions in relation to UDI? According to the two medical devices Regulations, manufacturers shall be responsible for the UDI assignment and placement of the UDI carrier, the initial submission and updates of the identifying information and other device data elements in the Eudamed database. Manufacturers shall update the relevant database record within 30 days of a change being made to an element, which does not require a new UDI-DI. Distributors and importers shall verify that, where applicable, a UDI has been assigned by the manufacturer. All economic operators and health institutions shall store and keep preferably by electronic means the UDI of the devices, which they have supplied or with which they have been supplied if those devices belong to class III implantable devices. Please note that the Commission may decide to adopt implementing acts to expand the scope of devices for which economic operators shall store and keep the UDI. 13. Is the software subject to UDI rules? The UDI shall be assigned at the system level of the software. Only software that is commercially available on its own and software that constitutes a device in itself shall be subject to that requirement. The software identification shall be considered the manufacturing control mechanism and shall be displayed in the UDI-PI. UDI requirements for software are laid down in Annex VI Part C of the two medical device Regulations. A dedicated guideline with additional information on this aspect is available at MDCG 2018-5 guidance document .614. Direct marking of reusable devices. Are there exemptions? Devices that are reusable shall bear a UDI carrier on the device itself. The UDI carrier for reusable devices that require disinfection, ster - ilisation or refurbishing between patient uses shall be permanent and readable after each process performed to make the device ready for the subsequent use throughout the intended lifetime of the device. The UDI carrier shall be readable during normal use and throughout the intended lifetime of the (reusable) device. The requirements shall not apply to the device in case of the following circumstances: • any type of direct marking would interfere with the safety or performance of the device; • the device cannot be directly marked because it is not tech - nologically feasible. 15. Is there an adjudication process for ad-hoc exemptions foreseen for medical devices? An adjudication process to allow for ad-hoc exemptions is not envisaged in the EU. All devices are therefore subject in principle to UDI requirements, with the only exceptions explicitly stated in the Regulation.However, the UDI Expert Group will analyse requests for adap - tation of UDI requirements to certain specific device types and recommend the Medical Device Coordination Group (MDCG) to issue dedicated guidelines, where necessary. 16. What are the UDI and device data sets to be provided in Eudamed? Dedicated guidelines containing information on this aspect are available at https://ec.europa.eu/health/md_sector/ new_regulations/guidance . Guidance Further information on EUDAMED is available at https://ec.europa. eu/health/md_eudamed/overview_en . NOTE: The Commission intends to expand this document on a regular basis based on the assessment of most frequently asked questions and/ or of other specific needs. ET-02-18-963-EN-N Funded under the Third EU Health Programme ISBN:XXXXX DOI: XXXXX01/08/2020 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39).https://ec.europa.eu/health/ md_sector/overview_en

mdcg_2019_1_budi_rules_ie_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2019 -1 Page 1 of 2 MDCG 201 9-1 MDCG guiding principles for issuing entities rules on Basic UDI -DI January 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commissio n document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2019 -1 Page 2 of 2 In order to ensure, to the maximum possible extent, the quality of the code value entered in Eudamed, the Basic UDI -DI requirements on format should be as close as possible to the ones for the UDI -DI. In particular,  the Basic UDI -DI code value sha ll have maximum 25 characters, so that it does not differ too significantly from the maximum length of the UDI -DI as established by the issuing entities;  a check digit/character must be part of the Basic UDI -DI, based on an algorithm defined by the issuin g entity. This algorithm shall be provided by the issuing entities to the Commission and to the manufacturers.

MDCG 2018-1 v3 Guidance on basic UDI-DI and changes to UDI-DI.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2018-1 v3 MDCG 2018-1 v3 Guidance on BASIC UDI-DI and changes to UDI-DI March 2020 This document has been endorsed b y the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed o f representatives of all Member States and it is chaired by a representative of the European Co mmission. The document is not a European Commission document and it canno t be regarded as reflecting the official position of the European Commission. Any views express ed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on BASIC UDI-DI and changes to UDI-DI Introduction The new Medical Device Regulations (EU) 2017/745 and (EU) 2017/746 introduce a Unique Device Identification (UDI) system for medical devices. Main provisions related to the establishment of the UDI system are contained in Chapter III and Annex VI of the two medical device Regulations. The main features of the UDI system and relevant obligations for operators will be provided in a dedicated Q/A paper to be published by the Commission in spring 2018. This guidance is intended to provide a clarification on the notion of Basic UDI-DI, its use in relevant documentation and the factors triggering UDI-DI changes. ----------------------------- The Basic UDI-DI The Basic UDI-DI is the main key in the database and relevant documentation (e.g. certificates, declaration of conformity, technical documentation and summary of safety and clinical performance) to connect devices with same intended purpose, risk class and essential design and manufacturing characteristics. It is independent/separate from the packaging/labelling of the device and it does not appear on any trade item. Any Basic UDI-DI shall identify the devices (group) covered by that Basic UDI-DI in a unique manner. Link with between Basic UDI -DIs and certificates or declaration of conformity In accordance with Annex XII of the medical device Regulations, the scope of the certificates shall unambiguously identify the device or devices covered. The scope of EU technical documentation assessment certificates, EU type-examination certificates and EU product verification certificates shall include, together with the Basic UDI-DI, a clear identification, including the name, model and type, of the device or devices, the intended purpose, as included by the manufacturer in the instructions for use and in relation to which the device has been assessed in the conformity assessment procedure and the risk classification. Each of the abovementioned certificates shall identify and cover all devices associated with the same Basic UDI-DI, that is referred to in that certificate. The association between different Basic UDI-DIs, where applicable, shall be identified through the technical dossiers. In accordance with Annex IV of the two Regulations, the declaration of conformity shall contain the Basic UDI-DI and the product and trade name, product code, 3 catalogue number or other unambig uous reference allowi ng identif ication and traceability of the device covered by the EU declaration of conformity. Changes of UDI-DI A new UDI—DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability. In particular, a new UDI-DI shall be required in the case of any change of the following elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilization before use, quantity of devices provided in a package, critical warnings or contra-indications (e.g. containing latex or DEHP), CMR/Endocrine disruptors 1 2. A UDI-DI shall be associated with one and only one Basic UDI-DI. Regarding changes to the specific data elements listed below 3, the following considerations should be noted: 1. Is the Device Directly Marked (Yes/No) The database design will force the creation of a new UDI-DI only if there is a change from Yes to No and not vice versa for this data element. 2. Manner in which production of the device Is controlled (expiry date or manufacturing date, lot number, serial number, software identification) - Type of UDI-PI As long as there is no change to the la bel, a change to this data element will not require the allocation of a new UDI-DI. 1 It should be noted that a new regulatory decision classifying an existing product as CMR/Endocrine disruptor might not result in a new UDI-DI for products already containing that substance. The decision on whether to assign a new UDI-DI should be based on the conformit y assessment of the product with regard to the impact of the information provided and the significance of the change. 2 Specific attention shall be paid to the fact that changes of colour or language might also require a new UDI- DI when those changes might lead to misidentification of produc t or change the product safety/performance. For example: A- Change of colour coding of e.g. connectors, latex-free surgi cal gloves, blood tubes B- Two identical self-testing de vices, that exist in parallel a nd cannot be substitute d due to local labelling requirements (IVD Article 10(10) of Regulation 746/2017), requi res different UDI-DIs Specifications of EU designated issuing entity should be used a s a reference source to identify other possible examples. 3 Please refer to Guidance UDIWG 2018-1 on "UDI database. Defini tions, descriptions and formats of the UDI core elements’ available at https://ec.europa.eu/docsroom/documents/28669 4 WARNING: This guidance does not address requirements for reprocessed devices, systems or procedure packs, software, Annex XVI, nor for cases of parallel trade or own brand labelling. Specific requirement s for those products are addressed in specific guidance.

mdcg_2018_5_software_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 1 of 3 MDCG 2018 -5 UDI Assignment to Medical Device Software October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 2 of 3 Specific consideration on UDI rules for software UDI Assignment to Medical Device Software - Scope of UDI requirements for software In accordance with Annex VI, Part C of the Medical Device Regulation (EU) 2017/745 (MDR) and the In -Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR), only software which is commercially available on its own as well as software which constitutes a device in itself shall be subject to UDI requirements. - Basic UDI -DI In line with the general Guidance on Basic UDI -DI and changes to UDI -DI1, the Basic UDI-DI connects software with same intended purpose, risk class and essential design and manufacturing characteristics. - Changes to UDI -DI in accordance with Annex VI Part C, Section 6.5 of the MDR and Section 6.2 of the IVDR, a new UDI -DI is required whenever there is a modification that changes the original performance, the safety of the software or the interpretation of data . Such modifications include new or modified algorithms, database structures, operating platforms, architecture, user i nterfaces and new channels for interoperability . Such changes would be considered “significant.” The Guidance on Basic UDI -DI and changes to UDI -DI2, defines standard rules on triggers that entail the creation of a new UDI -DI. It lays down that a new UDI —DI shall be required whenever there is a change that could lead to misidentification of a device and/or ambiguity in its traceability. In particular, a new UDI -DI shall be required in the case of any change of the following device related elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilization before use, quantity of devices provided in a package, critical warnings or contra -indications (e.g. containing latex or DEHP3), CMR4/Endocrine disruptors , colour, language. Not all those data elements are however applicable to software. 1 The Guidance is available at https://ec.europa.eu/docsroom/documents/28667 2 The Guidance is available at https://ec.europa.eu/docsroom/documents/28667 3 DEHP stands for Bis(2 -ethylhexyl) phthalate 4 CMR stands for carcinogenic, mutagenic, or toxic for reproduction Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 3 of 3 It can therefore be concluded that, in the specific case of software, - Any change of the Basic UDI -DI5 - Any changes which impact the original performance, safety, or the interpretation of data6 - A change to the name or trade name, version or model number, critical warnings or contra -indications, user interface language would require a new UDI -DI. This is to guarantee the traceability and correct identification of the med ical device software. - Minor software revisions In accordance with Annex VI, Part C, point 6.5.4 of the MDR and Annex VI, Part C, point 6.2.4 of the IVDR, minor software revisions require a new UDI -PI and not a new UDI-DI. Minor software revisions are generally associated with bug fixes, usability enhancements that are not for safety purposes, security patches or operating efficiency. Minor software revisions shall be identified by a defined manufacturer - specific form of identification. - Evaluation of ch anges to software by the manufacturers As part of their maintenance and post -market surveillance activities, manufacturers should evaluate the possible impact of any changes to the function of software on the software’s qualification as medical device soft ware, its classification, its intended purpose and essential design and manufacturing characteristics, as that could trigger a new Basic UDI -DI. Likewise, any changes shall be assessed in defining the need of a new UDI -DI. UDI Placement Criteria UDI plac ement criteria for software are laid down in Annex VI, Part C, point 6.5.4 of the MDR and Annex VI, Part C, point 6.2.4 of the IVDR. Additional considerations on this aspect will be provided in future guidance. 5 This is a general rule. As indicated in the Guidance on Basic UDI -DI and changes to UDI -DI (available at https://ec.europa.eu/docsroom/documents/28667 ), "a UDI-DI shall be associated with one an d only one Basic UDI-DI”. 6 Annex VI, Part C, point 6.5.2 of the MDR and Annex VI, Part C, point 6 .2.2 of the IVDR

mdcg_2018_7_languages_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 1 of 3 MDCG 2018 -7 Provisional considerations regarding language issues associated with the UDI database (Annex VI, Part A Section 2 and Part B of the Medical Device Regulation (EU) 2017/745 (MDR) and the In -Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR )) October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecti ng the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 2 of 3 General principles In consideration of the following: - In accordance with Article 28(3) MDR and Article 25(3) IVDR, the core data elements to be provided to the UDI database shall be accessible to the public, - Annex VI Part C of the MDR and IVDR on the UDI System requires explicitly in its section 5.10 that the user interface of the UDI database shall be available in all official languages of the Union and that the use of free - text fields shall, however, be minimized in order to reduce translations, - one of the main declared purposes of th e European database on medical devices (Eudamed) as per Recitals 43 -46 and Article 33(1a) of the MDR and Recitals 40 -43 of the IVDR is to enable the public (including the healthcare professionals) to be adequately informed about devices placed on the marke t, it is essential that the information in the UDI database is publicly available and easily understandable by any European citizen. Use of free -text and translation Among the UDI core data elements of Part B of Annex VI of the MDR and IVDR, only three data elements ("Additional product description", "Storage and handling conditions" and "Critical warnings or contra -indications") are expected to have a free - text format, while a fourth data element (nomenclature term) is associated with a text allowing to understand the meaning of the associated code (description). As to the nomenclature, ideally, all the terms/description associated with the nomenclature codes should be translated in the different Union official languages. However, it could be also consi dered having terms available only in English, particularly taking into account that the nomenclature will have a code. Appropriate budget and legal verifications will be made on this matter, in the context of the designation procedure for the new nomenclat ure. Among the three data elements that use free -text, one is an optional field: "Additional product description". It should be provided in English as well as in the languages of those countries where the device is made available. A data field will be av ailable for each relevant language. For the data elements "Storage and handling conditions" and "Critical warnings or contra -indications", relevant information (as per Annex I Section 23.2 of the MDR and Annex I Section 20.2 of the IVDR: (k) "any special s torage and/or handling conditions" and (m) "warning or precautions to be taken") should be provided in Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 3 of 3 English as well as in the languages of those countries where the device is made available. It shall be noted that, as laid down in the provisional guid ance related to formats and definitions of UDI data elements, only storage/handling conditions and critical warnings or contra -indications, that are required to be on the label, shall be transmitted to the UDI database. With respect to those two data eleme nts, the possibility to use (in EUDAMED) – as an alternative option - symbols and/or list of reference that can categorise and provide enough information understandable by anyone is currently being explored. Indication of hazardous substances (only appli cable for MDR) For CMR substances, the Commission intends to explore the feasibility for EUDAMED to provide the list of official CMR1 substances (from CLP Regulation2) available in the ECHA3 database. The CAS number4, EC number and/or official chemical nam e could be used to identify those substances. With regard to endocrine disruptor substances, pending verification that an official database managed by the Commission containing these substances is available, a solution is currently being explored. Inform ation to be provided is known by the economic operator in charge of the submission as it shall be displayed on the device label (Annex I Section 23.2 (f) of the MDR). 1 CMR stands for carcinogenic, mutagenic, or toxic for reproduction 2 Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (the 'CLP Regulation') 3 The European Chemicals Agency 4 A CAS Registry Number, also referred to as CASRN or CAS Number, is a unique numerical identifier assigned by the Chemical Abstracts Service (CAS) to every chemical substance described in the open scientific literature

mdcg_2018_6_art16_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -6 Page 1 of 2 MDCG 2018 -6 Clarifications of UDI related responsibilities in relation to Article 16 of the Medical Device Regulation (EU) 2017/745 and the In-Vitro Diagnostic Medical Device Regulation (EU) 2017/746 October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -6 Page 2 of 2 Relevant obligations arising from Article 16(1) Any distributor, importer or other natural or legal person that assumes the obligations incumbent on manufacturers in accordance with Article 16(1), assumes all the relevant responsibilities related to UDI, including UDI labelling. This means that those e conomic operators must also apply for registration as Manufacturers, receive a Single Registration Number (SRN), apply for the appropriate conformity assessment procedure and feed and provide UDI -product registration. However, in accordance with the provis ion of Article 16(1)a, when a distributor or importer enters into an agreement with a manufacturer whereby the manufacturer is identified as such on the label, the manufacturer is responsible for meeting the requirements placed on manufacturers in this Reg ulation, including the relevant UDI obligations. Relevant obligations arising from Article 16(2) to 16(4) The distributor or importer carrying out the operations in Article 16(2) shall ensure that: - the activities mentioned in points (a) and (b) of par agraph 2 are performed by means and under conditions that in no way compromise the readability of the UDI carrier and its information identifying the actual device. - the specific procedures are part of the distributor's or importer’s quality management sy stem.

mdcg_2018_2_nomenclature_en.pdf.txt

This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 1 MDCG 2018 -2 Future EU medical device nomenclature Description of requirements Introduction According to Article 26 of the Regulation 745/2017 on medical devices and Article 23 of Regulation 746/2017 on in-vitro diagnostic medical device , the Commission is required to make available a medical device nomenclature to support the functioning of the future EUDAMED . This document intends to provide a detailed description of requirements and criteria that the future nomenclature is expected to fulfil. This is expected to serve as a reference basis throughout the decision process and will also ensure th at all legal and technical issues associated with the future EU medical device nomenclature are properly mapped. 1. Description of legal requirements It arises from the text of the new Regulations (namely Article 26 of Regulation 745/2017 and Article 23 of Regulation 746/2017) that t he future EU medical device nomenclature will have to comply with certain defined requirements . First of all, t he future nomenclature shall be available free of charge to manufacturers and other natural o r legal persons required by the Regulation to use that nomenclature, this meaning that no manufacturer or natural/legal person should be subject to fee or suffer from any discrimination, compared to other operators, in relation to the use of the nomenclature under the new Medical Device Regulations. It shall be therefore ensured that relevant names and codes are accessible (in full) in EUDAMED to all operators that are requested to provide the relevant UDI submissions. Provisions in Chapter III and Annex VI of the new Regulations, and in particular the combination of Article 28( 3) of the Regulation 745/2017 on medical devices and point 8 of part B of Annex VI , provide that moreover names and codes are publicly availabl e in the UDI database (in EUDAMED ). By virtue of Article 26, t he Commission shall a lso endeavour to ensure that the nomenclature is available to other stakeholders free of charg e, where reasonably This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 practicable. The public availability of terms and codes in EUDAMED is in itself an ideal vehicle to provide sufficient access of all stakeholders . Finally the nomenclature shall be internationally recognised at the time of the date of application of the Regulations. In this context, global harmonisation principles and orientations followed and adopted by the International Medical Device Regulators Forum (IMDRF) and the World Health Organisation , are taken into particular account . Without prejudice to the fulfilment of requirements d escribed in previous paragraphs, the European Commission and the Competent Authorities from EU Member States shall benefit from the full access to the most up to date nomenclature system and its hierarchies free of charge . They shall not be charged for any service received from the nomenclature provider, which is necessary for them to exert their supervisory role over the nomenclature and the fulfilment of their obligations under the new Regulations. 2. Description of other relevant criteria In order for the system to leverage further the potential of the future EU nomenclature, some other essential requirements that the nomenclature shall fulfil have been identified . While those requirements are not explicitly mentioned in the texts of the two Regulation s, they are essential to guarantee the good functioning of the future EUDAMED and to the fulfilment of some of the regulatory objectives set in the new Regulation s, namely facilitating effective market surveillance operations and facilitating device traceability throughout the supply chain. Policies/rules for update, removal and creation of names and descriptions in the nomenclature are to be sound and must reflect regulators ’ and the wider healthcare economy needs . An EU regulatory team on no menclature composed of regulators , to be established possibly as an MDCG sub -group , will review, determine (preferably within a global perspective) and validate those rules prior to designation decision and will continue to hold an advisory role on these matters . On a periodic basis, in accordance with a pre -defined procedure, and in consultation with the nomenclature provider, that group shall also provide feedback and advice on the governance of terms and descriptions, based, inter alia, on the requests received from economic operators and other stakeholders. In the context of activities mentioned in the previous paragraph, it shall be aimed to ensure that the terminology structure used for it should not be unnecessarily granular and should not contain names that are only used by only a few economic operators This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 3 or stakeholders , unless it is proven to be advantageous to regulators or the wider healthcare economy. The structure and design of the future nomenclature should facilitate the establishment of lin ks with the codes defining N otified Bodies competence (designation scope) , the scope of medical device s QMS (Quality Management System)/QA (Quality Assurance) certificates , and product portfolio s in the mandate of Authorised Representatives . The nomenclature should have hierarch ies by which terms and codes could be meaningfully grouped into categories and subcategories The future nomenclature system shall adequately support the functioning of the EUDAMED database and the functioning of the new Regulations as a whole. In this context, EUDAMED shall make available the most updated names/codes related information, to the be nefit of operators and general public. Therefore, the nomenclature provider will need to have procedures and services in place that shall allow E UDAMED to be kept up -to-date at any time. When setting the procedure, in particular the frequency, related to the periodic review of nomenclature terms and descriptions , this shall be taken into account. For enforcement purposes , in relation to its obligations vis -à-vis the Commission and the EU economic operators, the nomenclature provider shall have a legal entity in either one of the EEA countries or Switzerland or Turkey1 with an exception being foreseen for international organisations in which the EU is one of the members . System/processes shall be in place to periodically review the terminology structure and content to incorporate learning from ongoing experience with real -world use of device nomenclature (ex. EUDAMED, GUDID, registries) as well as from technological innovation . Availability of names and descriptions in all the official EU langu ages is recognised as of being of high importance. All copyright s associated with the nomenclature shall be secured. 1 Indication of these countries is based on current situation with the applicable directives on medical devices as a result of the combination of the legal text of those Directives and relevant currently applicable international agreements . this list of countries might be subject to change in the context of the new m edical device framework.

12 MDCG 2020-12 Guidance on transitional provisions for consultations of authorities on devices.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 1 of 6 MDCG 2020-12 Guidance on transition al provisions for consultations of authorities on devices incorporating a substance which may be considered a medicinal product and which has action ancillary to that of the device, as well as on devices manufactured using TSE suscep tible animal tissues June 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 2 of 6 Guidance on transitional provisions for consultations of author ities on devices incorporating a substa nce which may be considered a medicinal product and which has action ancillary to that of the device, as well as on devices manufacture d using TSE susceptible animal tissues I. Consultations for a substance which may be considered a medicin al product and which has action ancillary to that of the device (including human blood derivatives) Consultation procedure under the MDD and AIMDD According to Annex I section 7.4 of Directive 93/42/EEC on medical devices (the MDD), and Annex I section 10 of Directive 90/385/EEC on active im plantable medical devices (the AIMDD), for devices containing a substance which, if used separately, would be considered to be a medicinal product and which is liable to act upon the body with an action ancillary to that of the device, the notified body is required, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, to seek a scientific opinion from one of the competent authorities designated by the Member St ates or the European Medicines Agency (EMA) on the quality and safety of the substance in the medical device, including the clinical benefit/risk profile of the incorporation of the substance into the device. Similarly, where changes are made to that substance, particularly relating to its manufacturing process, the notified body is required to consult with the same authority in order to confirm that the quality and safety of that substance are maintained and to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical device. This consultation on changes is referred to as supplementary consultation in this guidance document. There is an equivalent consultation requirement for medical devices containing a human blood derivative with ancillary action. In this case the notified body is required to consult the EMA only. Transitioning from MDD and AIMDD to MDR Regulation (EU) 2017/745 on medical devices (the MDR) establishes a similar requirement in Article 52 (9) (Annex IX section 5.2 and Annex X Section 6): fo r devices incorporating, as an integral part, a substance which, if used separately, may be considered to be a medicinal product 1 and which has an action ancillary to that of the device (hereafter referred to in this document as the ancillary substance), the notified body is required, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, to consult a medicinal products authority designated by a Member State or the EMA2 on the quality and safety of the substance, including the benefit or risk of the incorporation of the substance into the device. The notified body is 1 including a medicinal product derived from human blood or human plasma 2 only the EMA in the case of medicinal products derived from human blood or human plasma, or those falling exclusively within the scope of Regulation (EC) 726/2004 Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 3 of 6 required to do so both for the initial conformity assessment of the device (this consultation is referred to as initial in this guidance document) and for an y subsequent changes to the ancillary substance, in particular in relation to its manufacturing process (the consultation on changes is referred to as a supplementary consultation, by analogy to the M DD/AIMDD). A competent auth ority designated by a Member State in accordance with Directive 2001/83/EC or the EMA (hereafter referred as medicinal products authority in this document) consulted has 210 days since the receipt of all the necessary documentation to provide its opinion in the case of an initial consultation, or 60 days for a supplementary consultation. Unlike the MDD and AIMDD, the MDR also states that the notified body may not deliver the certificate if the opinion is unfavourable (Annex IX 5.2 (e) and (f)). This document provides guidance on fulfilling th is requirement for the first time under the MDR for devices which already underwent a consultation with a medicinal products authority according to Annex I 7.4 of the MDD or Annex I 10 of the AIMDD. Consultation for ancillary substances under the MDR for devices which have undergone the consultation under the MDD or AIMDD In order for the notified body to issue the first certificate for a given device under the MDR, a full conformity assessment covering all requirements has to be carried out even if the device has been certified under the MDD (Q&A IV.1 MDCG 2019-6). For devices containing ancillary substances, this includes the consultation of the medicinal products authority as per Article 52 (9) of the MDR. For some devices, there may be no change to the device, the ancillary substance and its manufacturing process since the last consultation of the me dicinal products authority under the MDD/AIMDD. Nevertheless, there may be changes in the documentation of the device due to the new requirements of the MDR, for example in clinical evaluation, which have a bearing on the quality, safety or usefulness of the ancillary substance. There may also be changes in the assessment of the device and its documentation by the notified body under the MDR. Lastly, the medicinal products authority may have new information on the substance, leading to a modified or different opinion. For the first consultation under the MDR, the notified body is required to submit the full documentation package to the medicinal products authority as described in dedicated guidance. The notified body is free to approach any medicinal products authority at its discretion, not necessarily the one consulted under the MDD/AIMDD. This should in clude the last opinion of the medicinal products authority under the MDD/AIMDD (whether initial or supplementary), as well as a consolidated list of changes, if any, in the following:  the ancillary substance,  its manufacturing process,  the way the substance is incorporated into the device,  design, manufacturing of the device which could influence the quality, safety or usefulness of the ancillary substance, and/or  the parts of the technical documentation related to the above aspects. If there were no changes to some or any of the above, the package may be accompanied by a declaration by the notified body to this effect, stating the elements that have remained identical. If there have also been no changes to the assessment of this documentation by the notified body, this may be included in the declaration. Should there be only administrative changes to the above (e.g. changes of names or addresses, changes in document layout, etc.), these should be clearly detailed in the declaration. The medicinal products authority may consider the depth of its review given the extent of the changes since the previous consultation under the MDD/AIMDD. It is at the discretion of the medicinal Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 4 of 6 products authority to issue its opinion in less than 210 days. If many elements concerning the substance remain identical, the medicinal products authority is highly recommended to expedite its review. The medicinal products authority may contact the authority consulted on this device under the MDD/AIMDD, who may, at its discretion, confirm the opinion provided in the previous consultation and/or share any additional information. The final opinion for the consultation under the MDR and its issuance according to the stipulated timeline remains the responsibility of the medicinal products authority to which the notified body submitted the request under the MDR. Note on “liability to act upon the body” It should be noted that Annex I 7.4 of the MDD refers to devices in which the substance is liable to act upon the body . In the MDR (Article 52(9), referring to Article 1(8), and Section 5.2 of Annex IX), this is no longer the case. Therefore, for al l those devices where the "liability to act upon the body" was used by the manufacturer as a justification not to follow the consultation, the consultation must take place under the MDR. In those cases where there are doubts on the applicability of the consultation, independently of any considerations concerning the classification of the device, the notified body should seek the scientific opinion as described in Annex IX Section 5.2 (b) of the MDR. Relevant text from MDD and MDR MDD – Annex I Section 7.4 [emphasis added] Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive 2001/83/EC and which is liable to act upon the body with action ancillary to that of the device, the quality, safety and usefulness of the substance must be verified by an alogy with the methods specified in Annex I to Directive 2001/83/EC. For the substances referred to in the first paragraph, t he notified body shall, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States or the European Medicines Agency (EMEA) acting particularly through its committee in accordance with Regulation (EC) No 726/2004 (1) on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the substance into the device . When issuing its opinion, the competent authority or the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the notified body. Where a device incorporates, as an integral part, a human blood derivative, the notified body shall, having verified the usefulness of the substance as part of the medical device and taking into account the intended purpose of the device, seek a scientific opinion from the EMEA , acting particularly through its committee, on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the human blood derivative into the device . When issuing its opinion, the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the notified body. Where changes are made to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the notified body shall be informed of the changes and shall consult the relevant medicines competent authority (i.e. the one involved in the initial consultation), in order to confirm that the quality and safety of the ancillary substance are maintained. The competent authority Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 5 of 6 shall take into account the data related to the usef ulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical device. MDR – Annex IX 5.2 b (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derive d from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (b) Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accor dance with Directive 2001/83/EC or from the EMA , either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device . Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA. (c) When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body. II. Consultations for medical device s containing TSE susceptible an imal tissue under the MDR, where such a consultation took place under the M DD or AIMDD Article 5(4) of Regulation (EU) 722/2012 requires that for all medical devices, including active implantable medical devices, manufactured utilising tissues of animal origin which are susceptible to transmissible spongiform encephalopathy (TSE), the notified body must, through their competent authority, carry out a consultation of the other competent authorities and the Commission. Under the MDR, this requirement rema ins unchanged (Annex IX Section 5.3.2). In order to fulfil the requirements of the MDR, during the first certification under the MDR, the notified body is required to submit the full summary evaluation report as stated in Regulation (EU) 722/2012 to the competent authorities. If there have been no changes to the documentation required from the manufacturer as per Regulation (EU) 722/2012, the summary evaluation report may be accompanied by a declaration by the notified body to this effect, stating the elements that have remained identical. If there have also been no changes to the assessment of this documentation by the notified body, this may also be included in th e declaration. Should there be only administrative changes to the above (e.g. changes of names or addresses, changes in document layout, etc.), these should be clearly detailed in the declaration. Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 6 of 6 As stated in Article 5(5) of Regulation (EU) 722/2012, the competent authorities and the Commission may agree on shortening the time periods for the consultation. If many elements of the summary evaluation report remain identical, it is highly recommended to expedite the review. Relevant text from Regulation (EU) 722/2012 Article 5 (4) and (5) 4. Before issuing an EC design-examination certificate or an EC type-examination certificate, the notified bodies shall, through their competent authority, hereinafter ‘coordinating competent authority’, inform the competent authorities of th e other Member States and the Commission of their assessment carried out pursuant to paragraph 2 by means of a summary evaluation report in accordance with Annex II to this Regulation. 5. The competent authorities of the Member States may submit comments on the summary evaluation report referred to in paragraph 4 within the following deadlines: (a) in relation to medical devices using starting materials for which a TSE certificate of suitability as referred to in paragraph 3 has been submitted, within four weeks from the date on which the notified body informed the coordinating competent authority pursuant to paragraph 4; (b) in relation to medical devices using starting materials for which a TSE certificate of suitability has not been submitted, within 12 weeks from the date on which the notified body informed the coordinating competent authority pursuant to paragraph 4. The competent authorities of the Member States and the Commission may agree on shortening the time periods set out in points (a) and (b).

mdcg_2018_8_crf_transfer_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -8 Page 1 of 2 MDCG 2018 -8 Guidance on c ontent of the certificates, voluntary certificate transfers November 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commissi on document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -8 Page 2 of 2 In the meeting of 30 November 2018, MDCG endorsed the below positions. These positions will be part of a more comprehensive guideline related to notified bodies, currently under development. Content of the certificate under MDR / IVDR Annex XII, Chapter II, section 10 Certificates do not need to include reference to relevant common specifications or harmonised standards as long as such information on all examinations and tests performed is traceable and available from e.g. report(s) which are ment ioned in the certificate. Voluntary certificate transfer under MDR Article 58 / IVDR Article 53 While MDR Article 58(1) / IVDR Article 53(1) sets out the requirements for a transfer agreement, it does not specify the conformity assessment activities to be performed by the incoming NB. The incoming NB may decide not to carry out full conformity assessment activities according to Article 52 MDR / Article 48 IVDR, as long as it does have sufficient information in respect to the conformity activities performed by the outgoing NB. For quality management system certificates, the incoming NB needs to perform appropriate on -site audit(s) and assessments to ensure that the manufacturer in question applies the approved QMS and the post -market surveillance plan prior to the issue of any certificate. In respect to the assessment of technical documentations on a sampling basis, the oncoming NB shall review the previous assessment results together with a sample of a technical documentation and draw up or amend a sampling plan. For product certificates (Annex IX Chapter II/Annex X), new certificates without a comprehensive (initial) review may be issued as long as the documentation received does not identify ongoing existing or other concerns. The incoming NB assumes full responsibility for the new certificates issued following the transfer.

mdcg_2019_14_MDR_codes.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2019-14 MDCG 2019-14 Explanatory note on MDR codes December 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Explanatory note on MDR codes 1 Introduction Commission Implementing Regulation 2017/2185 establishes the codes for the designation of notified bodies in medical devices under Regulation (EU) 2017/745 and in vitro diagnostic medical devices under Regulation (EU) 2017/746. These codes are primarily used by designating authorities to define the notified body scope of designation but they are also used by the notified body to: 1) describe the individual qualification of the NBs staff members 2) describe the qualification required for assessing a device These codes may be very broad and, furthermore, unequivocal authorisation of personnel to codes and the assignment of codes to a device is not always straightforward. However, the notified body’s system needs to ensure, in all cases, that the authorisation of personnel and team allocation for the conformity assessment of a device ensures adequate knowledge and expertise. 2 Scope The lists of codes and corresponding types of devices established by the above mentioned Regulation takes into account various device types which can be characterised by design and intended purpose, manufacturing processes and technologies used, such as sterilisation and the use of nanomaterials. These lists of codes should be used in a way that provides for a multi-dimensional application to all typology of devices. This will ensure that notified bodies as well as the staff assigned to conformity assessment are fully competent for the devices they are required to assess. This guidance is intended to explain the different level of codes and how they should be used, including the use of conditions with a view to ensure a harmonised use of the codes especially for the allocation of resources to conformity assessment activities. 3 3 Assignment of codes to devices within the conformity assessment procedure When a manufacturer lodges an application with a notified body, the type of devices and technologies subject to conformity assessment activities are to be indicated. Usually, at the application review stage (as defined in section 4.3 of Annex VII MDR), notified bodies will verify the assignment of codes provided by the manufacturer or will assign these codes to the devices themselves. This verification is carried out in order to ensure that the notified body is able to assess the application based on its designation, and that it has available resources to carry out the relevant conformity assessment activities (feasibility evaluation). The final assignment is made by the NB. After this application review, and signing of the contract, the notified body will allocate appropriately qualified and authorised personnel to carry out audit activities or product reviews. The following table presents an overview of the different types of codes and a summary of the main characteristics of each of them for the assignment to specific devices and the allocation of resources. Type Code Assignment of codes to the device Relevance for allocation of conformity assessment team MDA / MDN Codes reflect design and intended purpose of device Exactly 1 code per device. The codes should be selected according to their hierarchical order in Regulation 2017/2185. If more than 1 MDA/ MDN code is applicable, the one that is highest in the list should be selected. Allocation of personnel involved in the review of technical documentation (e.g. product reviewers) or in audits concerning product related aspects. MDS Horizontal codes that reflect the specific characteristics of the device 0 to several per device Assign all codes applicable to the device. Select once an MDN/MDA code has been assigned. Allocation of personnel involved in the review of technical documentation (e.g. product reviewers of sterilisation validation). May also be applicable to staff performing audits concerning certain special processes (e.g. sterilization).* MDT Horizontal codes that describe technologies or processes 1 to several per device Assign the codes which describe the main production technologies or processes. Select once an MDN/MDA code has been assigned. Allocation of personnel involved in audits (e.g. site auditors involved in the auditing of metal processing). * Note: Assessment of these codes could be performed by Product reviewers or Site auditors depending on their competence 3.1 MDN / MDA-codes MDA / MDN-codes reflect the design and intended purpose of the device and hence are mostly relevant for the allocation of personnel involved in the review of technical documentation. In some specific cases, the NB may assign product reviewers to assess product performance and safety aspects during an audit. This means that if there are product related issues to be audited and the auditors do not possess the required qualification, product reviewers who are qualified for the device in question should be part of the audit team. The NB needs to ensure that the personnel allocated to the project are competent to assess for the devices and technologies under assessment . Special attention should be paid in situations such as the one described in example 4 of this section. 4 The MDA / MDN codes may either specify a field of medical application (e.g. MDA 0309 Active non- implantable ophthalmologic devices) or the physical or technological principle of the device (e.g. MDA 0302 Active non-implantable devices utilising non-ionizing radiation or MDA 0315 Software). Therefore, there are cases where more than one specific code might apply to a device (e.g. surgical laser for refractive surgery of the eye ). Also, where there is a broad intended purpose, several codes may apply. Having these issues in mind, when drafting the Regulation 2017/2185, the codes were put in order such that the MDA/MDN codes that require very specific technological knowledge and experience are highest in the code lists. Therefore, in cases where more than one MDA/MDN code apply, the code highest in the list is to be selected. This approach ensures consistent assignment of codes (and therefore consistent assignment of suitably qualified staff) to devices. Example 1: A surgical laser for refractive surgery of the eye is assigned to MDA 0302 Active non-implantable devices utilising non-ionizing radiation and not to MDA 0309 Active non- implantable ophthalmologic devices because, even though both codes are specific for the device, since MDA 0302 is higher in the list. Example 2: A screw for orthopaedic surgery is assigned to MDN 1102 Non-active osteo- and orthopaedic implants and not to 1104 Non-active soft tissue and other implants, because MDN 1102 is higher in the list. Devices may be composed of different “components” which, if they were products on their own, would belong to different MDA/MDN codes (1). In such cases, the intended purpose or the main physical or technological principle of the device should be considered (Example 3). Nonetheless, the notified body needs to ensure that the assigned staff is qualified to assess all components of the device. Example 3: A medical devices is composed of a suture anchor (a bone screw attached to a surgical suture to reattach ruptured tendons) as well as a single use deployment instrument and a single use bone drill. The components are provided sterile in a blister, are covered by the same technical documentation and are not available individually (e.g. are not medical devices on their own). This product is assigned to MDN 1102 Non-active osteo- and orthopaedic implants and not to MDN 1208 Non-active non-implantable instruments because the implanted component of the device is associated with the intended purpose rather than the deployment instrument and the drill. Note that, given the complexity and the diversity of medical devices, in exceptional cases deviations from the guidance given above may be necessary when assigning codes to devices in order to ensure suitably qualified staff in the conformity assessment. In such cases, a brief rationale shall be documented (see Example 4). Example 4: A heater-cooler unit (HCU) for cardiac surgery is a device through which blood circulates, and which changes the circulating blood’s temperature in order to achieve hypo- or hyperthermia. Both the codes MDA 0303 Active non-implantable devices utilising hyperthermia/hypothermia and MDA 0306 Active non-implantable devices for extra-corporal circulation, administration or removal of substances and haemapheresis are specific to the device. Since MDA 0303 Active non-implantable devices utilising hyperthermia/hypothermia is a code that describes physical or technological characteristics higher in the list, according to the rule explained above MDA 0303 should be chosen. Nonetheless, the notified body assigns the device to the code MDA 0306 Active non-implantable devices for extra-corporal circulation, administration or removal of substances and haemapheresis and documents that the risks associated with the HCU are such that the staff having experience in this code is more suitable to assess the device. It is important to note that Stand-alone software (i.e. software that is not part of a physical medical device) should be assigned to MDA 0315 since assessment of software requires very specific knowledge (see annex VII 3.2.2 5 th indent MDR) and also that non-implantable cardiovascular 1 This description does NOT refer to procedure packs or systems according to MDR Article 2 (10) and (11) since those are combinations of individual CE-marked products that have been subjected to separate conformity assessments. 5 catheters, guidewires, introducers, filters and related tools shall fall under MDN 1203 (instead of MDN 1201 or MDN 1202). 3.2 MDS codes MDS codes are horizontal codes that are applicable to devices with specific characteristics. All codes that are applicable need to be assigned to a device in order to ensure that the review team possesses the full set of qualifications necessary for the conformity assessment. The MDS-codes are mainly relevant for the allocation of personnel involved in the review of technical documentation. This is because, generally, the auditing aspects linked to MDS codes have their corresponding MDT code for the relevant technology (e.g. MDS 1001 Devices incorporating medicinal substances vs MDT 2007 Devices which require knowledge regarding the production of pha rmaceuticals ). However, MDS codes may also be applicable to staff performing audits concerning certain special processes (for example MDS 1005 for staff auditing ethylene oxide sterilization processes). Example 1: A partially resorbable, sterile surgical implant that contains an antibiotic to prevent post-surgical infection will need to be assigned to the following MDS codes: 1) MDS 1005 - Devices in sterile condition: because it is provided sterile, 2) MDS 1008 - Devices utilising [...] being wholly or mainly absorbed or locally dispersed in the human body […]: because it is absorbed, and 3) MDS 1001 - Devices incorporating medicinal substances: because it contains an antibiotic. Example 2: An infusion pump should be assigned to MDS 1009 - Devices incorporating software/utilising software/controlled by software […] because the infusion pump is controlled by software. 3.3 MDT codes MDT codes relate to the technologies and processes that are used in the manufacturing and making available of the devices. MDT codes are relevant for the allocation of site auditors. Assignment of MDT codes should be done taking into consideration production of the device itself as well as for critical upstream production steps. This means that, even though many codes could be applicable when taking into consideration the processes involved in the entire supply chain of a medical device, these should not be considered for the use of MDT codes (e.g. for an electronic medical thermometer, at one point, metal processing, plastic processing, non-metal mineral processing, chemical processing, manufacture in clean rooms, manufacturing using electronic components, labelling and packaging are necessary to assemble the device from raw materials). Example 1: An electronic medical thermometer for layman’s use should be assigned to the following MDT codes: 1) MDT 2010 Devices manufactured using electronic components including communication devices because the product is assembled from electronic components and 2) MDT 2011 Devices which require packaging, including labelling because the device is packed and labelled. Example 2: A sterile animal derived bone graft substitute is manufactured using several steps. In the first step, the raw animal bone undergoes a sequence of chemical treatments to remove organic components. In a second step, the remaining mineral bone component is subjected to a heat treatment, then ground and sieved to obtain particles of defined sizes. The material is packed, labelled and sterilized. Therefore the following MDT codes should be assigned: 6 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant after the heat treatment is conducted in clean rooms, 2) MDT 2009 Devices manufactured using processing of materials of human, animal, or microbial origin because the implant is made from animal bone 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Note: MDT 2006 Devices manufactured using chemical processing and MDT 2003 Devices manufactured using non-metal mineral processing (e.g. glass, ceramics) were not applied since the chemical treatment and (bone) mineral processing are already considered within the scope of processing of animal materials. Example 3: A calcium phosphate bone cement is provided as a sterile powder composed of a mixture of calcium salts and a vial with sterile saline. The following MDT codes should be assigned: 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant is in a controlled environment, 2) MDT 2006 Devices manufactured using chemical processing, because the main risks in manufacturing are related to the testing and mixing of the components, 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Example 4: A manufacturer of cross-linked hyaluronic acid implants has no in-house manufacturing. The finished, labelled implant is bought from a supplier. The implant raw material (hyaluronic acid) is produced by fermentation using bacteria. The following MDT codes should be assigned: 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant is in a controlled environment, 2) MDT 2005 Devices manufactured using bi otechnology, because the main risks in manufacturing are related to the production and cross-linking of the hyaluronic acid. 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Note that, despite the fact that the manufacturer itself does not physically manufacture the device, the MDT codes concerning the manufacturing steps are assigned to the device since they are relevant when auditing suppliers / subcontractors. 4 Competence description: conditions (including limitations) Conditions should be established by the notified body for individual codes in cases where the qualification of the staff authorised to a certain code is not sufficient to cover the entire spectrum of the devices within this code. The designating authority could also apply conditions to the notified body's designation where the notified body does not have sufficient competence to cover a given code or could seek designation for conformity assessment of only certain devices within a code. Conditions, including limitations, should be formulated in an unambiguous way (see example 1). Furthermore, since the technical codes basically mirror the competence system of the notified body, the conditions and limitations should concern device characteristics (see example 2). Example 1: “MDN 1101 Non-active cardiovascular, vascular and neurovascular implants. Condition: heart valves”. This condition is unsuitable since it is not clear whether the notified body is restricted to assessment of heart valves or whether those products are excluded from 7 the scope of designation. Therefore, the condition should be “excluding heart valves” or “including only heart valves”. Example 2: “MDN 1102 Non-active osteo- and orthopaedic implants. Condition: excluding class III devices”. The scope of designation is intimately linked to the qualification of the staff that the notified body needs to have available. Conditions serve to exclude the devices for which the notified body does not have competent staff and/or suitable procedures; therefore, they need to be expressed in a way that they relate to knowledge and experience of staff and/or procedures. The condition “excluding class III devices” does not allow this and therefore it is unsuitable. In this case, the designating authority has to determine, based on the qualification of the notified body’s staff, which devices are included in the scope. This might result, for example, in the following condition: “including only orthopaedic plates and screws; excluding implants that are applied in or on the spine”. Further examples of conditions are illustrated in the final column of the table below. Considerations of the conditions should be based on the demonstrated competence of the applicant body . 8 5 Specific clarifications linked to individual codes The devices included in the third and fourth columns are only a few examples of the devices covered in the relevant code. The t hird column is not intended to provide an exhaustive list of devices included in each code. MDA CODE Active implantable devices Devices covered and Specific Considerations1 Examples of conditions MDA 0101 Active implantable devices for stimulation / inhibition / monitoring Implanted defibrillator Spinal cord stimulator Implantable cardiac pacemakers Implantable bladder stimulators Excluding brain stimulation MDA 0102 Active implantable devices delivering drugs or other substances Implanted drug delivery pump MDA 0103 Active implantable devices supporting or replacing organ functions Artificial heart Cochlear implants MDA 0104 Active implantable devices utilising radiation and other active implantable devices Prostate radioactive seed implant 1 The assessment also should consider Section 5.1 of Annex IX applies as well as Validation of SSCP acc. Article 32 . 9 MDA CODE Active non-implantable devices for imaging, monitoring and / or diagnosis Devices covered and Specific Considerations Examples of conditions MDA 0201 Active non-implantable imaging devices utilising ionizing radiation X-ray computer tomography equipment Gamma cameras Fluoroscopy equipment PET scanner Restricted to X-ray and gamma cameras MDA 0202 Active non-implantable imaging devices utilising non-ionizing radiation MRI computer tomograph MDA 0203 Active non-implantable devices for monitoring of vital physiological parameters Blood pressure monitor Medical thermometer Pulse oximeter Apnoea monitors Intensive care patient monitoring system Spirometers Electrocardiographs Electroencephalographs MDA 0204 Other active non-implantable devices for monitoring and / or diagnosis Ocular tonometer Audiometers Retinal cameras 10 MDA CODE Active non-implantable therapeutic devices and general active non-implantable devices Devices covered and Specific Considerations Examples of conditions MDA 0301 Active non-implantable devices utilising ionizing radiation Radioactive sources for cancer after loading therapy Therapeutic cyclotrons and linear accelerators MDA 0302 Active non-implantable devices utilising non-ionizing radiation Surgical laser for refractive surgery of the eye Laser for pain treatment Including only microwave and magnetotherapy medical devices MDA 0303 Active non-implantable devices utilising hyperthermia / hypothermia Medical heating blanket Warming and cooling blankets Blood warmers Paraffin bath MDA 0304 Active non-implantable devices for shock-wave therapy (lithotripsy) Extracorporeal shock wave lithotripsy device MDA 0305 Active non-implantable devices for stimulation or inhibition Automated external defibrillator Device for the transcranial magnetic brain stimulation Device for transcutaneous electrical nerve stimulation (TENS) Muscle stimulators Electrical acupuncture External bone growth stimulators 11 MDA 0306 Active non-implantable devices for extra- corporal circulation, administration or removal of substances and haemapheresis Haemodialysis machine and equipment Cardiopulmonary bypass pump Infusion pumps Feeding pumps Jet injectors for vaccination Blood pumps for heart-lung machines Anaesthesia machines MDA 0307 Active non-implantable respiratory devices Medical ventilator Hyperbaric chambers Nebulisers MDA 0308 Active non-implantable devices for wound and skin care Water jet for wound debridement MDA 0309 Active non-implantable ophthalmologic devices Aspiration pump for opthalmological use (removal of crystalline residue) MDA 0310 Active non-implantable devices for ear, nose and throat Hearing aids MDA 0311 Active non-implantable dental devices Powered dental surgical unit and hand pieces Surgical suction device for dental use Ultrasonic scalers Chairs with equipment MDA 0312 Other active non-implantable surgical devices RF electrosurgical generator Electrosurgical instrument Cauterization devices. Powered surgical drills and saws 12 MDA 0313 Active non-implantable prostheses, devices for rehabilitation and devices for patient positioning and transport Hospital beds Patient hoists Electric Wheelchairs Active limb prostheses Exoskeletons MDA 0314 Active non-implantable devices for processing and preservation of human cells, tissues or organs including in vitro fertilisation (IVF) and assisted reproductive technologies (ART) IVF cryopreservation systems blood bank refrigerator MDA 0315 Software Radiotherapy planning system. MDA 0316 Medical gas supply systems and parts thereof Medical gas supply system in a hospital Gas manifold and line pressure regulator for medical regulators Medical gas supply pipeline systems MDA 0317 Active non-implantable devices for cleaning, disinfection and sterilisation Sterilizers like autoclaves etc Washer disinfector for medical devices. MDA 0318 Other active non-implantable devices 13 MDN CODE Non-active implants and long term surgically invasive devices Devices covered and Specific Considerations Examples of conditions MDN 1101 Non-active cardiovascular, vascular and neurovascular implants Cardiac vascular stent Peripheral vascular stent Artificial heart valve Cardiac Valve Prostheses, Vascular and neurovascular grafts, shunts, vascular stents, cardiovascular patches Sutures for cardiovascular surgery For biological heart valves MDS 1003 should be applied. For drug eluting stents - MDS 1001 should be appliedIncluding only cardiac stents MDN 1102 Non-active osteo- and orthopaedic implants Artificial spinal disc Spinal cage Bone graft substitute for orthopaedic indications Prosthetic joint replacements (i.e knee, hip implants) Bone cement Hyaluronic acid implant for intra-articular use Orthopaedic nails, screws,plates Bone graft substitute for maxillofacial indications sutures, suture anchors, staples for orthopedic surgery spacers, ligament reconstruction products For antibiotic bone cements- MDS 1001 should be applied For absorbable substances MDS 1008 should be applied 14 MDN 1103 Non-active dental implants and dental materials Dental implant Dental fillers Root canal filler Abutments 15 MDN 1104 Non-active soft tissue and other implants Hyaluronic acid dermal fillers Intraocular lenses Intrauterine dispositive- IUD Breast implant Hernia mesh Urethral stent implants Sutures (not falling within the above codes) Eyelid implants Bariatric surgery devices: Intragastric Balloons, Gastric Bands, Anti-Reflux implants. Lung Volume Reduction devices: Coils, Valves, Sealants. Biliary and Pancreatic stents For contraceptive intrauterine devices containing copper or silver – MDS 1001 should be applied Excluding breast implants MDN CODE Non-active non-implantable devices Devices covered and specific conditions Examples of conditions MDN 1201 Non-active non-implantable devices for anaesthesia, emergency and intensive care Device for pleural drainage Masks, tubes for the administration of gases. Endotracheal tube Tracheostomy tubes Endotracheal tube introducers 16 MDN 1202 Non-active non-implantable devices for administration, channelling and removal of substances, including devices for dialysis Intravenous line Hypodermic needle Syringe tubing, bags for injection or transfusion Dialysis filter Dialysis solution Epidural catheters, Urinary Catheter Amnioscopic needles MDN 1203 Non-active non-implantable guide catheters, balloon catheters, guidewires, introducers, filters, and related tools Vascular filter catheter Embolectomy catheter Cardiovascular guidewires and catheters Neurovascular catheters central venous catheter. MDN 1204 Non-active non-implantable devices for wound and skin care Wound dressing Cotton wool Gauze dressings Bandages Sutures for dermal wound closure (of less than 30 days) Surgical gloves For dressings incorporating an antimicrobial agent - MDS 1001 should be applied MDN 1205 Non-active non-implantable orthopaedic and rehabilitation devices Orthoses Crutches Wheelchairs 17 MDN 1206 Non-active non-implantable ophthalmologic devices Contact lenses Eye drops Instrument for ophthalmologic surgery Solutions for contact lenses. MDN 1207 Non-active non-implantable diagnostic devices Thermal expansion thermometer MDN 1208 Non-active non-implantable instruments Instruments for general use in surgery: Forceps, clamps, scalpels, dental instruments MDN 1209 Non-active non-implantable dental materials Etching solution for dental use Braces Dental cements (when not considered long term surgically invasive) Dental impression materials MDN 1210 Non-active non-implantable devices used for contraception or prevention of the transmission of sexually transmitted diseases Condom Contraceptive diaphragms MDN 1211 Non-active non-implantable devices for disinfecting, cleaning and rinsing Solutions for disinfecting medical devices Contact lens care, catheter lock solutions MDN 1212 Non-active non-implantable devices for processing and preservation of human cells, tissue or organs including in vitro fertilisation (IVF) and assisted reproductive technologies (ART) Freezing solution for egg cells Embryo transfer catheters Artificial insemination probes Media, substances or mixture of substances intended for washing, separating, sperm immobilizing, cryoprotecting solutions. 18 MDN 1213 Non-active non-implantable devices composed of substances to be introduced into the human body via a body orifice or the dermal route MDN 1214 General non-active non-implantable devices used in health care and other non- active non-implantable devices Ultrasound gels 19 MDS CODE Devices with specific characteristics Devices covered and specific conditions Examples of conditions MDS 1001 Devices incorporating medicinal substances Devices incorporating medicinal products including herbal substances and human blood derivatives are included in this code. MDS 1002 Devices manufactured utilising tissues or cells of human origin, or their derivatives Section 5.3.1 of Annex IX applies MDS 1003 Devices manufactured utilising tissues or cells of animal origin, or their derivatives Section 5.3.2 of Annex IX applies Devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non- viable or rendered non- viable, unless such devices are intended to come into contact with intact skin only MDS 1004 Devices which are also machinery as defined in point (a) of the second paragraph of Article 2 of Directive 2006/42/EC of the European Parliament and of the Council1 MDS 1005 Devices in sterile condition Including aseptic processing, ethylene oxide gas sterilisation (EOG), low temperature steam, formaldehyde sterilisation, moist heat sterilisation, radiation (gamma, x-ray, electron beam), sterilisation with hydrogen peroxide, sterilisation with liquid chemical sterilising agents, thermic sterilisation with dry heat 1 Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/E C (recast) (OJ L 157 9.6.2006, p. 24). 20 MDS 1006 Reusable surgical instruments Reusable surgical instruments according to art. 52 (7) c) MDR MDS 1007 Devices incorporating or consisting of nanomaterial MDS CODE Devices with specific characteristics Devices covered and specific conditions Examples of conditions MDS 1008 Devices utilising biologically active coatings and / or materials or being wholly or mainly absorbed or locally dispersed in the human body or are intended to undergo a chemical change in the body Section 5.4 of Annex IX applies for devices intended to be introduced into the human body via a body orifice or applied to the skin and devices at are systemically absorbed by the human body in order to achieve their intended purpose MDS 1009 Devices incorporating software / utilising software / controlled by software, including devices intended for controlling, monitoring or directly influencing the performance of active or active implantable devices MDS 1010 Devices with a measuring function MDS 1011 Devices in systems or procedure packs MDS 1012 Products without an intended medical purpose listed in Annex XVI to Regulation (EU) 2017/745 21 MDS 1013 Class III custom-made implantable devices MDS 1014 Devices incorporating as an integral part an in vitro diagnostic device 22 MDT CODE Devices for which specific technologies or processes are used Examples of device manufacturing technologies MDT 2001 Devices manufactured using metal processing 3 d printing, Casting, Welding 3d printing (metal), turning (metal), anodization, passivation, polishing, surface modification, laser tube cutting, honing MDT 2002 Devices manufactured using plastic processing Injection molding, Extrusion, Bonding polymer compounding, 3d printing (plastics), thermoforming, blow moulding, turning (plastics) MDT 2003 Devices manufactured using non-metal mineral processing (e.g. glass, ceramics) Ceramic sintering, ceramic compounding, MDT 2004 Devices manufactured using non-metal non-mineral processing (e.g. textiles, rubber, leather, paper) Weaving, knitting MDT 2005 Devices manufactured using biotechnology Fermentation using cell cultures, enzymatic production processes, purification and modification of biomolecules MDT 2006 Devices manufactured using chemical processing Compounding, buffering MDT 2007 Devices which require knowledge regarding the production of pharmaceuticals production, handling and incorporation into a device of substances which, if used separately, can be considered to be a medicinal product MDT 2008 Devices manufactured in clean rooms and associated controlled environments MDT 2009 Devices manufactured using processing of materials of human, animal, or microbial origin Handling, dissection, storage, processing, inactivation and sterilization of human and animal tissues MDT 2010 Devices manufactured using electronic components including communication devices MDT 2011 Devices which require packaging, including labelling 23 MDT 2012 Devices which require installation, refurbishment Installation of devices at the point of use by or under the manufacturer’s responsibility MDT 2013 Devices which have undergone reprocessing

QA requirements for notified bodies V2 01102019.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 1 of 14 MDCG 2019-6 v2 Questions and answers: Requirements relating to notified bodies Version 2 - October 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 2 of 14 Introduction This document presents questions and answers on requirements relating to notified bodies under Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). The issues covered by this document have been identified in the context of joint assessments, and the document may be updated from time to time as new issues are identified. I. ORGANISATIONAL AND GENERAL REQUIREMENTS I.1. Are CABs obliged to follow guidance endorsed by the Medical Devices Coordination Group (MDCG)? Guidance documents are by definition not compulsory. However, all guidance documents endorsed by the MDCG reflect the interpretation of the EU law jointly agreed by the authorities which are in charge of interpreting and applying the EU law. Hence notified bodies should be encour aged to apply these guidance documents (also taking into consideration Section 1.6.2 of Annex VII to the MDR/IVDR 1). Furthermore, it is to be noticed that the European Court of Justice often refers to guidance documents when developing its rulings. Hence Notified Bodies have an interest, also in terms of liabilit y risk, to follow that guidance. I.2. What is the meaning of “legal personality” under Section 1.1.1 of Annex VII 2? The CAB needs to have legal personality, meaning that it has to exist as a legal entity. To that end, it must be registered as legal entity, also called "legal person". The wording of the MDR/IVDR does not exclude that only a part of a legal entity undertakes conformity assessment activities in the field of medical devices. In this case, where the CAB is part of a wider legal entity, the documentation provided should be clear as to where the CAB sits within that legal entity. In case the entire legal entity is the CAB, the documentation to be provided refers to the legal entity as such. It is always this legal entity as such which is designated (and not its organisational part). I.3. What is the meaning of “organ isation” as described in 1.1.2 of Annex VII? The term of "organisation" as described in 1.1.2 refers to the whole organisation (e.g. corporate group) to which the CAB belongs including the CAB's legal entity. The concept of "organisation" should be based not only on ownership rights (e.g. shares), but also functional/hierarchical links, such as voting/management/other control rights. One typical example of organisation is a holding company owning different companies (i.e. separate legal entities), one of them being or containing the CAB. 1 1.6.2. The notified body shall take into consideration guidance and best practice documents. 2 Unless specified otherwise, a reference to Annex VII means a reference to both Annex VII of the MDR and Annex VII of the IVDR. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 3 of 14 I.4. Does the term “organisational structure” as per 1.1.5 refer only to hierarchical relationships? If a notified body is part of a larger organisation, both hierarchical (i.e. mother and daughter companies of the CAB) and horizontal relationships (e.g. sister companies where there is a common mother company) between the notified body and other entities belonging to that organisation are covered by the term "organisational structure". The organisational structur e of the CAB will vary depending on the complexity of the legal entity and the organisation to which it belongs. For instance, in the case of holding companies, the CAB could provide a matricial organisational chart with dual reporting relationships (i.e. functional and managerial). In this case, hierarchical and reporting lines should be clear and should match the information provided in job descriptions for the activities related to the MDR/ IVDR certification. I.5. Is a 3-year competitor clause for consultants covered in the MDR / IVDR requirements? The MDR/IVDR does no longer define the timelines for clearance of consultants that were defined in Section 1.3b of Annex I to the Implementing Regulation (EU) 920/2013, except in case that the person worked for the same company or the group (Section 1.2.4 of Annex VII). However, the requirements under the Implementing Regulation (EU) 920/2013 on the management of impartiality for consultants are included in sections 1.2.2, and 1.2.3 (c), (d) and (e) of Annex VII. Therefore, it is expected that CABs will have similar measures in place under both regimes. It is essential that competitors, authorised representatives and suppliers are also included in the identification, analysis and resolution of potential conflicts of interests. I.6. May CAB provide pre-certification services? Pre-certification services are not allowed before an application is lodged by the manufacturer (e.g. review of clinical data or assessment of the quality management system aside from regulatory standards such as ISO 13485) and therefore these services have to take place under the scope of the application. Every activity carried out once an application has been submitted will be considered part of the conformity assessment activities and therefore if the manufacturer withdraws its application after this process has started, the notified body has to inform the other notified bodies through Eudamed according to Article 53(2) of the MDR / 49(2) of the IVDR. Whenever these activities consist in providing solutions to the manufacturer, they fall under the definition of consultancy and therefore the notified body impartiality policy and procedure(s) will need to cover that these pre-certification activities could be seen as consultancy. The CAB has to implement in their policy and/or procedures how it prevents that pre-certification activities carried out as part of the conformity assessment activities are falling into consultancy. Services provided by the CAB that could fall under the definition of conformity assessment activities are not allowed outside of an application as they would be regarded as consultancy (e.g. gap analysis, check of MDR/IVDR readiness, use of mock-up files produced instead of “real” TD assessments). Nevertheless, general Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 4 of 14 training activities that are not client specific and that relate to regulation of devices or to related standards are allowed. I.7. Can the CAB accept applications prior to being notified? No, applications under the MDR / IVDR cannot be accepted before the designation of the CAB became valid, i.e. the day after the notification is published in NANDO. I.8. How are the conditions on remune ration to be assessed within the meaning of 1.2.5 of Annex VII? The MDR/IVDR establishes that remuneration cannot depend on the results of the assessments. Both direct and indirect correlations between results of the assessments and remuneration are prohibited. Hence an individual examination is needed. Special care has to be applied with regard to bonuses. Bonuses on the basis of general objectives, even when not directly linked to the result of the individual conformity assessments, might still be problematic if they indirectly correlate to the average result of assessments. In the context of a joint-assessment, sampling of contracts or agreements covering remuneration (sheets) should take place. The sampling should cover different grades of influence, e.g. project handlers, final reviewers/decision makers, or head of the CAB / medical devices' certification. I.9. Are declarations of absence of conflict of interests sufficient to ensure compliance with legal re quirements for impartiality? No, declarations are not sufficient in isolation to ensure compliance. CABs should define their own system to comply with the legal requirements for independence and impartiality, but a system based on analysis of risk and control measures should be generally in place. This system will usually include a comprehensive risk analysis of the CAB's activities, its staff (including top- level management) and the activities of its organisation or related bodi es. Risks posed to impartialit y from each individual should be assessed with regard to past employment, consultancy services and financial interests. For instance, shares in companies certified by the notified body or in competitors of these companies (investment funds can be seen differently) as well as relatives of the person under analysis. Also, the risks linked to subcontractors/suppliers (1.2.1) of the manufacturer need to be assessed. Section 2.4 of Annex VII also requires, as part of this system, a “multi-level” statement. Firstly, a general one, listing any existing or prior association with clients or devices or processes under assessment. This general one needs to be renewed from time to time (e.g. annually). In addition, there is a need for a written statement and verification by the notified body within each conformity assessment project. Any involvement in processes (e.g. design, risk management, manufacturing processes) being related with the devices and quality management systems for economic operators covered by the application/designation needs to be seen as consultancy. Other activities not specifically linked with the product will be also regarded as consultancy (e.g. internal audi ts to manufacturers or client specific training). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 5 of 14 I.10. Does a CAB that is part of a larger organisation need individual liability insurance? The CAB is responsible for taking out liability insurance and therefore there must be evidence that the legal entity is covered by a liability insurance that fulfils the legal requirements. The contract with the insurance company can be signed by other legal entity of a larger organisation (i.e. mother company) provided that the contract gives the CAB the individual right to be protected against liabilit y claims. The notified body must be able to invoke that right directly towards the insurance company, and not only indirectly via the company which has signed the contract (this is important e.g. in case of insolvency of the signing company or in case of unwillingness or inability of the signing company to effectively invo ke the insurance contract towards the insurance company). Furthermore, the signing legal entity must involve the notified body in any change of insurance conditions affecting the medical devices conformity assessment activities of the CAB so that the notified body has the possibility to react if it considers that the coverage is insufficient. Any change on the liability insurance which may affect the compliance of the notified body with the requirements set out in Annex VII should be communicated by the body to the authority responsible for notified bodies in accordance with articles 44 (1) of the MDR / 40(1) of the IVDR. II. QUALITY MANAGEMENT SYSTEM III. RESOURCES REQUIREMENTS III.1. Is a complete re-author ization of existing personnel necessary to document satisfaction of the new qualification criteria under section 3 of Annex VII? Yes, all personnel that will be used to per form conformity assessment tasks under the MDR/IVDR shall be authorized under the new criteria. For the satisfaction of the work experience criteria, the CAB can accept previous experience in a notified body but it cannot automatically grandfather authorisations (i.e. transfer authorisations) granted by other notified body or by the same notified body under the Directives. However, the experience in a notified body needs to be extensive and traceable and always specific to the tasks to be carried out and the specific technology or product (specific codes) in order to satisfy the MDR/IVDR qualification criteria. In addition, comprehensive and objective evidence of such previous experience in a notified body in the relevant scope shall be part of the personnel files. III.2. What is the meanin g of “permanent ava ilability of sufficient personnel” within Section 3.1.1 of Annex VII? In respect to the availability of personnel, MDR / IVDR Annex VII Section 3.1.1 do not establish the number of auditors / reviewers per code to ensure permanent availability of sufficient personnel. As a ve ry minimum, it is considered that notified body should have one person available and authorised per applied-for scope code Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 6 of 14 and role as per Section 3.2 of Annex VII at the time of the joint assessment. Nevertheless, it is recommended that the notified body has two product reviewers/auditors authorised per code to ensure a sufficient capacity to allow fulfilment of other related requirements such as rotation of personnel. When this is not the case, an observation may be raised at the joint assessment in order to flag that for certain codes the available resources are limited. The notified body is expected to have 2 auditors / reviewers available and authorised per applied-for scope in order to fulfil the legal requirements under Section 3.1.1 of Annex VII at the moment of its re-assessment joint assessment. III.3. What is the meaning of “possess or have access to all equipment and facilities” needed to perform its tasks within the meaning of Section 3.1.1 of Annex VII of the MDR? This question refers to the requirements in relation to possessing or having access to sufficient equipment and facilities to properly perform the conformity assessment activities within the CAB's applied-for scope. It is expected that the CAB would have internal testing facilities or access to testing subcontractor(s) (e.g. by a framework agreement) for device tests in support of the codes for which it seeks designation under Annex X and Annex XI(B). In order to be designated under Annex X and XI(B), the CAB's personnel needs to have the technical knowledge to identify and select all the tests needed; the CAB must have implemented detailed procedures ensuring the identification of the relevant tests; and have access to at least some of the tests to be performed within the scope of designation. In particular, for each MDA or MDN code for which the CAB applies under Annex X or XIB it should identify at least the basic tests to be performed and the corresponding testing fac ilities (internal or subcontracted). The CAB should be able to demonstrate how t he facilities available are linked to the codes the CAB applies for. Nevertheless, the CAB is not expected to hav e testing equipment and facilities (either in house or a framework agreement) covering all possible tests within a code under Annex X or XI(B) or as part of surveillanc e or unannounced audits as some of the tests are very specific or rarely used. For these purposes, the CAB should have procedures in place in order to find additional subcontractors whenever needed or to define under which circumstances the CAB will perform witness testing (i.e. when the test equipment needed is very specialised) III.4. What is the meaning of "two years' professional experience" in cases where the experience h as been gained within a CAB under section 3.2.5 of Annex VII? According to MDR/IVDR Annex VII 3.2.5 product reviewers have to demonstrate two years’ professional experience in the design, manufacture, testing or use of the device or technology to be assessed or related to the scientific aspects to be assessed. Experience related to the scientific aspects to be assessed could include, Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 7 of 14 but not be limited to, extensive experience in conformity assessment activities in a specific type of device or technology gained within a CAB3 . In such case, when professional experience – based on a relevant background education – is to be proven by activities only within a CAB, this experience should have been gained during at least two years. As a guideline if one individual has carried out at least five full technical documentation assessments of devices in the relevant code (or aspects to be assessed) or under the equivalent code under the Directives, during at least 2 years, this can be accepted as a valid work experience within the meaning of 3.2.5 of Annex VII. Nevertheless, based on the assessment of the educational background and specific work experience of the individual, the CAB has always to analyse if additional assessments must be performed (i.e. under supervision). In addition, in situations where the objective evidence for the experience gained during technical file reviews is insufficient (e.g. if the staff was authorised for the code in a different CAB without detailed supporting evidence), as a guideline, the technical documentation assessments on the code (or aspects to be assessed) to which the individual wishes to be authorised have to be carried out under close supervision of an experienced product reviewer (e.g. mirror review 4). At least five of these assessments should be related to a full assessment. In addition to technical documentation assessments or product tests, product-related audit activities can be considered as work experience as long as they are not used solely and they are adequately documented and assessed by the authorising personnel of [or within] the CAB. In all of the cases above, the CAB has to analyse individual training needs (e.g. on relevant standards) especially when the work experience was gained a few years ago in the past or when the individual has experience related to a very similar technology. Before authorisation, the authorising personnel needs to ensure that all the qualification criteria under 3.2.5 of Annex VII are fulfilled and their satisfaction fully documented (including an adequate justification in the exceptional cases where the criteria cannot be fully demonstrated as established in 3.3.1 of Annex VII) and that the knowledge is state-of-the-art. For codes (MDR/IVDR) comprising a broad range of devices, the CAB has to ensure that the individual has carried out technical documentation assessments in different devices covered by the code or the authorisation to the code is to be granted with appropriate limitations. III.5. Does the CAB need to defi ne qualification criteria for monitoring and maintenance of competences in accordance with Section 3.5 of Annex VII? 3 As defined in section 6.2.2. of NBOG BPG 2017-2 4 Mirror review is to be understood as a review carried out simultaneously by two product reviewers of the notified body, one being on training and the other one being an experienced product reviewer on that code. Once the review is finalised from the two reviewers, the most experienced will assess and document the quality of the review carried out by the person in training. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 8 of 14 Yes. The CAB’s personnel competence needs to be maintained and therefore reviewed at regular intervals. For this purpose, the authorising personnel5 (as per 3.2.3 of Annex VII) needs to define qualification criteria for monitoring and maintenance of competence of its entire staff (internal and external, as well as subcontractors), involved in conformity assessment activities. Such "re-qualification" or "maintenance" criteria will be used as a basis for re-authorisation of personnel to codes and roles. In respect of monitoring of competence, such criteria should be defined for personnel involved in conformity assessment activities, at least for personnel with relevant clinical expertise, product reviewers, site auditors and final reviewer / decision-maker, and authorising personnel. III.6. What is the meaning of the term “employed” in MDR Article 36(1) / IVDR Article 32(1)? The personnel referred to in Article 36(1) MDR / Article 32(1) IVDR carries out the key functions within the notified body, and therefore the Regulations expressly require that this personnel is employed by the notified body. This requirement is estimated to be complied with when the contractual relationship between the notified body and the individual meets at the minimum the following criteria:  direct employment contract between the notified body and the employee setting out the rights and obligations of the latter;  control and supervision over the activities of the employee by the notified body  direct reporting obligations of the employee towards the notified body; and  a direct paid remuneration by the notified body to the employee for the work carried out, accompanied by the payment of any relevant taxes and social security contributions. Any reference to “internal activities” sha ll be intended as activities being carried out by personnel employed by the Notified Body. N.B. Whenever needed and appropriate, any action from the Notified Bodies aimed at ensuring compliance with those requirements should be taken throughout the designation period as soon as possible and completed at the latest by the time of their first re-assessment. III.7. What is the meaning of “pe rmanent availability of personnel with relevant clinical expertise” in accordance with sections 3.2.4 and 3.1.1 of Annex VII? With regard to “personnel with relevant clinical expertise”, in order to fulfil the tasks covered in Section 3.2.4 of Annex VII it is expected that the CAB has at least one "internal clinician" who, where possible, has to be employed by the CAB. This does 5 Short term used in NBOG BPG 2017-2 to refer to "personnel responsible for establishing qualification criteria and for authorising other personnel to perform specific conformity assessment activities" according to Section 3.2.3 of Annex VII. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 9 of 14 not preclude the possibility to subcontract su ch a role, provided that the notified body produces a justification as to why it is not possible to employ the person(s). In any case, when the CAB does not have the possi bility of employing that person(s), it should at least ensure that she/he is fully integrated throughout the conformity assessment and the decision-making process, which means that the person is involved in the CABs assessment and decision-making process in the same way as an employed staff. However, it should be noted that when the internal clinician is a subcontractor even if this person will suppo rt the final review and decision making process as indicated in 3.2.4 (e.g. in case an external clinical expert has been involved making a recommendation to the final reviewer or decision maker) they cannot be authorised as final reviewer or decision maker as these personnel should be employed by the notified body itself as required in Art. 36 of the MDR and Art. 32 of the IVDR. Accordingly, all “internal clinicians” are integrated, whereas some internal clinicians are not employed. Given that the term "internal clinician" is widely spread and it has been used to defined personnel carrying out tasks established in Section 3.2.4 of Annex VII it is assumed that when the term "internal clinician" is used, it could refer either to an employee of the CAB or not. IV. PROCESS REQUIREMENTS IV.1. Do devices certified under the Directives need to be subject to a full conformity assessment under the new Regulations if the manufacturer applies for certifi cation under the MDR / IVDR? The conformity assessment activities described under Article 52 / Article 48 apply to any certificate issued under the new regulations. As no exceptions were established under the regulations for the migration or transfer of MDD/AIMDD/IVDD certificates to the MDR / IVDR the general provisions should apply. Therefore, all devices to be certified under the MDR / IVDR should be subject to an initial certification according to the applicable annex. The notified body should ensure that all requirements under the MDR / IVDR are fulfilled. It may not restrict its procedures to gap audits or gap file reviews. It should be noted that MDD/AIMDD/IVDD certificates will remain valid until their expiration date and at the latest on 27 May 2024 as long as conditions laid down in Article 120(3) of the MDR and 110 (3) of the IVDR are complied with. IV.2. What should be the criter ia for auditing suppliers and subcontractors? The MDR/IVDR established that the audit of the manufacturer pr emises must include an audit on the premises of subcontractors and/or suppliers if appropriate. Therefore, the notified body should have criteria for auditing these actors on the basis of their criticality. At the very least, the criteria defined in Section 4.5.2(b) of Annex VII should Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 10 of 14 be applied (i.e. the control over the supplier/subcontractor and its influence on the conformity of the device is essential whereas the sole existence of a certificate against ISO 13485 is not sufficient). IV.3. What is the meaning of "examinations and tests" to be included in a certificate in accordance with Section 10 of Annex XII of the MDR / IVDR? 6 Certificates do not need to include reference to relevant common specifications or harmonised standards as long as such information on all examinations and tests performed is traceable and available from e.g. report(s) which are mentioned in the certificate. IV.4. What are the applicable requirements for voluntary certificate transfer under MDR Article 58 / IVDR Article 53? While MDR Article 58(1) / IVDR Article 53(1) sets out the requirements for a transfer agreement, it does not specify the conformity assessment activities to be performed by the incoming NB. he incoming NB may decide not to carry out full conformity assessment activities according to Article 52 MDR / Article 48 IVDR, as long as it does have sufficient information in respect to the conformity ac tivities performed by the outgoing NB. For quality management system certificates, the incoming NB needs to perform appropriate on-site audit(s) and assessments to ensure that the manufacturer in question applies the approved QMS and the post-market surveillance plan prior to the issue of any certificate. In respect to the assessment of technical documentations on a sampling basis, the oncoming NB shall review the previous assessment results together with a sample of a technical documentation and draw up or amend a sampling plan. For product certificates (Annex IX Chapter II/Annex X), new certificates without a comprehensive (initial) review may be issued as long as the documentation received does not identify ongoing existing or other concerns. The incoming NB assumes full responsibility for the new certificates issued following the transfer. IV.5. What are the applicable requirements for OBL manufacturers? The MDR / IVDR does not distinguish between OBL 7 and other manufacturers. There are just "manufacturers" and therefore OBL manufacturers must comply with the legal requirements, as any other manufacturer 8. 6 See also Q&A IV.8 7 OBL” (own brand label manufacturer) is a term used in the fiel d that describes manufacturer that are supplied with the finish ed medical device by their supplier, who often is called “OEM” (original e quipment manufacturer). Neither of both are defined in the MDR (or ever were defined in the Directives). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 11 of 14 IV.6. What is the role of the intern al or integrated clinician in the notified body´s assessment and decision-making process? The internal or otherwise integrated clinici an is responsible to identify when specialist input is required for the assessment of the clinical evaluation as defined in Section 3.2.4 of Annex VII of the MDR and IVDR. This decision will be made by the internal or integrated clinician on a case-by-case basis, based on the products covered by the applications lodged by the manufacturer and the clinical expertise available. The internal clinician or integrat ed clinician will be responsible fo r this process in all cases where the conformity of the device to the requirements of annex I is achieved also by clinical data. In cases where demonstration of conformity to requirements of Annex I based on clinical data is not deemed appropriate (in accordance with Article 61(10)) the internal or integrated clin ician will also examine the ju stification provided in order to assess its adequacy. The internal or otherwise integrated clinicians will decide if the review of clinical evaluation is to be carried out by themselves, to be delegated to other qualified staff or if it necessitates the input of external clinical experts. This process is also defined in Section 4.3 of Annex IX of the MDR and Section 5.4 of NBOG’s best practice guide 2017-2 as endorsed by the MDCG. Section 3.2.4 of Annex VII defines that there must be a clinician who is either internal (= employee) or otherwise integrated into the CAB's assessment and decision-making process. To be regarded as integrated, a clinician (who is not an employee) must have access to all the information, required to perform its activities, circulating in the CAB and must be involved in the internal processes in the same way as an employee, the only difference to an employee being that there is no employment contract, but a service contract and therefore this person should not be considered final reviewer or decision-maker as per 3.2.7 of Annex VII. In addition to this, the internal or otherwise integrated clinician will clinically judge the opinion provided by any external expert (including verificati on of comparability and consistency of the assessments of clinical evaluations conducted by clinical experts) and will be responsible to make a recommendation to the decision maker on the adequacy of the clinical evaluation. IV.7. What is the meaning of allocation of resources under Section 4.4 of Annex VII? Allocation of resources is to be understood as the allocation of appropriately authorised and qualified perso nnel and means (including eq uipment and facilities) for a given project (application), as stated in second paragraph of Section 4.4 of Annex VII "appropriate resources including personnel". Section 4.4 of Annex VII describes the assignment of tasks within a project to “individuals”, starting with the individual responsible for ensuring that the assessment of that application is conducted in accordance with the relevant procedures and for ensuring that the appropriate resources including personnel are utilised for each of the tasks of the assessment 8 Including but not limited to having: full and permanent access to the technical documentation; (ability for) post-market surv eillance including post market clinical follow-up; sufficient technical competence; and control of the quality system (control of the d esign, manufacture and/or final verificat ion and testing of the device s). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 12 of 14 (often referred to as project leader) and following with the identification of individual personnel that will carry out each task of a given project. The assessment of the resources needed for each application is a key function that has to be fulfilled as part of the internal activities of the CAB as indicated in Section 4.1 of Annex VII and any changes on such allocation should be documented. IV.8. How can a CAB ensure that information on "examinations and tests" in accordance with Section 10 of Annex XII of the MDR / IVDR is available to all interested parties (as referred to in Section IV.3 of this document)? According to Annex XII information on tests and examinations performed as part of the conformity assessment activities need to be included on the certificates issued by notified bodies. This information might be of interest for competent authorities and third parties. If the certificates do not include explicitly references to relevant common specifications, harmonised standards or other standards or referential but include a reference to the relevant report(s), the CAB should ensure that competent authorities and interested parties can have access this information on request. For example, the certificate may include a sentence like "information on examinations and tests as per Annex XII, section 10 is available on reques t" and possibly provide a contact (e.g. e- mail). IV.9. Which changes need prior approval by the CAB? The Regulations - in Annex VII and in the specific conformity assessment annexes (i.e. Annex IX, X and XI) -establish the need for the manufacturer to notify certain planned changes. Section 4.9 of Annex VII contains general requirements for notified bodies in respect to changes. For manufacturers, the specific conformity assessment annexes (i.e. Annex IX, X and XI) detail such requirements e.g. asking for plans for “any” changes (e.g. MDR Annex IX, 5.2 f), 5.3.1 d) or Annex X 5.2), for changes could affect the safety and performance of the device or the conditions prescribed for use of the device (e.g. MDR Annex IX 4.10) or for “substantial” changes only (e.g. MDR / IVDR Annex IX 2.4). With regard to the latter, the CAB needs to make clear in its communication to the manufacturer (e.g. in the terms and conditions) what it considers as “substantial changes” to the quality management system or the device-range covered. In order to fully comply with all the relevant requirements the CAB must have documented procedures defining how different changes need to be notified and assessed prior to their implementation and how the assessment will be documented. In particular, the CAB will define in its procedures when the approval of such changes will take the form of a supplement of the previously issued certificate. IV.10. What is the frequency of surveillance audits according to the Regulations? According to the Regulations (Section 3.3 of Annex IX and Section 7 of Annex XI), surveillance audits have to be carried out at least every 12 months. This means that Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 13 of 14 the audit planning defined in Section 4.5.2 and 4.10 of Annex VII will need to take into consideration that surveillance audits have to be scheduled on at least an annual basis with a maximum of 12 months after the previous surveillance audit was carried out The first surveillance audit should be scheduled taking as a reference the certification decision date. IV.11. What is the meaning of the last sentence in Section 4.5.1 of Annex VII with regard to the need for notified bodies to take into consideration standards and guidance even if the manufacturer does not claim compliance? CABs need to consider all the availabl e guidance, common specifications and harmonised standards to carry out its assessments. This means, that CABs will have to consider this documentation when developing its own procedures and processes (including checklists and report templates) and when assessing the manufacturers QMS (e.g. by taking into consideration EN ISO 13485) and technical documentation. For instance, in order to assess if the solutions adopted by the manufacturer are state of the art and in line with expectations, the CAB need to use the available guidance documents and standards. It should be noted that non-conformities will not be raised against standards or guidance but need to be phrased against legal requirements. For instance, Annex I Chapter I Section 1 of the Regulation which states that “devices shall be safe and effective […] taking into account the generally acknowledged state of the art” can be used when the technical documentation does not follow standards or guidance. IV.12. What are the applicable requirements for re-certification? Conformity assessment activities to be carried out in case of renewal of certificates/re-certification are laid down in Article 56(2) of the MDR / Article 51(2) of the IVDR, where the Regulations establish that the notified body can extend the validity of the certificate for further periods based on a re-assessment in accordance with the applicable conformity assessment procedures (i.e. as described in annexes IX-XI). In addition, Section 4.11 of Annex VII states that the notified body must use the same methods and principles for the decision on re-certification as for the initial certification decision. While for EU Technical documentation assessment certificates and EU type examination, Section 4.11 of Annex VII establishes a targeted conformity assessment (i.e. focusing in certain elements of the technical documentation review), this is not the case for the quality management system certificates. The notified body will ensure that all relevant Regulation requirements for conducting audits (i.e. those covered in Section 4.5.2 of Annex VII, and sections 2.2 and 2.3 of Annex IX) are assessed in its entirety at le ast once after issuin g the certificate and before its expiry date. In addition, prior to the renewal of a QMS certificate, it is required that the notified body will assess the results of the surveillance audits carried Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 14 of 14 out during the period of validity of the certificate in accordance with section 4.10 of Annex VII, also including any unannounced audits and all audits carried out at subcontractors and suppliers. This review must include the manufacturer´s system for vigilance, post-market surveillance, PMCF and risk management as well as all open non-conformities Furthermore, re sults of the notified body´s ev aluation of additio nal scientific and clinical data and clinical evaluations and post-market information as well as the outcome of latest technical documentation assessments on sampling basis and product tests have to be considered. V. OTHER REQUIREMENTS V.1. Are activities described under arti cles 16 and 17 of the Medical devices Regulation (MDR) and Article 16 of the in vitro medical devices Regulation (IVDR) will be covered during joint assessments? Conformity assessment bodies (CABs) can i ssue certificates following the process described in articles 16 and 17 of the MDR and Article 16 of the IVDR but these are not considered conformity assessment activities covered by Chapter IV and Annex VII of the Regulations and therefore w ill not be part of joint assessments. V.2. What is the meaning of “publicly available” as regards the list of standard fees of a notified body under Article 50 MDR / Article 46 IVDR? Whenever the Regulations require certain information to be made “publicly available”, that implies that a member of the public can access this information at any point in time, without the need for additional steps. In view of the public functions carried out by notified bodies, this requirement supports transparency of their activities. Not only Article 111 MDR / Article 104 IVDR re fer to different type of fees (i.e. fees levied by Member States), but also it uses different wording. It cannot therefore be used to support the interpretation of Article 50 MDR / Article 46 IVDR. Moreover, public availability of fees levied by Member States will usually result from the official publication of national laws setting out such fees (therefore, there will be no need to request information on such fees).

mdcg_2020_4_nb_audits_covid-19_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 1 of 6 MDCG 20 20-4 Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID -19 quarantine orders and travel restrictions April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 2 of 6 1. Introduction In the context of the current COVID -19 global outbreak as well as the rapid spread of the virus across various regions of the globe, the resulting travel and quarantine restrictions have significantly affected the ability of notified bodies to conduct mandatory on -site audits under the medical devices legislation. Theref ore, in the interest of public health, this document has been developed to outline temporary extraordinary measures for notified bodies to follow in this interim period in order to allow continued availability of safe medical devices to the market and as sist in the prevention of the risk of medical device shortages. In this context, it is considered that alternative solutions to carrying out on -site audits by notified bodies under the medical devices Directives1 should be allowed under specific circumst ances, including the possibility to perform remote audits under certain conditions. This guidance takes immediate effect and is valid for the whole period of duration of the pandemic COVID -19 as declared by the World Health Organisation. 2. Scope This guida nce is intended to cover the following audits notified bodies are requested to carry out as part of medical devices conformity assessments:  surveillance audits under the medical devices Directives,  audits conducted for re -certification purposes under the medical devices Directives,  in cases where a manufacturer submits a change notification to a notified body that would typically require on -site audit or verification,  in cases where a manufacturer terminates (voluntarily or involuntarily) its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device(s). Although this guidance applies to the medical device Directives only, for Regulations (EU) 2017/745 (MDR) and 2017/746 (IVDR) in the event that the availability of devices is affected by COVID -19 restrictions the principles in this guidance may apply. 1Directive 90/385/EEC, the AIMDD; Directive 93/42/EEC, the MDD; Directive 98/79/EC, the IVDD. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 3 of 6 The temporary extraordinary measures proposed in this guidance should not apply to unannounced audits, or, to special a udits which require on -site assessment (such as the verification of implementation of specific corrective actions which can only be assesed on -site). This does not prevent the use of the alternative measures for these types of audits in cases where doubt has been raised on the conformity / safety of a device and it is not in the interest of public safety to wait until the end of the restrictions put in place due to the COVID -19 pandemic. In general, initial certification audits or audits to extend the s cope of certification under the Directives should not be performed using these temporary extraordinary measures. However, notified bodies may apply these extraordinary measures on a case -by-case basis for such audits in cases where devices are considered r elevant to ensure medical care, especially if clinically necessary during the period of COVID -19 restrictions. 3. Proposed temporary alternative extraordinary measures and arrangements to on -site audits Notified bodies may introduce temporary alternative extraordinary measures in place of on -site conformity assessment audits that have been impacted by COVID -19 restrictions and that are within the scope of section 2 above. Notified bodies should have documented procedures detailing the alternative temporary measures to be utilised and should define the criteria for implementing such measures (e.g. procedure for “force majeure”). The relevant procedures should also take into account the technologies to be used during such audits and also address the impact of the alternative measures on the audit duration. These temporary alternative extraordinary measures may include the following principles and arrangements:  Postponement of on-site surveillance audits under the Directives in line with documented procedures of the notified body for force majeure.  On-site audits may be replaced by remote audits using the most advanced available Information and Communication Technologies as ap propriate in accordance with legislation on information security and data protection.  Assessment of all relevant and required documents/records off -site by the notified body.  To take into account existing recent results from MDSAP audits (or other approp riate audits) in lieu of Directive audits, where available  To consider published international guidance such as those issued by the International Accreditation Forum (IAF) e.g. on how to use information and Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 4 of 6 communication technologies2 and for alternat ive auditing methods in extraordinary circumstances3. 4. Eligibility criteria and procedural aspects To be eligible for these temporary alternative extraordinary measures the audits must be covered within the scope of section 2 above. The possibility to make use of temporary alternative extraordinary measures to on - site audits should be carefully assessed and documented by notified bodies on a case -by-case basis and performed using a risk -based approach. In particular, when determining the possibility to use t hese alternative measures, the risk assessment should take into account the experience gained with a manufacturer. For example, manufacturers who have a history of a high number and/or critical non -compliances related to production/operational control ma y have an impact on the appropriateness to conduct such temporary measures. However, in these cases an alternative measure could be performed as a temporary measure to assess the progress of the manufacturer and should be be supplemented by an on -site audi t once travel restrictions are lifted. In order to assess which alternative extraordinary measure (as outlined in section 3 above) is most appropriate, the notified body should review their files relating to the status and operations of the manufacturer re lated to the audit in question, for example the activities conducted at the site to be audited, its quality management system, and its level of compliance from previous audits. Following this review, a risk analysis should be made as to whether or not the audit could be performed with alternative measures. Where a postponement cannot be justified, the notified body should assess which alternative extraordinary measure should be performed (e.g. remote audit; off -site document review; conference calls with r elevant personnel of the manufacturer). For remote audits, both the notified body and the manufacturer must have the required information and communication technologies or tools available and established (e.g. web conferences with document sharing, use of web cams for audits of production lines). Confidentiality of intellectual property aspects shall be safeguarded. Notified bodies should clearly document and communicate any such requirements for their audits with their auditees, along with the required documentation to be shared before and within such audits, including the necessary data protection and cybersecurity measures . The technological capability of the manufacturer to ensure that such an audit can be accomplished should be verified by the notified body in advance of the audit. 2 Requirements on how to use information and communication technologies to support and maintain the integrity of the audit/assessment process may be found in International Accreditation Forum document IAF MD 4 (Mandatory Document for the Use of Information and Communication Technology (ICT) for Auditing/Assessment Purposes). 3 ID3:2011 (IAF Informative Document For Management of Extraordinary Events or Circumstances Affecting ABs, CABs and Certified Organizations) Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 5 of 6 Designating Authorities may request to observe/witness such remote audits via information and communication technologies or to ols available and established. When establishing the audit plan, the notified body should adjust the duration for review of the areas on the audit plan, along with the overall duration of the audit, in coordination with the manufacturer in order to make ef fective use of these alternative extraordinary measures. The audit plan should also clearly indicate which alternative extraordinary measures will be used and what will be conducted remotely. When issuing their audit reports the notified body should also c learly indicate that the audit was conducted remotely and the method(s) used for such audits should also be specified. Remote surveillance audits should cover all of the surveillance tasks that can be verified remotely, including an off -site review of all documents that would normally be assessed on -site. Following such an alternative extraordinary measure the notified body should review and adjust the audit programme for each manufacturer to ensure that all required elements are assessed during the certi fication cycle. 5. Decisions taken on certification Remote audits undertaken for re -certification purposes should cover all of the mandatory re -certification tasks that can be verified remotely. Subsequent to a succcessful remote audit a notified body may r e-issue the certification with the condition that such audits should be followed up by an on -site verification audit at the next available opportunity to verify the elements that could not be assessed remotely (the timeline for the on -site verification aud it should be justified by the notified body). At the request of the notified body, the manufacturer may provide the notified body with records (e.g. product release documentation) on an ongoing or regular basis,. If the re -certification remote audit is uns uccessful, the certification should be suspended or should expire as appropriate. Remote audits conducted by the incoming notified body in the context of cases where a manufacturer terminates its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device (s), should also cover all of the tasks that can be verified remotely to allow the incoming notified body to ensure a proper assessment of the conformity of the device. If the remote audit is unsuccessful (as per the notified body’s procedures for unsucces sful audits), the incoming notified body should not issue the certification. In the exceptional circumstance of the issuance of an initial or extended scope certificate under these alternative extraordinary measures (as per section 2 Scope above), the no tified body should consider the clinical risk / benefit of their decision and should clearly document their rationale for these decisions. At the request of the designating authority the notified body should inform the national authority of any such decisi ons and provide any supporting documentation. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 6 of 6 Note: A task force established in March 2020 under the MDCG NBO working group is tasked with the development of guidance to define the operational implementation details of this guidance document.

Guidance on significant changes &amp; annexes.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2020 - 3 MDCG 2020 -3 Guidance on significant changes regarding the transitional provision under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD March 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it ca nnot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on significant changes regarding the transitional provision under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD1 1 Introduction Article 120( 2) and 120( 3) of the Medical Device Regulation (EU) 2017/745 (MDR) states that devices which have a valid certif icate issued by a notified body under the Active Implantable Medical Devices Directive 90/385/EEC (AIMDD) or the Medical Devices Directive 9 3/42/EEC (MDD) may be placed on the market or put into service after th e date of application of the MDR under certain conditions and no later than 26 May 2024. Questions 8 and 9 of the CAMD Transition Sub Group guidance : “FAQ – MDR Transitional provisions, V1.0 of 17. January 2018”2 state that the certificates covered by MDR Article 120(3) include “all certificates which are commonly issued by notified bodies with reference to the Council Directives MDD and AIMDD” . Conditions referred to in the first paragraph require that no significant change s in design or intended purpose of a device be performed after the date of application of the MDR . Therefore, it is important for manufacturers and notified bodies to get clarity on the significant changes to be considered under MDR Art icle 120(3). It is also important that the AIMDD and MDD certificates remain valid following changes that are not significant with regard to design or intended purpose , provided that the required surveillance is carried out by the notified body that issued the certificate. See also Question 17 of the above mentioned CAMD guidance2. 2 Scope This guidance document is intended to provide clarification on the changes to a device that should be considered a “significant change in design or a significant change in the intended purpose” under MDR Art icle 120(3). Assessment s should be made on a case -by-case basis. 1 The principles outlined in this guidance can be applied also for class I devices requiring the involvement of a notified body for the first time. 2 https://www.camd -europe.eu/wp -content/uploads/2018/05/FAQ_MDR_180117_V1.0 -1.pdf 3 This guidance document does not elaborate on the process for manufacturers’ submission and notified bodies’ assessment of such changes as these should be part of the conformity assessment process and surveillance defined by the relevant notified body under the MDD or AIMDD. It is expected that manufacturers adjust their change not ification procedures, i.e. their provisions to inform their notified body on changes, in accordance with the principles outlined in this guidance until the date of application of the MDR. The adjusted procedures will be subject to notified body assessment within their surveillance activities according to MDR Art. 120(3). 3 Changes to Directive certificate s It is important to highlight that no issuing of new MDD/AIMDD certificates, including modified, amended or supplemented certificates , is allowed under MDR Article 120(3). In particular, i f the manufacturer wishes to make a “significant chang e in design or intended purpose” under MDR Article 120(3), the implementation of such a change would prevent the manufacturer from continuing to place that device on the market under the Directives . 4 Assessment of changes' significance in accordance with MDR Article 120(3) In line with agreed arrangements for notification of changes between the manufacturer and the notified body according to the AIMDD/MDD (e.g. contractual relationships, approved procedures) changes and their implementation will be verified by the notified body as part of the surveillance activities, or following a manufacturer’s submission for prior approval . The outcome of this verification will determine whether a certificate in accordance with AIMDD/MDD remains valid according to Article 120 MDR. To use this derogation from Article 5 MDR manufacturers are not allowed to make s ignificant change s in design or a significant changes in the intended purpose. In case of doubt whether a change is significant they should ask their notified body . For instance, administrative changes of organisations are considered in principle as non - significant. This includes changes of the manufacturer’s name , address or legal form (legal entity remains) or changes of the authorised representative. Furthermore, all changes not having an impact on the design or the intended purpose of the device can be regarded as not significant in the meaning of MDR Article 120(3) . This is the case for example of relocation or addition of new manufacturing sites, including when it affects subcontractors or suppliers , or of certain changes of the quality management system, provided that the conditions for which the conformity assessment certification was granted are maintained. Nevertheless, such changes continue to be subject to the agreed notification procedure identified in the first paragraph of the current secti on. T he manufacturer should always remain responsible for providing evidence that all the above -mentioned changes do indeed neither affect the design nor the intended purpose. 4 On the other hand, when the change is likely to affect the design or the inten ded purpose of the device, the significance of such a change must be assessed on a case -by-case basis. To facilitate a harmonised judgement of the significance of changes flowcharts (see Annex) have been developed. If a change is not a significant chang e in design or intended purpose under MDR Article 120(3), the implementation of such a change is therefore allowed during the transitional period. Acc. to section 3 the certificate should not be amended. The notified body that issued the AIMDD or MDD certif icate may confirm in writing (after having reviewed manufacturer’s description of the (proposed ) change) that the implementation of the change does not represent a significant change in design or intended purpose under MDR Article 120(3) and that the relat ed AIMDD or MDD certificate remains valid after the date of application of the MDR, but no longer than its expiry date or 26 May 2024, whichever comes first. Such written confirmation corrects or complements information on an existing certificate but does not represent the issuance of a “supp lemented certificate” as this is prohibited as mentioned in Section 3 . In case of requests from authorities the manufacturer should number such letters received from the notified body and submit them together with the certificate. In relation to class I medical devices requiring the involvement of a notified body for the first time, manufacturers of such devices must be able to justify their decision when the changes are considered to be non -significant. The justificat ion shall be documented and made available when requested. This guidance document provides in its Annex several flowcharts based on NBOG’s Best Practice Guide 2014 -3: “Guidance for manufacturers and Notified Bodies on reporting of Design Changes and Change s of the Quality System” . In particular, Chart C , which is specific to software, draws inspiration from Annex VI, Part C, section 6.5 of the MDR to identify modifications that are considered as significant change in (software) design. The assessment of a proposed change by using the main flowchart and any of the applicable sub-charts in the Annex, is intended to assist manufacturers and notified bodies in deciding whether or not a change is to be considered significant in the design or intended purpose of the device under MDR Art icle 120(3). The flowcharts are divided into a main chart and five sub -charts (A to E) . There are six categorical questions in the main chart that are linked to one or more sub -charts with more detailed questions . The change is considered a non -significant change of design or intended purpose per MDR Art icle 120(3) if the answer to every question in a sub -chart leads to “ non- significant change ” also when returnin g to the main chart. On the contrary, if any sub-chart 5 delivers the result “significant change” , the change being assessed is a “ significant chang e in design or intended purpose” of a device according to the MDR Article 120(3). 6 Annex Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Main Chart Change of an existing Medical Device certified under MDD or AIMDD Change of the Intended Purpose? Software change? Chart A Chart B Chart C Yes Yes Yes No No If non -significant If non -significant If non -significant A B C Change of the design or performance specification? No No X Design change related to corrective actions*? *assessed and accepted by the relevant Competent Authority acc. to CAMD FAQ no 17 Yes 7 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Main Chart (ctd.) Change of a Material*? Change of terminal sterilization method of device or packaging design with impact to the sterilisation? Chart D Chart E The change is considered a non - significant change per MDR Art. 120(3) Yes Yes No No No If non -significant D E *The termmaterial includesany substance ( synthetic, natural, biological, chemical, physical, medicinal, ...) that is used to make or compose the device 8 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart A FromMain Chart: Change of the IntendedPurpose* The changeisconsidered significantper MDR Art. 120(3) Extension or change of the Intended Purpose? New user or patient population? Change of clinical use**? Yes Yes Yes No No No Limitation of the Intended Purpose? Return toMain Chart QuestionX Yes No A1 A2 A3 A4 ** Example: - Change in the anatomical site; - Change in the access site or deployment methods; * Labellingchangesshouldbe assessedtoensuretheyarenot potentiallysignificantwhen linkedtothe intendeduse(e.g. contraindicationsandwarnings). Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart B FromMain Chart: Change of theDesignorPerformance Specification* Yes No No B1 Change of built -in control mechanism, operating principles, source of energyor alarms ? Yes No Return toMain Chart QuestionC (or move directly to E if Chart D was previously used) Yes B3 The changeisconsidered significantper MDR Art. 120(3) betakeninto not * Itshall accounthowthe changeis achieved. A changein specification maybetriggeredby, but isnot limited to, changeof hardwareor software, includingchangeof a component. Does the change require further clinical or usability data to support safety and perfor - mance? ** Do new risks require control measures or are existing risks negatively affected? B2 ** Compare MEDDEV 2.7/1 rev.4 forfurtherguidance Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart C FromMain Chart: Software Change New or modified architecture or database structure, change of an algorithm? Required user input replaced by closed loop algorithm ? Yes Yes No No New or major change of operating system or any component? No Yes C1 C2 C3 New diagnostic or therapeutic feature, or new channel of inter-operability ? Yes C4 No Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart C (ctd.) The changeisconsidered significantper MDR Art. 120(3) Yes No Return toMain Chart QuestionD C5 No New user interface or presentation of data*? *“Presentationof data“ goesbeyondthe appearanceof theuser - interface whichmayinclude newlanguages, layoutsor graphicsandisconsidered a minor change. Itisconnectedtomedical datawhicharepresentedin a newformatorby a new dimensionormeasuring unit. Yes *Minor changeswithout impacttodiagnosisor treatmentdeliveredmay include: - correctionof an error whichdoesnot posea safetyrisk(bugfixes), - Security update (e.g. cyber -security enhancements, longevitycalculations), - appearanceof the user interface, - operatingeffeciencies. - Changestoenhancethe userinterfacewithout changesin performance Minor Change*? C6 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart D FromMain Chart: Change of a Material* Change to a material of human/animal origin including addition of new materials? No Yes Change to a material containing a MS** ortothe MS itselfor, a change which may impact the quality, safety or efficacy of a MS *** ? Yes No D1 D2 **MS: Substancewhich, if used separately, would be considered to be a medicinal substance ***Including a change in its manufacturing process, which result in changes to the existing specification of the medicinal substance. * These relate to changes involving existing ingredients and materials. Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart D (ctd.) Ingredient new ormaterial from uppliermeetsexisting s specification? The changeisconsidered significantper MDR Art. 120(3) No Yes Yes Changed ingredientor material fromexisting suppliermeetsexisting specification? No Return toMain Chart QuestionE D3 D4 Change tobeassessedin accwithChart B Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart E FromMain Chart: Change of terminal sterilization method of device or packaging design with impact to the sterilization Design Change which affects or changes the sterility assurance**? Yes No No Yes Change in packaging design which affects functionality, safety, stability or seal integrity? E2 E3 Shelf-life change validated by protocols approved by the notified body ***? The changeisconsidered significantper MDR Art. 120(3) The change is considered a non-significant change per MDR Art. 120(3) No Yes E4 ** Guidance on assessing changes for their impact on the effectiveness of the sterilization process is provided in the respective sterilization standards such as:  EN ISO 11135 (Ethylene Oxide),  EN ISO 11137 -1 Radiation), (  EN ISO 17665 -1 (Moist Heat),  EN ISO 13408 -1 (Aseptic Process). Change* of terminal sterilization method? No Yes E1 * Includes change from non-sterile to sterile or a change to the sterilisation method. Changes of cycle parameters under the approved quality management system are not deemed as significant in the meaning of Art. 120(3) MDR ***In principle, an increase in shelf life can be considered non -significant ( e.g. the increase is made following the completion of a real time test whose method and end -point was validated and previously assessed by the notified body).

md_application-transitional-provisions-certificates_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-10 rev.1 Page 1 of 2 MDCG 201 9-10 rev. 1 Application of transitional provisions concerning validity of certificates issued in accordance to Directives 90/385/EEC and 93/42/EEC October 2019 July 2020 rev. 1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-10 rev.1 Page 2 of 2 MDCG 2019 -10 revision 1 changes MDR postponement dates: from 2020 to 2021 Application of transitional provisions concerning validity of certificates issued in accordance to Directives 90/385/EEC and 93/42/EEC1 According to Article 120(2) of Regulation (EU) 2017/475 on Medical Devices (the MDR), certificates issued in accordance with Directives 90/385/EEC and 93/42/EEC (the Directives ) will remain valid until 26 May 2024 at the latest. However, Article 120(3) establishes specific conditions that such certificates, and the related devices thereof, have to comply with. In particular, it is required that the notified body that issued the certificate – under a valid designation – continues to be responsible for the appropriate surveillance activities with respect to all of the applicable requirements related to the devices it has certified and that it has the possibility to take any necessary measure in relation to those. It has to be noted that, as reported in FAQ n.17 of the MDR transitional provision document published by the CAMD Transition Sub Group, the contract between the manufacturer and the notified body who issued the certificate under the relevant Directive shall include provisions allowing the appropriate performance of such surveillance activities. In order to allow manufacturers to take advantage of Art. 120( 2) and Art. 120(3) of the MDR, it needs to be ensured that Authorities responsible for notified bo dies have the right to and do monitor those notified body’s activities to the extent appropriate and necessary. For this purpose, Article 120(3) and Article 122(1) of the MDR provide the necessary legal basis for Member States to establish the necessary le gal empowerments2 by means of National law to carry out the needed monitoring activities in relation to Notified Bodies. All this is regardless of whether the Notified Body has applied or not to be designated under the MDR and/or it has a still valid desig nation under the Directives during the validity of certificates issued in accordance to the Directives . Concerning information published in the NANDO database, in accordance to Article 120(1) of the MDR, any publication of a notification in respect of a no tified body in accordance with the Directives will become void as from 26 May 2021 . Therefore, NANDO will only be used in relation to the Directives for information purposes after 25 May 2021 . NANDO will therefore list those notified bodies that have bee n designated under the Directives with a clear message that they are not able to issue new certificates but only allowed to carry out surveillance activities for valid certificates in the transitional period, as established in Article 120 of the MDR. 1 This document specifically refers to transitional provisions laid down in Regulation (EU) 2017/745 but can be applied by analogy to Regulation (EU) 2017/746. 2 It should be noted that relevant legal empowerments might be already available by means of National law which build on different EU pieces of legislation.

md_2020-14-guidance-mdsap_en.pdf.txt

1 Medical Devices Medical Device Coordination Group Document MDCG 2020-14 MDCG 2020-14 Guidance for notified bodies on the use of MDSAP audit reports in the context of surveillance audits carried out under the Medical Devices Regulation (MDR)/ In Vitro Diagnostic medical devices Regulation (IVDR) August 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and a representative of the European Commission chairs it. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance for notified bodies on the use of MDSAP audit reports in the context of surveillance audits carried out under the Medical Devices Regulation (MDR)/ In Vitro Diagnostic medical devices Regulation (IVDR) Background In fulfilling the EU’s commitment to encourage notifi ed bodies to make use of audit reports from the Medical Device Single Audit Program (MDSAP) in a manner that is compatible with EU legislative requirements, the Medical Device Coordination Group (MDCG) endorsed this guidance which has been developed by a group of experts comprised of interested Member State representatives, notified body associations and stakeholders. Scope The purpose of this document is to provide guidance to notified bodies on how to take into account MDSAP Medical Device Regulatory Audit Reports 1 (from hereafter “MDSAP audit reports”) issued by MDSAP auditing organisations2 when performing surveillance audits under Regulation (EU) 2017/745 – Medical Devices Regulation (MDR) and Regulation (EU) 2017/746 – In Vitro Diagnostic medical devices Regulation (IVDR). This is of particular use when a manufacturer has undergone an MDSAP audit and wishes to present this audit report (including the associated attachments) in context of the regular surveillance audits performed in accordance to the MDR or IVDR. General regulatory considerations Under the MDR/IVDR, most conformity assessme nt procedures consist of both the quality management system audit and the assessment of a device’s safety and performance. Notified body’s conformity assessment activities, which are a prerequisite for the manufacturer’s declaration of conformity, when concluded successfully result in a conformity assessment certificate, a pre-market requirement for most classes of medical devices and IVDs. In that regard, notified bodies designated under the MDR/IVDR fulfil roles, which correspond to combined functions of both MDSAP auditing organisations and MDSAP participating regulatory authorities. 3 Therefore, the roles performed by notified bodies and MDSAP auditing organisations differ as the latter solely perform quality management system audits which are then utilised by regulatory authorities in their evaluation of a product’s safety and performance for the purpose of issuing a marketing authorisation. 1 MDSAP audits are recorded using the Medical Device Regulatory Audit Report form (MDSAP AU F0019.1). Final MDSAP audit reports are signed in section 18 of the form. 2 Auditing Organization: An organization that audits a medical device manufacturer for conformity with quality management system requirements and other medical device regulatory re quirements. Auditing Organizati ons may be an independent organization or a Regulatory Authority which perform regulatory audits. (IMDRF/MDSAP WG/N3 FINAL:2016) 3 Regulatory Authority: A government body or other entity that exercises a legal right to control the use or sale of medical devices within its jurisdiction, and that may take enforcemen t action to ensure that medical products marketed within its jurisdiction comply with legal requirements. (GHTF/SG1/N78:2012, cited from IMDRF/MDSAP WG/N3 FINAL:2016) 3 Requirements of the MDR/IVDR The MDR/IVDR clearly state that all manufacturers need to have a quality management system in place so as to ensure that devices manufactured in se ries are in conformity with the requirements of the respective regulation and that experience from the use of devices is taken into account in the production process (MDR Recital 32/IVDR Recital 31). This becomes an explicit requirement for manufacturers to establish, document, maintain, keep up to date and continually improve quality management systems so that to ensure compliance with the Regulations (MDR Article 10 (9)/IVDR Article 10(8)). Notified bodies are charged with the assessment of quality management systems of devices in accordance with MDR Article 52 and IVDR Article 48. Specifically, notified bodies are responsible for auditing and certifying manufacturers’ quality management systems (MDR/IVDR Annexes IX and XI and Annex VII section 4.5 ), following up with appropriate surveillance audits (MDR/IVDR Annex IX section 3 and Annex VII section 4.5.1, 4.10) as well as conducting unannounced audits (MDR/IVDR Annex VII section 4.5.1). Notified bodies are also responsible for the development of their appropriate procedures for conformity assessments according to the MDR /IVDR. The MDR/IVDR specifically state that notified bodie s’ audit programmes should clearly identify the number and sequence of activities required to demonstrate complete coverage of a manufacturer’s quality management system (MDR/IVDR Annex VII 4.5.2) and that surveillance audits need to be carried out on at least an annual basis (MDR/IVDR Annex VII section 4.10 and Annex IX section 3.3). For each surveillance audit identified in the audit programme, the objectives, criteria and scope of the surveillance audit are defined in an audit plan which adequately addresses and takes into account specific requirements for the devices, technolog ies and processes involved (MDR/IVDR Annex VII section 4.5.2(a) – third bullet point). Surveillance audits are expected to gather sufficient information to verify the proper implementation of the quality management system and ensure that it continues to comply with the requirements of the MDR/IVDR. When and how to take MDSAP audit reports into account It is important to stress that the MDR/IVDR remain applicable in their entirety. The use of MDSAP audit reports within the EU legislative framework is possible only where the MDSAP audit covers similar or equivalent MDR/IVDR requirements. Designated notified bodies maintain the full authority over their judgement, conclusion and final decision about the conformity of quality management systems to the relevant provisions of the MDR/IVDR and the safety and performance of medical devices and IVDs intended to be placed on the market in the EU. Given that surveillance audits, their periodicity and EU auditors’ competencies are mandated by law, yearly surveillance audits need to be maintained. Ho wever, it could be possible to take into account the scope and outputs of manufacturers’ recent MDSAP audit reports as an input for developing surveillance audit programmes. The taking into account of MDSAP audit reports could define in a more precise manner the activities to be performed during a surveillance audit. For example, the positive quality management system conformity appraisal through MDSAP might lead to a reduction 4 of the focus on aspects already covered by MDSAP audit reports. The notified body may then focus their surveillance audit on specific MDR/IVDR requirements which are either not covered or only partially covered by the MDSAP audit report. Non-exhaustive list of examples (alphabetical order): - clinical evaluation/performance evaluation process (including post-market clinical/performance follow-up), - EU authorised representative contractual provisions, - EU UDI assignments within the quality management system, - manufacturer financial coverage in respect of potential liability, - person responsible for regulatory compliance qualification and role, - records control, - system for risk management, - vigilance and post market surveillance activities, including the associated corrective actions and preventive actions. Similarly, non-conformities identified in recent MDSAP audit reports can trigger the notified body to pay particular attention to those aspects in the MDR/IVDR planned surveillance audit. It is important to highlight the following details: - The taking into account of MDSAP audit reports is not applicable to initial quality management system audits required for the issuing of EU QMS certificates. Notified bodies designated under the MDR/IVDR would always need to conduct these audits in their entirety. - The taking into account of MDSAP audit reports is not applicable to MDR/IVDR unannounced audits. - Reports of MDSAP unannounced audits or special audits should not be taken into account in the narrowing of focus in MD R/IVDR surveillance audits. - Regular surveillance audits would still take place on a yearly basis. However, the positive QMS conformity appraisal through an MDSAP audit may lead to a limitation of the surveillance focus from aspects already covered by the MDSAP audit reports. - When MDSAP audit reports are considered as input to the planning of an MDR/IVDR surveillance audit, these reports should be taken into account in their complete form, including all associated attachments. Both positive and negative statements about the conformity of the manufacturer should be incorporated in the planning of the MDR/IVDR audit. If there is concern about the functioning of the quality management system, for instance due to information gathered through the assessment of vigilance cases or post market activities, previous surveillance audits or technical documentation assessments, a complete surveillance audit should be carried out. Notified bodies may wish to determine and establish additional guidance in order to support their procedures for evaluating MDSAP audit reports. Such guidance could for example specify the content details of MDSAP audit reports considered acceptable (i.e. may be taken into consideration) in the notified body assessment programme and what modifications may be done to the notified body assessment programme after the taking into consider ation of the MDSAP audit report (to ensure that 5 any specific assessment items that are not covered in the MDSAP audit reports are performed by the notified body). The notified body shall remain fully responsible for its decision, to whether or not, and to what extent, an MDSAP audit report can be taken into account. The Annex to this guidance identifies and analyses aspects within MDSAP audit reports that are relevant in relation to the EU requirements. Part I focuses on providing an explanation of where to find relevant information in MDSAP audit reports that could be used to a greater or lesser extent as supporting evidence for MDR/IVDR quality management system requirements. Part II provides examples on how correlations between MDR requirem ents to sections of MDSAP audit reports may be established in the notified bodies’ additional guidance or procedures. Although the examples in Part II focus on MDR requirements, the same methodology could be applied for the IVDR. 6 Annex Part I – Explanation of relevant information in MDSAP audit report The following table shows where information with relevance for MDR/ IVDR quality management system audits can be found in MDSAP audit reports and highlights specifics that should be understood by notified bodies when taking into account such information. A comprehensive description of MDSAP audit report content can be found in MDSAP AU P0019 MDSAP Me dical Device Regulatory Audit Reports and MDSAP AU G0019 Medical Device Regulatory Audit Report Form Guidelines 4 Sections of MDSAP audit report Relevant information Section 1 – Audit Information Name of MDSAP auditin g organisation, audit dates and duration, audit team Section 2 – Audited Facility Audited facility name and address. In case of a multi-site audited organization, a separate audit report is generally required for each audited facility. This means, the audited facility described in Section 2 is not necessarily the manufacturer responsible for the overall product. Also see Section 4. Section 3 – Certification Schemes, Scopes & Criteria, Audit Types Certification schemes with scope of certification, audit type and audit criteria. In some cases, a list of medical devices covered in the scope is attached to the audit report. The “CE marking” scheme may be referenced, but this is not mandatory. For unannounced audits, it is important to understand that they are commonly performed to verify effectiveness of corrective actions on non-conformities, and their content is not the same as that of unannounced audits under MDR/IVDR. 4 Both documents are available in the “MDSAP Documents” / “MDSAP Audit Procedures and Forms” section of the MDSAP program homepag e (https://www.fda.gov/medical-devices/cdrh- international-programs/medical-device-single-audit-program-mdsap , accessed on 2020-03-25). 7 Sections of MDSAP audit report Relevant information Section 4 – Certification Holder and Multi- site Organization Relationship between audited facilities and reference to other audited facilities included in the audit. Certification Holder is the main facility shown on the title page of the certificate. Campus is a group of facilities that can be described in one audit report by derogation from general requirement of separate audit reports for each facility. Related sites are other audited facilities that are described in separate audit reports. Corporate Information describes the use of multiple names and identities by the organization and its significant relationships of the manufacturer with related companies in the context of the audited QMS and its associated activities and devices. Section 5 – Audit Objectives Additional audit objectives applying to schemes other than MDSAP may be included, but this is not mandatory. Section 6 – Audited Facility Description Regulatory Roles of th e audited facility are indicated separately for each MDSAP parti cipating country. It may additionally include the roles in other countries, such as Europe, but this is not mandatory. Activities at the Audited Facility describe what is actually done at the audited site. Activities not included in the Scope of Certification are activities performed at the facility which are not required to be listed in the MDSAP certificate. Section 7 – Critical Suppliers Critical suppliers of the audited facility that are relevant to the scope of audit, including pr oducts or services obtained from them and indication whether this audit extended to visit a supplier. Instead of a detailed description in this section, the list may be attached to the report. Section 8 – Audit History Outcomes of previ ous audits that have been taken into consideration in preparation for this audit. Section 9 – Exclusion and Non- Applications of requirements in the QMS Exclusion and non-application of ISO 13485 requir ements in the QMS of the audited facility. Section 10 – Outcome of Pre-Audit Activities Outcome of the preceding documentation review and/or stage 1 audit, if applicable. Instead of detailed description in this section, additional records may be attached to the report. 8 Sections of MDSAP audit report Relevant information Section 11 – Audit Findings Sections 11.1-11.7 describe audit findings and ev idence related to ISO 13485 and country-specific requirements. Please refer to MDSAP Audit Model and details of requirements5 for more information. Section 11.7A is only included, if the critical suppliers we re visited as part of the audit, to describe the audit findings made at the visited supplier locations. Section 11.8 may include findings according to scheme s other than MDSAP, but this is not mandatory. Section 12 – Non-conformities List of non-conformities, references to which are made in Section 11. Grade is a numeric classification of significance of non-conformity between 1 and 5 according to GHTF/SG3/N19:2012 - Quality Management System - Medical Devices – Non-conformity Grading System for Regulatory Purposes and Information Exchange Section 13 – Significant Deviations from the Audit Plan Circumstances that lead to deviations from the audit plan and obstacles experienced by the audit team during the audit. Section 14 – Follow-up of Past Non-conformities Results of audit team’s evaluation of effectiveness of ac tions taken in response to non-conformities identified in prior audits with the possible status Closed, Superseded of Left Open. A record with the details of this evaluation may be attached to the report. Section 15 – Summary of Major Changes to the Audited Facility Summary description of major changes since previous audit, especially those changes not described in Section 11. Section 16 – Conclusions Extensive conclusion of the audit, including the statement on the conformity of the QMS with the audit criteria and recommendations of the audit team. Section 17 – Attachments List of records th at are considered as part of the audit report, including those referenced in Section 6 (list of medical devices), Section 7 (list of critical suppliers), Section 10 (outcome of pre-audit activities), Section 11.2 (review of sampled technical documentation), Section 14 (updated non-conformity report relative to past non- conformities). Section 18 – Audit Report Approval Date and signature of review and approval of the final audit report. 5 The MDSAP Audit Model can be found in the “MDSAP Documents” / “MDSAP Audit Procedures and Forms” section of the MDSAP program homepage ( https://www.fda.gov/medical- devices/cdrh-international-programs/medical-device-single-audit-program-mdsap , accessed on 2020-03-25). 9 Part II – Examples on how correlations between MDR requirements to sections of MDSAP audit reports may be established The following examples of established correlations between MDR qua lity management system requirements and the MDSAP Audit Model show how certain overlapping requirements may be covered in MDSAP audit reports, and what specific MDR requirements are not covered. The referen ces direct to MDSAP audit processes and tasks that overlap with MDR requirements and are linked to same or similar ISO 13485 requirements. It is recommended that notified bodies develop more detailed gu idance for determining the extent in which MDR/IVDR quality mana gement system requirements correlate to those covered in MDSAP audit reports. Any such fully developed correlation should be revised in the event of a pub lication of changes to any basic criteria document including EN ISO 13485, MDSA P Audit Model and MDR/IVDR, or any documen t utilised to establish correlation, su ch as CEN/TR 172236. The examples provided in the below table cover only the following three blocks of MDR requirements: Clinical evaluation, Suppli er controls, and Post-market surveillance. MDR requirement Sections of MDSAP audit report addressing this topic(s) Particular MDR requirements not covered in an MDSAP audit Clinical evaluation MDR Article 10, paragraph 3 MDR Annex IX, Chapter I, 2.1, indents 10-11 MDR Annex XI, Part A, 6.1 indent 17 Section 11.5 – Design and Development, Task 11 Specifics of Article 61 and Annex XIV Part A Clinical evaluation plan and procedures to keep up to date the clinical evaluation plan Supplier controls MDR Article 10, paragraph 9 (d) MDR Annex IX, Chapter I, 2.2 paragraph 2 b) indent 3 Section 11.1 – Management, Task 5 Section 11.3 – Measurement, Analysis and Improvement, Tasks 2, 7, 13 Section 11.5 – Design and Development, Tasks 1, 7, 8, 16 Section 11.6 – Production and Service Controls, Tasks 7, 14, 19, 21, 22 Section 11.7 – Purchasing, all tasks Annex II 3. (c) 6 CEN/TR 17223:2018 Guidance on the relationship between EN ISO 13485: 2016 (Medical devices – Quality management systems – Requ irements for regulatory purposes) and European Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation. 7 MDR Annex XI, Part A, 6.1 indent 1 refers back to MDR Annex IX, Chapter I, 2.1 10 MDR requirement Sections of MDSAP audit report addressing this topic(s) Particular MDR requirements not covered in an MDSAP audit Post-market surveillance MDR Article 10, paragraph 10 MDR Annex IX, Chapter I, 2.1 indent 8-9 MDR Annex XI, Part A, 6.1 indent 1 8 MDR Annex XI, Part B, 13 Section 11.3 – Measurement, Analysis and Improvement, Task 12, 14, 15 Section 11.4 – Medical Device Adverse Events and Advisory Notices Reporting, Tasks 1, 2 Specific requirements on the PMS system incl. PMS plan, PMS report, PSURs, and PMCF plan (Articles 83-86 and Part B of Annex XIV as well as obligations resulting from the provisions on vigilance (Articles 87 to 92) 8 MDR Annex XI, Part A, 6.1 indent 1 refers back to MDR Annex IX, Chapter I, 2.1

mdcg_2019_13_sampling_MDR_IVDR.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2019 -13 MDCG 2019 -13 Guidance on sampling of MDR Class IIa / Class IIb and IVDR Class B / Class C devices for the assessment of the technical documentation Decem ber 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on s ampling of MDR Class IIa / Class IIb and IVDR Class B / Class C devices for the assessment of the technical documentation 1 Introduction Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) establish the requirements for sampling of Class IIa / Class IIb and Class B / Class C devices for the assessment of the technical documentation. Article 52(4) and (6) of the MDR and Article 48( 7) and ( 9) of the IVDR est ablish the need to assess the technical documentation of at least one representative device per generic device group (for Class IIb and Class C) and for each category of devices (for Class IIa and Class B) prior to issuing the certificate. Section 2.3 and 3.4 of Annex IX of both Regulations (and section 10 of Annex XI of the MDR ) defines that the quality management system assessment has to be accompanied by the assessment of technical documentation for devices selected on a representative basis . Section 4.5.2(a) of Annex VII of both Regulations1 requires the notified body to draw up and keep up to date, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III prior to the audit . Section 4.5.2(b) of Annex VII requires the notified body to assess t he technical documentation as preparation for the audit (s). This assessment is expected to be finalised in due time of such audit (s). 2 Scope This guidance is intended to define the requirements of sampling for Class IIa and Class IIb devices under the MDR and Class B and Class C devices under the IVDR for the purpose of assessing the technical documentation . This guidance defines and further elaborates on the sampling criteria and use of such criteria for drawing up and maintaining a sampling plan. In addition, th is guidance clarifies th e tasks to be performed by the notified body including the applicability of Chapter II of Annex IX of both Regulations and the extent of the technical documentation assessment. See Section 5.3 for exemptions for specific types of devices. 1 Hereafter referred to as “Annex VII” for both, the MDR and the IVDR. 3 3 Definitions The Regulations do not contain definitions of certain terms applicable to sampling , and in some instances certain definitions given cannot be used on an operational level. Therefore , only for th e purpose of this guidance the following definitions apply : 3.1. Category of devices : category of devices should be understood as the relevant M DA/MDN codes (MDR) or IV R code s (IVDR) according to Regulation (EU) 2017/2185 on the codes for the designation of notified bodies . 3.2. Generic device group2: is to be understood :  in respect of the MDR3,4 as the 4th level of the European Nomenclature on Medical Devices (EMD N) 5, 6 (i.e. combination of one letter plus 6 digits ), and  in respect of the IVDR as the 3rd level of the EMD N (i.e. combination of one letter plus 4 digits respectively) in combination with the most appropriate IVP code. 3.3. Device range: device range is to be understood as all “device categories" for Class IIa and Class B devices and all “generic device groups ” for Class IIb and Class C devices covered in a certificate . 3.4. Device : device should be understood as the device(s) associated with one Basic UDI -DI7. 3.5. QMS certificates: QMS certificates are EU q uality management system certificates (MDR and IVDR) , EU quality assurance certificates (MDR) and EU production quality assurance certificates (IVDR) issued by notified bodies as a result of conformity assessments . 2 "A set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics" (Art. 2 (7) MDR and Art. 2(8) IVDR). 3 In cases, where the 4th level for the MDR do es not exist the notified body should use the next higher level . 4 If the notified body considers that for a particular device level 4 for the MDR/level 3 for the IVDR is not sufficiently specific to define a generic device group, it can use the next lower level if available. 5EMDN nomenclature can be found currently at : http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_15_file. pdf 6 In case where more than one EMDN code applies to one device, only the most appropriate one of these EMD N codes will be assigned for sampling purposes. The technical documentation related to that particular device will be assessed in its entirety. 7 As defined in MDCG 2018 -1 v2 Guidance on BASIC UDI-DI and changes to UDI -DI. 4 4 Sampling criteria The Regulation s establish minimum requirements for sampling prior to issuing the certificate and during its validity. The notified body will ensure that these requirements will be complied with when drawing up a sampling plan. In addition, other considerations have to be observed in order to ensure an adequate coverage of devices on a representative basis. 4.1. Quantitative Sampling Criteria 4.1.1. Sampling prior to issuing a QMS certificate The Regulations establish the need for the notified body to assess technical documentation for a number of devices prior to issu ing the QMS certificate : - For Class IIb and Class C the technical documentation of at least one representative device per generi c device group (as per Article 52(4) of the MDR and Article 48( 7) of the IVDR ). This means that the notified body shou ld asses s how many generic device groups as per 3.2 are covered in the application (how many nomenclature's 4th levels for MDR / 3rd levels in combination with applicable IVP codes for the IVDR8), select per group at least one representative device covered by a Basic UDI -DI and assess the technical documentation for the device(s) selected . - For Class IIa and Class B the technical documentation of at least one representative device per category of devices (as per Article 52(6) of the MDR and Article 48( 9) of the IVDR ). This means that the notified body should asses how many categories of devices as per section 3.1, (how many MDA/M DN or IVR codes ), are covered by the ma nufacturer’s application, select per category at least one representative device covered by a Basic UDI -DI (MDA/MDN or IVR code ) and assess the technical documentation for the device(s) selected . The outcome of these assessments is an essential input for the final review according t o Annex VII section 4.7 of the R egulations prior to issuing of the certificate . 4.1.2. Sampling during surveillance After issuing the certificate, the notified body will continue to assess technical documentation in line with the sampling plan. Section 3.5 of Annex IX of both Regulations indicates that surveillance assessment shall also include an 8 Generic device groups for Class C devices will consist on an EMDN + an IVP code. Therefore, when different products are covered under the same EMDN but corresponds to different IVP codes, the notified body will assign the most appropriate IVDP code to each device. 5 assessment of the tech nical documentation9 which means that at least one technical documentation must be reviewed each year . In addition, notified bodies will ensure that the entire device range is covered during the period of validity of the certificates as required by Section 4.5.2 (a) of Annex VII . This means that at least one device per each category, in case of Class IIa and Class B devices , and at least one device per each generic device group, in case of Class IIb and Class C devices, should be samp led and the relevant technical documentation assessed between the issue of a certificate and its expiry date. Furthermore, in addition to the above -mentioned criteria , the number of samples to be assessed need to be selected on a representative basis ( as per Annex VII 4.5.1 9th indent MDR, An nex IX 2.3 3rd paragraph MDR / IVDR, and An nex VII 4.5.1 8th indent IVDR). Therefore, in developing the sampling plan (see section 6), the notified body should also ensure that the number of devices sampled is proportionate to the total number of devices contained in the certificate. For this purpose, it is expected that 15%10 of devices from each category and from each generic device group covered in the certificate will be sampled during its validity – taking into account the maximum validity of 5 years . In cases where the certificate contains very few devices and the technical documentation s of these have been already reviewed, it is expected that during surveillance audit s the notified body will focus on the review of the technical documentation related to post -market surveillance in accordance with Annex III . Normally, the devices to be sampled after the certificate has been issued would be spread evenly during the validity of the certificate. However, the notified body might decide to perform different number s of reviews in a given year for different reasons (e.g. workload , vigilance concern ) as long as throughout the surveillance period all initially determined assessments are performed . Such an approach is acceptable as long as the minimum requirements mentioned in the first paragraph of this section are complied with. 4.2. Qualitative Sampling Criteria Section 2.3 of Annex IX of both Regulations establishes qualitative criteria to be used when drawing up sampling plans. While s ome of these criteria such as similarities in design, technology and manufacturing and sterilisation methods may be covered already by the fact that devices belong to the same category or generic device group , all the criteria defined in Section 2.3 of Annex IX including novelty of the technology intended purpose or the results of any previous relevant assessments such as with regard to physical, chemi cal, biological or clinical properties must be individually considered when prioritising the review of one device over another. This prioritisation should take into account the inherent risk of the different devices included in the relevant category of devices / generic 9 The follow -up of change notifications according to Section 4.9 of Annex VII (e.g. “the device range covered” in Annex IX section 2.4), and other surveillance activities as laid down in Section 4.10 of Annex VII are to be carried out in addition to sampling during surveillance . 10 For the first certification cycle under the MDR/IVDR the 15% may be decreased to a minimum of 5%. 6 device group which means that , for instance, novel devices, will usually be prioritised over well -known technologies (unless there are specific concerns over the latter). Additional criteria may be also taken into consideration by the notified body11. As required by the Regulation, the notified body must document its rationale for the samples taken , in particular, mentioning what specific criteria have been taken into account. It should be noted, that as long as there are devices that have not been sampled , each device should only be sampled once during the period of validity of the certificate unless vigilance cases or other information which have been brought to the notified body ’s attention will require it . 5 Assessment of the technical documentation 5.1. Depth of the assessment The depth and extent of the technical documentation assessment of Class IIa / IIb and Class B / Class C devices will be the same as the depth of assessment carried out for Class III and Class IIb implantable and Class D devices . This means that the technical documentation of a device shall be assessed against all General Safety and Performance Requirements (Annex I) and requirements of Annex II and III. Records of the assessment shall be prepared which allow a third party to understand the functionality of the device and all aspects of the assessment including judgements made by the assessor . It should be taken into account that every device (i.e. Basic UDI -DI) might include different variants, models or sizes. In that case, the review of the technical documentation will also include the assessment of how the differences among these have been addressed in the technical documentation and whether all of them are in line with the relevant requirements. 5.2. Applicability of Chapter II, Section 4 of Annex IX Taking into account the wording of article s 52(4) and 52(6) of the MDR and Article 48(7) and 48(9) of the IVDR, as combined with annex es VII and IX, the tasks to be carried out by the notified body as part of the conformity assessment activities described in Chapter II , Section 4 of Annex IX comprise t he complete review of the technical documentation in accordance with Annexes II and III . In addition, the manufacturer will grant access to the technical documentation as referred to in Section 2.2 of Annex IX and the notified body will provide the manufacturer with a report on the technical documentation assessment. For Class IIa / IIb and Class B / Class C the notified body will neither require an application nor issue an EU technical documentation assessment certificate (see 5.3 for exceptions) . 11 For instance, where controls or calibrators are specifically intended to be used in conjunction with a specific IVD device, these controls or calibrators will preferably be assessed alongside that device 7 5.3. Additional requirements for s pecific types of devices under the MDR and the IVDR For class IIb implantable devices12, Article 52(4) second subparagraph of the MDR establish es the need to review the technical documentation in accordance with the complete Section 4 of Annex IX for every device, therefore an application as well as the issuance of an EU technical documentation assessment certificate are req uired . They are exempt from sampling. According to Article 54 , Class IIb active devices intended to administer and/or remove a medicinal product falling into rule 12 of Annex VIII are subject to the clinical evaluation consultation procedure prior to issuing of the certificate . These devices can be subject to sampling but according to Article s 54(3) and 55 the notified body must ensure that at least the clinical evaluation assessment report (CEAR) for each device is uploaded in Eudamed prior to issuing the QMS certificate. This means that the sampling will not apply to the clinical evaluation as it has to be assessed for every device. Article 48 (7, 8 and 9) and Section 5 of Annex IX of the IVDR establish that class B and C devices for self -testing, near-patient testing and companion diagnostics are exempt from sampling . The manufacturer will lodge an application as per sections 5.1 (a) and 5.2 (a) of Annex IX of the IVDR , and , as described in section 5.1 (c-e) and 5.2 ( a-e), the notified bod y will review the technical documentation of all the devices covered in the certificate and will issue an EU technical documentation assessment certificate. 5.4. Reporting The technical documentation assessment of Class IIa / IIb and Class B / Class C devices and its reporting should follow the principles established in Annex VII and the applicable provisions of the conformity assessment annexes and should use or be similar to those procedures and checklists developed by the notified body for the assessment of Class III / IIb implantable devices and Class D devices . In order to fulfil the legal requirements, the reporting requirements established in Section 4.6. of Annex VII will apply. 6 Drawing up and keeping up to date a sampling plan According to Section 4.5.2(a) of Annex VII the notified body shall draw up and keep up to date a sampling plan . This plan should contain at least the devices covered by the certificate, their Basic UDI -DI, the generic device group (in case of Class IIb ), the generic device group plus the IVP code (in case of Class C devices) or the category of devices (in case of Class IIa / Class B devices) , the identifier of the respective technical documentation , the (planned) assessment dates and the status of such asse ssments . 12 Except fo r sutures, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors, which are subject to sampling 8 The notified body should update the sampling plan whenever needed on the basis of the criteria defined in this guidance as well as on the basis of its post - certification activities laid down in Section 4.10 of Annex VII. In particular, the outco me of the screening of relevant sources of scientific and clinical data and post-market information relating to the scope of their designation , or the review of vigilance data should be taken into account. If the manufacturer makes a change in the product range during the period of validity of the certificate, the notified body should review the sampling plan accordingly. When a dding new devices to the scope of the certificate which do not fall into the alrea dy covered generic device groups / categories of devices , the initial sampling criteria (section 4.1) apply. If the manufacturer applies for re -certification, the notified body should update the sampling plan with the samples to be assessed during the upc oming certification period according to the principles laid down under section 4.1.2 Sampling during surveillance and keep the sampling plan up to date as described above.

11 MDCG 2020-11 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90385EEC and 9342EEC.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-11 1 MDCG 2020-11 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90/385/EEC and 93/42/EEC to be performed in accordance with Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 May 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-11 2 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90/385/EEC and 93/42/EEC to be performed in accordance with Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 1. Introduction The COVID-19 pandemic has created extraordinary circumstances that demand substantial additional resources, as well as a continued availability of vitally important medical devices, that could not reasonably have been anticipated at the time of adoption of Medical Devices Regulation (EU) 2017/745 (hereafter referred to as ‘MDR’). In order to allow Member States, health institutions and economic operators to prioritise the fight against the COVID-19 pandemic it was considered necessary to defer the application of certain MDR provisions by one year (i.e. until 25 May 2021)1. To ensure the continuous presence of a functioning regulatory framework for medical devices it was necessary to also defer by one year the date of repeal of the Medical Devices Directives 90/385/EEC and 93/42/EEC (hereafter referred to as ‘the Directives’). The deferral of the date of repeal has a consequential impact on the designations of certain notified bodies under the Directives, including their ability to carry out their obligations and be operational until 25 May 2021. The current COVID-19 pandemic also affects the way in which designating authorities are able to perform the required appropriate surveillance and monitoring activities over notified bodies. To take account of these extraordinary circumstances, the Commission and the Member States, on 18 May 2020, adopted Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 as regards the renewal of designations and the surveillance and monitoring of notified bodies (hereafter referred to as ‘the Implementing Regulation’)2. The amendment provides for a derogation from certain requirements on the renewal of designations of notified bodies and for alternative surveillance and monitoring activities that designating authorities should carry out. In particular, in the interest of health and patient safety, and, to ensure consistency among the activities performed by designating authorities, this guidance document has been developed to outline common criteria for the renewal of designations of notified bodies under the Directives until 25 May 2021. In addition, this document intends to provide clarification on the appropriate activities performed by designating authorities over notified bodies in order to ensure an adequate level of surveillance in accordance with Article 5 paragraph 1, third subparagraph, of the Implementing Regulation. 1 OJ L 130, 24.4.2020, p. 18–22. 2 OJ L 156, 19.5.2020, p. 2–5 Medical Device Medical Device Coordination Group Document MDCG 2020-11 3 2. Scope This guidance covers the following activities performed by designating authorities under exceptional circumstances, as referred to in Article 4(6) of the Implementing Regulation:  renewal of designation under the Directives of notified bodies whose designation expires in the period from 26 May 2020 to 25 May 2021;  surveillance activities to be performed by designating authorities in accordance with the Implementing Regulation under COVID-19 related restrictions, notably quarantine orders and travel restrictions. This guidance does not apply to the procedure for the initial designation of a notified body under the Directives nor to the procedures for extensions of the scope of a notified body nor the lifting of limitations to the scope of a notified body3. 3. Renewal of designation of a notified body until 25 May 2021 When deciding upon the renewal of the designation as a notified body in accordance with Article 4(6) of the Implementing Regulation, designating authorities should perform an appropriate assessment of the continuous competence of the notified body and its ability to accomplish the tasks for which it has been designated. Designating authorities should base their decision to renew a designation on a review of documents, resources and activities, which lay ground for the verification of the criteria for designation as set out in the Directives and in Annex I to the Implementing Regulation. This review should include in particular the following:  assessment of relevant quality management system procedures, forms and records, in particular qualification criteria, procedures for selection and authorisation of persons involved in conformity assessment activities, procedures to ensure independence, objectivity and impartiality of the notified body’s activities;  assessment of an appropriate number of the notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations;  assessment of an appropriate number of the notified body’s personnel files;  discussion of the results of the assessments of quality management documents and records with responsible personnel, including management responsible for the implementation and update of the quality management system as well as the notified body’s assessors responsible for product review, including clinical evaluation, final review and decision-making processes;  review of the outcome of the most recent on-site surveillance assessments and observed audits as well as of recent extraordinary assessment activities conducted by the designating authority 3 See Article 11 of Directive 90/385/EEC and Article 16 of Directive 93/42/EEC. Medical Device Medical Device Coordination Group Document MDCG 2020-11 4 When performing the above-mentioned review, the designating authority could also consider, if relevant, the outcome of the most recent joint assessment carried out in accordance with Article 3 of the Implementing Regulation as well as joint assessments recently carried out in accordance with the MDR. In order to ensure a sufficient assessment the selection of the appropriate number of manufacturer’s technical documentation reviews and personnel files to be reviewed should take into account the volume of the activities performed by the notified body, its scope of designation and any relevant vigilance data. The designating authority should be able to justify the number and type of files selected. The designating authority should ask the notified body to implement appropriate measures to correct any non-conformities found during the review Normally, the renewal should include an on-site assessment. However, when exceptional circumstances prevent a designating authority from carrying out such an on-site assessment, alternative assessment measures should be used. Principles and arrangements of alternative measures described in Section 5 of this document concerning surveillance activities may apply. The results of the assessment performed by the designating authority should be documented and the final decision on the renewal of a designation should be substantiated. 4. Notification and information to be provided to the Commission In accordance with Article 4(6) of the Implementing Regulation, any decision by a Member State on the renewal of a designation as a notified body should be notified to the Commission and the other Member States through the New Approach Notified and Designated Organisations information system (NANDO) on or before the date of designation expiry. In line with the ordinary procedure, this should take place by means of submitting an update of the existing notification under the relevant Directive. The Commission may request further information relating to a decision taken by a designating authority on the renewal of a designation. In particular, designating authorities should make available, upon request from the Commission, the reports describing the assessments performed in relation to the renewal of the designation and the relevant outcome as described in Section 3 of this guidance. This should clearly document the basis for the renewal decision detailing the elements reviewed by the designating authority to substantiate the decision, including the results of any surveillance and monitoring activities as described in Section 5 of this guidance. Relevant notified body’s documentation should also be made available to the Commission on request. 5. Surveillance activities to be performed under exceptional circumstances In the context of the current COVID-19 pandemic, the resulting travel and quarantine restrictions may significantly affect the ability of designating authorities to conduct their Medical Device Medical Device Coordination Group Document MDCG 2020-11 5 mandatory surveillance and monitoring activities such as on-site assessments and observed audits of their notified bodies. Therefore, in accordance with Article 5(1) of the Implementing Regulation, in order to ensure an adequate level of surveillance, designating authorities should at least assess an appropriate number of notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations, and of personnel files, in addition to carrying out alternative surveillance measures. These alternative measures may include the following principles and arrangements:  on-site surveillance assessments may be replaced by remote surveillance assessments using the most advanced available Information and Communication Technologies as deemed appropriate in accordance with Union legislation on information security and data protection;  assessment of all relevant and required documents/records off-site. In order to ensure a sufficient assessment, the selection of the appropriate number of notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations, and personnel files to be reviewed, should take into account the volume of the activities performed by the notified body, its scope of designation and any relevant vigilance data. The designating authority should be able to justify the number and type of files selected.

mdcg_2019_5_legacy_devices_registration_eudamed_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 1 of 4 MDCG 201 9-5 Registration of legacy devices in EUDAMED April 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 2 of 4 This document deals with registration of devices, which can continue to be placed on the market under Directive certificates by virtue of Article 120(3) of Regulation 745/2017 (MDR), and Article 110(3) of Regulation 746/2017 (IVDR) after the relevant MDRs application dates. Those products are, for the purpose of this document, referred to as “legacy devices”1. All following considerations, which are made in relation to the MDR shall apply to the IVDR, mutatis mutandis. Art 120(3) of the MDR lays down that t he requirements of the MDR relating to post - market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply to legacy devices placed on the market after the application date of the MDR in place of the corr esponding requirements of the Directives. The MDR is not explicit in requiring that these “legacy devices” are subject to relevant UDI obligations. The MDR device registration requirements (Annex VI Part A Section 2 and Part B that are complementary) mak e the Basic UDI -DI and UDI -DI the access keys for device -related information in the future Eudamed, which is reflected in the database design. Therefore, any registration of a device is normally possible in Eudamed only if a proper Basic UDI -DI and UDI -DI are assigned to the device and registered in the database together with the other device -related data. In light of this, taking all views heard into account, and considering that Article 120(3): - Refers to legacy devices to be registered in line with MDR provisions, - Lacks any explicit reference to UDI obligations for legacy devices the MDCG considers it appropriate to adapt the Eudamed design to allow the registration of legacy devices in Eudamed in the absence of a (Basic) UDI -DI. This is intended to prevent any technical constraint to the applicability of Art 120(3) for legacy device registration in Eudamed. A comprehensive description of the technical implications is provided in the Annex. 1 It shall be noted that, in other contexts, the term “legacy devices” might be used with a different meaning. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 3 of 4 Annex Basic considerations related to functioning of future registration of legacy devices in Eudamed 1. Legacy devices – covered by a valid Directive certificate - that will continue to be placed on the market after the MDR date of application should be registere d in Eudamed without a Basic UDI -DI and UDI -DI. The registration deadlines for those devices is clearly the one referred to in Article 123(3)(e): 18 months after the date of application (provided that Eudamed is fully functional on time)2. 2. However, in ca se of serious incident or field safety corrective action to be reported during the 18 months referred to in point 1, where the legacy devices have not been registered in Eudamed yet, they must be registered at the moment of the serious incident/field safet y corrective action reporting. 3. Point 1 will be applicable only to the devices that are not already registered as MDR devices. NOTE: All the Directive -compliant devices which have been placed on the market ahead of the general application dates and will not continue to be placed on the market afterwards, should be registered in Eudamed (without a Basic UDI -DI and UDI-DI) only if a serious incident report and/or a field safety corrective action report (with the field safety notice) occurs after the applica tion date. Technical implementation in Eudamed 4. Legacy devices that will be registered in Eudamed will need two other unique access keys (IDs) to replace the Basic UDI -DI and UDI -DI for the sake of the workability of Eudamed . 5. For this purpose, a Eudamed DI will be assigned to the device instead of the Basic UDI -DI and a Eudamed ID will be assigned by Eudamed instead of the UDI-DI allowing the system to work and to keep the design of Eudamed as close as possible to the MDR design. These Eudamed DI and Eudamed ID will be unique for a given legacy device. 6. The Eudamed DI could be either entirely generated by Eudamed or the manufacturer could partly assign the DI code. On the other hand, the Eudamed ID will be always automatically and fully generated b y Eudamed 2 It should be noted that all class I devices that are not sterile and/or with a measuring function under the Directives, are not eligible for any grace period. When placed on the market after the MDR date of application, they will have to be MDR compliant and be registered in EUDAMED as MDR devices. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 4 of 4 from the Eudamed DI. The proposed rules for the assignment (still under discussion) are that Eudamed DI start with character "B", where Eudamed ID will start with character "D" (only difference between Eudamed DI and Eudamed ID). Beside this f irst character, the Eudamed DI/ID will include the SRN of the manufacturer, a number (assigned by the manufacturer or Eudamed) and a check digit. 7. The relationship between the Eudamed DI and a Eudamed ID will be one to one. 8. Furthermore, the registration o f the legacy devices will require the manufacturer to enter the directive certificate identification (NB number, certificate number, revision number and expiry date) since they will not be registered in Eudamed by the NBs. In case a legacy device has been already registered in Eudamed and that same device becomes at any point in time an MDR compliant device, that MDR device should be considered as a new device requiring a new registration (due to the change in the applicable legislation) with a Basic UDI -DI and UDI -DI in Eudamed. However, only a UDI -DI should be entered, if another device with the same Basic UDI-DI has already been registered. Eudamed should facilitate this (copy) process and allow the linking between the MDR device and the corresponding legacy device .

mdcg_2019_4_devices_registration_eudamed_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-4 Page 1 of 2 MDCG 201 9-4 Timelines for registration of device data elements in EUDAMED April 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission docum ent and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-4 Page 2 of 2 “With regard to timelines for device registration, the text of the MDR presents an inconsistency. On the one hand, Article 123(3)(d) lists the full Article 29 as being applicable from the application dates or, if EUDAMED is not functional on time, six mont hs after the date of publication of the notice referred to in Article 34(3). On the other hand, Article 123(3)(e) grants an additional 18 -month transitional period for obligations contained in Article 29(4). Taking into account: - the declared will of the c o-legislator to grant an 18 -month additional transitional period for device registration and registration of certificates, - the logical correspondence and complementary character of device data elements in Part A (Section 2) and Part B of Annex VI, - the nee d to ensure that information on devices in EUDAMED is not displayed to public in a partial or misleading nature, the obligation for registration in EUDAMED of device data elements listed in both part A, Section 2, and Part B of Annex VI, shall be applicabl e as from the timelines indicated in Article 123(3)(e) (meaning from 18 months after the general application date or, if EUDAMED is not fully functional on time, from 24 months after the date of publication of the notice referred to in Article 34(3)). This is without prejudice to the fact that the obligation related to the operation of assignment of Basic UDI —DI and UDI -DI to devices remains applicable as from the general application dates. This is also without prejudice to the fact that at any time after the general application date, for MDR compliant devices, the full registration of devices (Article 29) remains a pre-condition for the possible registration of their relevant serious incident in EUDAMED These considerations apply mutatis mutandis to the IV DR”.

2020-15-position-paper-actor-registration-module_en.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 2020-15 MDCG 2020-15 MDCG Position Paper on the use of the EUDAMED actor registration module and of the Single Registration Number (SRN) in the Member States August 2020 This document has been endorsed by the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States an d a representative of the European Commission chairs it. The document is not a European C ommission document and it cannot be regarded as reflecting the official position of th e European Commission. Any views expressed in this document are not legally binding and on ly the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 2020-15 MDCG Position Paper on the use of the EUDAMED actor registratio n module and of the Single Registration Number (SRN) in the Member States Article 33 of Medical Devices Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 (her eafter: ‘MDR’) sets out that the Commission, after consulting the MDCG, shall set up, maintain and manage the European database on medical devices (EUDAMED). EUDAMED shall be composed of multiple electronic systems (so called ‘modules’), including an elect ronic system on registration of economic operators, also referred to as the actor registration module . In accordance with Article 30(1) MDR, the actor registration module shall allow for the creation of a unique single registration number (‘SRN’) referred to in Article 31(2) and to collate and process information that is necessary and proportionate to identify the manufacturer (including producer s of system/procedure packs) and, where applicable, the authorised representative and the importer. As such, the actor registra tion module forms a pre- requisite for the use of the other EUDAMED modules and facilitates a secure way of accessing EUDAMED. The responsibility to assign SRNs to economic operators lies with the Member States. To that end, Artic le 31(2) stipulates that, after having verified and validated the data entered by an economic operator, the competent authority of a Member State shall obtain an SRN from the actor registration m odule and approve the issuing of it to the requesting manufacturer, authorised representative or importer. On 30 October 2019, the Commission published a notice by which it concluded that the full functionality of EUDAMED require s the availability and full opera tion of all six modules in accordance with the technical specifications and confirmed by an audit as referred to in Article 34. The notice foresees the launch of a fully functional EUDAMED for May 2022. However, at its meeting of 12 March 2020 th e MDCG agreed that the Commission makes available to Member States each EUDAMED module on a gradual basis as soon as it is operational. In line with the MDCG decision referred to above, the Commissi on has confirmed its readiness to deploy the actor registration module as of 1 December 2020. The members of the MDCG strongly encourage the use of the actor registration module by all relevant actors on their territories, including the use of the single registration number by actors as stipulated in the MDR (e.g. indicating the SRN on certificates). The members of the MDCG agree that double registration requirements for actors should be avoided as much as possible . Therefore, actors that obtai n an SRN should be considered in compliance with the actor registration requirements (for manufacturers, authorised representatives, importers, system/procedure pack producers) to the extent that national laws accommodate for this. In such cases, thos e actors should follow the obligations and requirements of the MDR related to both the registration of relevant actors (via the actor registration module) and the us e of their SRN as required.

05 MDCG 2020-5 Guidance on Clinical Evaluation - Equivalence.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-5 MDCG 2020-5 Clinical Evaluation - Equivalence A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 2 of 20 Clinical Evaluation - Equivalence A guide for manufacturers and notified bodies Page 3 of 20 1 Table of contents 1. Introduction .......................................................................................................... 4 2. Scope ................................................................................................................... 5 3. Equivalence ......................................................................................................... 5 3.1 Technical characteristics ............................................................................... 5 3.2 Biological characteristics ............................................................................... 6 3.3 Clinical characteristics ................................................................................... 9 4. Demonstration of equivalence ............................................................................ 10 5. Use of data from similar devices ........................................................................ 14 6. Clinical data identification ................................................................................... 15 Annex I – Equivalence table ..................................................................................... 16 Page 4 of 20 1. Introduction This guidance document is not legally binding. It has been put together following contribution from national competent authorities, industry and relevant stakeholders and it should therefore be recognised as best practice. The Regulation (EU) 2017/745 on medical devices1, hereafter referred to as the MDR (medical device regulation), provides a possibility to use clinical data related to an equivalent device in the clinical evaluation required for a device under conformity assessment2. Whilst carrying out a clinical investigation is the most direct way to generate clinical data concerning the safety and performance of medical devices for the purpose of CE marking, clinical data can also be sourced from3  clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,  reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated Equivalence shall be demonstrated according to the MDR requirements4. The European Commission has published a guide on clinical evaluation under the directives 93/42/EEC and 90/385/EEC; MEDDEV 2.7/1 rev. 45. This MEDDEV guide should be used also during the process of demonstrating equivalence under the MDR. However, it has been recognised that some of the requirements set out in MEDDEV 2.7/1 rev. 4 are not fully aligned with the MDR and that further guidance to address the differences would be of benefit to industry and other stakeholders. Only the text of the MDR is legally binding. In cases of divergence between the MEDDEV 2.7/1 rev. 4, this MDCG guidance and the MDR, the MDR shall take precedence. This MDCG guidance does not introduce any new requirements. The demonstration of equivalence does not remove the requirement to always conduct a clinical evaluation in accordance with the MDR. It is the demonstration of equivalence6 that allows the manufacturer to let clinical data from an equivalent device enter the clinical evaluation process of the device in question for the purpose of confirmation of conformity with relevant general safety and performance 1 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2017:117:TOC 2 MDR, Article 61 and Annex XIV Part A. 3 MDR, Article 2 (48) 2nd and 3rd indent. 4 MDR, Annex XIV, Part A (3). 5 MEDDEV 2.7/1 revision 4, Guidelines on medical devices, clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC https://ec.europa.eu/growth/sectors/medical-devices/current-directives/guidance_en 6 MDR, Annex XIV, Part A (3). Page 5 of 20 requirements7. There may also be other sources of clinical data than from an equivalent device8 to include in the process of clinical evaluation. 2. Scope This MDCG guidance covers the demonstration of equivalence, based on data pertaining to an already existing device on the market9, for the purpose of CE-marking under the MDR. One of the purposes of this document is to highlight the differences between the MDR and the MEDDEV 2.7/1 rev.4 specifically with regards to equivalence. It is also intended to provide additional guidance and support a harmonised approach to the demonstration of equivalence across the EU. In addition, non-exhaustive guidance and references have been provided with respect to device considerations for medical devices incorporating an ancillary medicinal product. This MDCG guidance also covers products without an intended medical purpose listed in Annex XVI of the MDR. 3. Equivalence The MDR requires10 that technical, biological and clinical characteristics are considered when demonstrating equivalence to another device. Whilst these general characteristics are described in the MEDDEV 2.7/1 rev. 4 Appendix 1 and are aligned with the MDR requirement, there are differences in the criteria that are set out for each of the three characteristics. Differences in criteria between the MDR and the MEDDEV 2.7/1 rev. 4 are highlighted below and are accompanied by some explanatory text. 3.1 Technical characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev 4, Appendix A1 The device is of similar design; is used under similar conditions of use ; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms ; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements. - be of similar design, and - used under the same conditions of use , and - have similar specifications and properties (e.g. physicochemical properties such as type and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions such as nitrocarburising, oxidability), and - use similar deployment methods (if relevant), and - have similar principles of operation and critical performance requirements 7 MDR, Article 61 (1) and (3 (a)). 8 MDR, Article 2 (48) 1st and 4th indent. 9 Whether the ‘market’ is presumed to be the EU market or not is related to requirements in Article 61. See section 4 (d) and (e) in this document for further guidance. 10 MDR, Annex XIV Part A (3). Page 6 of 20 (a) The MDR requires that technical characteristics shall be taken into consideration for the demonstration of equivalence including that the device in question and the device presumed to be equivalent are “used under similar conditions of use”. MEDDEV 2.7/1 rev. 4, however, specifies use under the same conditions with regard to technical characteristics11. The conditions of use shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance between the device in question and the device presumed to be equivalent. For further guidance on the assessment of ‘similar’, see also section 4 of this document. (b) Different examples are given for specifications and properties of the device when considering technical characteristics across the two definitions. These are examples only and are to be considered as such. They must not be interpreted as an exhaustive list of specifications and properties of technical characteristics when considering equivalence to another device. Note however that the MDR specifically points out that software algorithms shall be similar in the device presumed to be equivalent. This includes software algorithms in software driving or influencing the use of a device, and in software intended to be used alone12. It is the functional principle of the software algorithm, as well as the clinical performance(s) and intended purpose(s) of the software algorithm, that shall be considered when demonstrating the equivalence of a software algorithm. It is not reasonable to demand that equivalence is demonstrated for the software code, provided it has been developed in line with international standards for safe design and validation13 of medical device software. Software solely intended for the configuration of a device (e.g. presentation on a graphical user interface etc), and not related to any medical purpose14 (e.g. diagnosis, treatment etc), does not need to be similar when considering equivalence as long as it can be justified to not negatively affect the usability, safety or clinical performance. 3.2 Biological characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev. 4, Appendix A1 The device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables Use the same materials or substances in contact with the same human tissues or body fluids. Exceptions can be foreseen for devices in contact with intact skin and minor components of devices; in these cases risk analysis results may allow the use of similar materials taking into account the role and nature of the similar material. 11 “Conditions of use” with regard to technical characteristics may e.g. be environmental factors such as magnetic fields, temperature, moisture, conditions during transport of device in use etc. See section 3.3 in this document regarding use for the same clinical condition or purpose. 12 See MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 - MDR and Regulation (EU) 2017/746 – IVDR. 13 E.g. IEC 62304 Medical device software – Software life cycle processes, and IEC 82304-1 Health software – Part 1: General requirements for product safety. 14 MDR, Article 2(1). Page 7 of 20 (a) Manufacturers must consider the additional text in the MDR and adequately specify all applicable characteristics. The exceptions, outlined in the MEDDEV 2.7/1 rev 4, to not use the same materials are NOT acceptable under the MDR. The MDR requires that biological characteristics shall be taken into consideration for the demonstration of equivalence, i.e. the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact, and with similar release characteristics of substances, including degradation products and leachables, as the presumed equivalent device. The distinction between “same materials or substances” and “similar release characteristics of substances” is made to account for the fact that processing, design and the use environment may introduce small changes even when the raw materials are the same. Processing can make materials more susceptible to degradation by changing properties of the material and/or by inducing different stresses. For example, small changes in pH or oxidative stress can increase or decrease release characteristics. For this reason, it is the final device that shall be assessed. (b) The principles outlined in ISO 10993 series of standards for the biological evaluation of medical devices can be adopted, in particular the ISO 10993-1 for a risk-based approach to biological evaluation15 and also for material characterization. In addition, the ISO 10993-18 which covers chemical characterization of materials can be adopted to specify the identity of materials and to estimate the type and quantity of leachables from the final device. Annex C of this standard addresses biological equivalence. The ISO 10993-17 includes principles on the toxicological risk assessment of leachables. Leachables may include degradation products or other substances from the materials or substances that the device is made of, but also other constituents for example residuals from the manufacturing process or sterilisation, any contaminations etc. Therefore, for the consideration of equivalence, it is the properties and characteristics of the final device that shall be taken into account. For degradable materials, ISO 10993, Parts 13, 14 and 15 address the identification and quantification of degradation products. Note, that there may be further parts in the ISO 10993 series of standards that are relevant for the device in question. (c) The MDR has additional requirements16 for devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed 15 ISO 10993-1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process, and collateral standards in the 10993 series. 16 MDR, Annex I, (12.2). Page 8 of 20 in the human body. For the consideration of equivalence, the substances shall be the same. Those devices are not medicinal products, but for the conformity assessment they shall comply with the relevant requirements laid down in Annex I to Directive 2001/83/EC17 for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. This means that for the demonstration of equivalence under the MDR, those aspects shall also be taken into consideration. Note that the requirement18 that the notified body shall seek a scientific opinion from a competent authority for medicinal products or the EMA, for the device or its products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, on the compliance with the relevant requirements laid down in Annex I to Directive 2001/83/EC, always applies for the device under evaluation even if equivalence has been demonstrated under the MDR. (d) The demonstration of equivalence may also concern medical devices with an ancillary medicinal substance , for example drug-eluting stents or heparin- bonded central venous catheters. The MDR requires19 that biological characteristics shall be taken into consideration for the demonstration of equivalence, including that the device in question and the device presumed to be equivalent, use “the same materials or substances in contact with the same human tissues or body fluids”. This applies also to the medicinal substance and any related excipients/coatings. Excipients/coatings may potentially have a significant effect for example on the release characteristics of the medicinal substance intended only for a local effect from a stent, and thereby a significant effect on the clinical performance. In all cases, concerning the device under evaluation, the notified body shall20  verify the usefulness of the substance as part of the device, taking account of the intended purpose of the device, and  seek a scientific opinion from a competent authority for medicinal products or the EMA to ensure that the quality, safety and benefit/risk of using the ancillary medicinal product, including whether the manufacturing process have been adequately assessed. 17 Directive 2001/83/EC relating to medicinal products for human use. 18 MDR, Annex IX, Chapter II, 5.4 (b). 19 MDR, Annex XIV Part A (3) second indent. 20 MDR, Annex IX, Chapter II, 5.2. (b) and (c). Page 9 of 20 Note that medical devices with an ancillary medicinal substance are class III devices21. In cases where a manufacturer intends to claim equivalence to a device not manufactured by him, the MDR requires that the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis22 . Manufacturers cannot claim equivalence of a device with an ancillary medicinal substance to a device without an ancillary medicinal substance and vice versa. For example, the manufacturer of a heparin coated catheter shall not claim equivalence to a drug-free catheter even if both catheters are otherwise identical23 . See also section 4 of this document. Similarly, manufacturers shall not claim equivalence of the ancillary medicinal substance to a ‘standalone’ medicinal substance. 3.3 Clinical characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev . 4, Appendix A1 The device is used for the same clinical condition or purpose , including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user ; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. - used for the same clinical condition (including when applicable similar severity and stage of disease, same medical indication ), and - used for the same intended purpose, and - used at the same site in the body, and - used in a similar population (this may relate to age, gender, anatomy, physiology, possibly other aspects), and - not foreseen to deliver significantly different performances (in the relevant critical performances such as the expected clinical effect, the specific intended purpose, the duration of use , etc.) (a) The MDR additionally requires that, for manufacturers to compare clinical characteristics, the device shall have the same kind of user . The MDR clearly points out that a user means any healthcare professional or lay person who uses a device24, and that a lay person means an individual who does not have formal education in a relevant field of healthcare or medical discipline25. Manufacturers must therefore take into consideration whether the intended user’s competence or knowledge can have any implication for the safety, clinical performance and outcome when considering equivalence between the device in question and the presumed equivalent device. For example, a device intended for professional use and a device intended for home use, but for the same clinical condition or purpose, may have a different safety and performance profile due to the environment in which they are intended to be used. 21 MDR, Annex VIII, Rule 14. 22 MDR, Article 61 (5). 23 MDR, Annex XIV Part A (3). 24 MDR, Article 2 (37). 25 MDR, Article 2 (38). Page 10 of 20 (b) The MDR does not explicitly state that the medical device needs to be used for the same medical indication, gender and duration of use as the equivalent device. However, it is understood that in general, this is covered by the MDR requirement that both devices should be used for the same clinical condition or purpose including similar severity and stage of disease and also have similar relevant critical performance which is also outlined in the MEDDEV 2.7/1 rev. 4. This is supported by the definitions in the MDR of the ‘intended purpose’26, and the ability of the device to achieve its intended purpose by the ‘clinical performance’27 including measurable ‘clinical benefit’28. 4. Demonstration of equivalence MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev. 4, Appendix A1 The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification . For assuming equivalence, - all three characteristics (clinical, technical, biological) need to be fulfilled; - similar means that no clinically significant difference in the performance and safety of the device would be triggered by the differences between the device under evaluation and the device presumed to be equivalent. There are a number of prerequisites that shall be fulfilled for the demonstration of equivalence: (a) The overall considerations of equivalence shall conclude whether the listed technical, biological and clinical characteristics in the MDR29 are similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Note that some of the listed characteristics in the MDR shall be the same, not only similar. The corresponding wording from MEDDEV 2.7/1 rev. 4 is presented for information above. Consideration must be given to the characteristics mentioned above and a gap analysis should be conducted by the manufacturer to evaluate any clinically significant difference(s). Modifications30 of a device may be implemented for a variety of reasons. If the differences have been introduced to address specific safety and/or performance issues it shall be duly justified, that there would be no clinically significant difference in the safety and clinical performance other than the intended improvements related to the specific issue that triggered the modification / difference. For all modifications and concomitant claims of equivalence, there must be no additional risks or potential of negatively altered performance related to the introduced modifications. 26 MDR, Article 2 (12). 27 MDR, Article 2 (52). 28 MDR, Article 2 (53). 29 MDR, Annex XIV Part A (3). 30 MDR, Article 61 (4). Page 11 of 20 See a template example of an Equivalence table in the Annex I of this document. A manufacturer of a medical device shall not claim equivalence to a product without an intended medical purpose listed in the MDR Annex XVI. (b) Manufacturers may identify more than one equivalent device to the device under evaluation, but each device shall be equivalent to the device under evaluation in all the listed technical, biological and clinical characteristics31. Equivalence to each device shall be fully investigated, described and demonstrated in the clinical evaluation report. This means that manufacturers shall not use different parts of different devices to claim equivalence to the device under evaluation. The MEDDEV 2.7/1 rev. 4 is in line with this approach. In exceptional cases, a deviation from this principle may be considered. There may be device systems comprised of several more or less “stand alone” devices, where it may be justified to consider equivalence of a device in the system to a presumed equivalent device in a device system already on the market (by the same manufacturer) provided that all technical, biological and clinical characteristics are same/similar32, and that the devices in the system do not affect the safety and performance of each other. This should be duly investigated and documented both on the level of potential interference between the devices in the system, as well as on the overall safety and clinical performance of the device system. (c) Regarding the clinical evaluation, the MDR requires33 that the manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose34. In addition, considerations of equivalence shall be based on proper scientific justification35. This implies that technical, biological and clinical characteristics shall be duly investigated and documented. The manufacturer is expected to fully identify and disclose any differences between the two devices. Pre-clinical data for the consideration of equivalence should allow a scientifically sound evaluation of technical and biological characteristics. Examples of data sources: 31 MDR, Annex XIV Part A (3), the requirement refers to only “a device” and “the device”. 32 MDR, Annex XIV Part A (3). 33 MDR, Article 61 (1) second paragraph. 34 MDR, Article 61 (1) second paragraph It may under certain circumstances be justified to demonstrate conformity without support of clinical data, see MDR, Article 61 (10), but note that this is not applicable for implantable devices or class III devices. 35 MDR, Annex XIV Part A (3) For guidance see also MEDDEV 2.7/1 rev 4, Annex A6, Appraisal of clinical data - examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety. Page 12 of 20  data from the technical documentation of a manufacturer’s own presumed equivalent device (specifications, test-results, chemical/physical/biological analyses, data from pre-clinical investigations etc)  data published in the scientific literature, e.g. animal or other pre-clinical data The assessment of whether any differences in characteristics would result in clinically significant difference in safety and clinical performance shall also be duly substantiated and based on proper scientific justification. This assessment may be supported by e.g. clinical data from the scientific literature, common specifications (CS)36, harmonised standards or other established technical specifications. Furthermore, for the assessment of safety, a risk-based approach37 is expected, both for the identification of characteristics that may affect safety as well as for the final assessment of equivalence regarding safety. It is important for the consideration of equivalence that pre-clinical data and any clinical data relate to the actual device under evaluation, and to a defined generation/version of the actual device considered for equivalence, bearing in mind that there may be significant differences between different generations of the other device. If a manufacturer is not able to demonstrate sufficient levels of access to the data38 relating to the presumed equivalent device and needed for the consideration of equivalence, equivalence claims cannot be made for the purpose of conformity assessment. (d) The MDR notes specific requirements in addition to the demonstration of equivalence in order not to perform a clinical investigation which must be taken into account. A manufacturer of implantable devices and class III devices shall perform clinical investigations except if the device has been designed by modifications of a device already marketed by the same manufacturer and equivalence can be demonstrated according to the MDR39. In this context, a marketed device is considered to be a device already placed on the market and CE marked with respect to either the MDR or the directives 93/42/EEC or 90/385/EEC. The CE marking should still be valid, should be based on an updated clinical evaluation, and the benefit/risk ratio for this device should be favourable. 36 MDR, Article 2, (71) ‘common specifications’ (CS) means a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system. 37 ISO 14971 Medical devices – Application of risk management to medical devices, and also other related standards as applicable e.g. ISO 10993-1 and ISO 10993-18. 38 MDR, Annex XIV Part A (3) last paragraph. 39 MDR, Article 61 (4), and Annex XIV (3). Page 13 of 20 For a manufacturer of implantable devices and class III devices claiming equivalence to an already marketed device not manufactured by him , in addition to the requirements in MDR Article 61(4), the manufacturer must have a contract in place that allows full access to the technical documentation on an ongoing basis40. Furthermore, the MDR also requires that the original clinical evaluation of the equivalent device has been performed in compliance with the requirements of the MDR. This implies that the presumed equivalent device is certified under the MDR. As such, it will not be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC. (e) For devices other than implantable devices and class III devices and where the manufacturer wants to claim equivalence, MDR Article 61 (3) is applicable. This requirement does not specify whether the device is presumed to be marketed within the EU. Therefore, it will be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC or the MDR. However, exceptions can be considered, and equivalence claimed to a device that is not CE-marked, provided all relevant MDR requirements regarding equivalence and clinical evaluation can be met. This includes  that the manufacturer shall have sufficient levels of access to the data relating to devices with which they are claiming equivalence41 . In the circumstance that the presumed equivalent device is from another manufacturer, there is no MDR requirement of a contract between the manufacturers for regulating the access to the technical documentation.  that clinical investigations were conducted in accordance with international guidelines42  that the clinical data meet the requirements of the MDR, and a justification is provided whether the clinical data are transferrable to the European population. The regulatory status of the presumed equivalent device should be disclosed. See MEDDEV 2.7/1 rev. 4 Appendix A1 for further guidance. (f) In case of products without an intended medical purpose listed in MDR Annex XVI clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified43. An analogous device, in this context, is understood as a medical device which is similar in terms of functioning and risks profile and has a medical purpose44. To duly justify reliance on existing clinical data from an analogous 40 MDR, Article 61 (5). 41 MDR, Annex XIV Part A (3) the last sentence. 42 MDR, Recital (64) Clinical investigation of medical devices for human subjects – Good clinical practice (ISO 14155), and World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. 43 MDR, Article 61 (9). 44 MDR, Recital (12). Page 14 of 20 medical device, the principles of demonstration of equivalence45 should be applied with the acceptance that the device under evaluation will only have an aesthetic or another non-medical purpose whereas the analogous device has a medical purpose. The general requirement to demonstrate a clinical benefit46 shall be understood as a requirement to demonstrate the performance of the device. In addition, since the common specifications (CS) for the products without an intended medical purpose may have requirements related to the clinical evaluation regarding safety47 these requirements must be taken into consideration when demonstrating equivalence and concluding whether there would be no clinically significant difference in the safety48. There shall be no significant difference in the safety and performance between the product and the presumed analogous medical device. 5. Use of data from similar devices The term ‘similar devices’ may be understood as devices belonging to the same generic device group. The MDR defines this49 as a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics. In cases where equivalence cannot be demonstrated under the MDR, the data from similar devices may be useful for a variety of other purposes, for example: 1. Ensuring that the risk management system is comprehensive by identifying relevant hazards and clinical risks. 2. Understanding the state of the art, the natural course of disease and alternative available treatment options. 3. Helping to define the scope of the clinical evaluation, by identifying any design features in similar devices that pose special performance or safety concerns. 4. Provide input for clinical investigation design or post-market clinical follow-up design, and the post-market surveillance system. 5. Identification of relevant and specified clinical outcome parameters for the intended clinical benefits, based on the published clinical data pertaining to the similar device(s). 6. To define minimum requirements for a quantified clinical benefit that is considered clinically relevant, and/or to identify acceptable occurrence rates of risks and adverse events. 45 MDR, Annex XIV Part A (3). 46 MDR, Article 61 and Annexes XIV and XV. 47 MDR, Article 1 (2). 48 MDR, Annex XIV Part A (3). 49 MDR, Article 2 (7). Page 15 of 20 6. Clinical data identification A clinical evaluation of the device under assessment shall be made according to the MDR50. All the clinical data, both favourable and unfavourable shall be identified. This applies to clinical data from both the device in question and the device for which equivalence can be demonstrated. If the data meet the definition of clinical data as defined in the MDR51, the data shall then progress to data appraisal and analysis in order to evaluate whether the clinical data are providing sufficient clinical evidence for the purpose of confirmation of conformity with the relevant general safety and performance requirements (GSPR)52. For identifying, appraising and analysing available clinical data from the scientific literature to establish clinical evidence53, manufacturers will find facilitative guidance in sections 8-10 of MEDDEV 2.7/1 rev. 4. In the event that the data do not meet the MDR definition of clinical data these are not clinical data and cannot be subject to data appraisal, analysis and evaluation for the purpose of providing clinical evidence for the confirmation of conformity with the relevant GSPR. 50 MDR, Annex XIV Part A. 51 MDR, Article 2 (48). 52 MDR, Annex I. 53 MDR, Article 2 (51). Page 16 of 20 Annex I – Equivalence table A table, such as the table below, may be used to clearly demonstrate equivalence and to identify the supporting data on a device by device basis. The items in the first column of the table are examples only and are to be considered as such. They must not be interpreted as an exhaustive list of specifications, properties, parameters and/or aspects for demonstrating equivalence to another device. The manufacturer should identify differences and place emphasis on the differences between the two devices rather than the similarities. Considerations shall include the potential additive effect of multiple small differences. For further considerations of equivalence, see sections 3 and 4 in this document. Scientific justifications shall be provided for the different characteristics when claiming no clinically significant difference in the safety and clinical performance of the device. Where more than one device is assessed for equivalence, the table should be completed separately for each presumed equivalent device. The documentation of the demonstration of equivalence shall be included in the clinical evaluation report. Medical Device Medical Device Coordination Group Document MDCG 2020-5 Equivalence table for the comparison of a device with a presumed equivalent marketed device for the purpose of demonstrating equivalence 1. Technical characteristics (add a separate row for each of the assessed characteristics) Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Device is of similar design 1.1 Used under similar conditions of use 1.2 Similar specifications and properties including physiochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms 1.3 Uses similar deployment methods where relevant 1.4 Has similar principles of operation and 1.5 Page 18 of 20 critical performance requirements Scientific justification why there would be no clinically significant difference in the safety and clinical performance of th e device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No 1.1 1.2 1.3 1.4 1.5 2. Biological characteristics (add a separate row for each of the assessed characteristics) Device 1 Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Uses the same materials or substances in contact with the same human tissues or body fluids (The characteristic must be the same for the demonstration of equivalence) 2.1 Similar kind and duration of contact with the same human tissues or body fluids 2.2 Similar release characteristics of substances including degradation products and leachables 2.3 Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No Page 19 of 20 2.1 2.2 2.3 3. Clinical characteristics (add a separate row for each of the assessed characteristics) Device 1 Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Same clinical condition or purpose, including similar severity and stage of disease 3.1 Same site in the body (The characteristic must be the same for the demonstration of equivalence) 3.2 Similar population, including as regards age, anatomy and physiology 3.3 Same kind of user (The characteristic must be the same for the demonstration of equivalence) 3.4 Similar relevant critical performance in view of the expected clinical effect for a specific intended purpose 3.5 Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No Page 20 of 20 3.1 3.2 3.3 3.4 3.5 Summary In the circumstance that more than one non-significant difference is identified, provide a justification whether the sum of differences may affect the safety and clinical performance of the device.

10-1 MDCG 2020-10-1 Guidance on safety reporting in clinical investigations.pdf.txt

Page 1 of 16 1 MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745 May 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the Europea n Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union ca n give binding interpretations of Union law. Page 2 of 16 MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745 May 2020 Table of contents 1 INTRODUCTION .................................................. ............................................................... ............................................................... ........................................................ 3 1.1 SAFETY REPORTING IN THE ABSENCE OF EUDAMED .............................................................. ............................................................... ............................................................... ..... 3 2 SCOPE ......................................................... ............................................................... ............................................................... ............................................................... . 4 2.1 CLINICAL INVESTIGATIONS OF MEDICAL DEVICES .............................................................. ............................................................... ............................................................... ......... 4 2.2 MEDICAL DEVICES USED IN CLINICAL TRIALS OF MEDICINAL PRODUCTS (DRUG TRIALS ) ............................................................. ............................................................... ........................ 4 3 DEFINITIONS ................................................... ............................................................... ............................................................... ............................................................ 5 3.1 INVESTIGATIONAL DEVICE .............................................................. ............................................................... ............................................................... ...................................... 5 3.2 ADVERSE EVENT (AE) .......................................................... ............................................................... ............................................................... ............................................... 5 3.3 SERIOUS ADVERSE EVENT (SAE).......................................................... ............................................................... ............................................................... ................................. 5 3.4 DEVICE DEFICIENCY .............................................................. ............................................................... ............................................................... .............................................. 5 4 REPORTING METHOD .............................................. ............................................................... ............................................................... ................................................... 6 4.1 TRANSITION TO REPORTING VIA EUDAMED .............................................................. ............................................................... ............................................................... ............... 6 4.2 OVERVIEW OF FORMATS TO BE USED BY SPONSORS WHEN REPORTING TO NCA S .............................................................. ............................................................... ............................. 6 4.3 COLLECTING REPORTS FROM INVESTIGATORS .............................................................. ............................................................... ............................................................... ............. 6 5 REPORTABLE EVENTS ............................................. ............................................................... ............................................................... .................................................... 7 5.1 EXCEPTIONS FOR PMCF INVESTIGATIONS ACCORDING TO MDR ARTICLE 74.1 .......................................................... ............................................................... ................................... 7 5.2 REPORTABLE EVENTS OCCURRING IN THIRD COUNTRIES .............................................................. ............................................................... .............................................................. 7 5.3 TRANSITION PERIOD FOR REPORTABLE EVENTS IN PRE -MARKET CLINICAL INVESTIGATIONS INITIATED UNDER DIRECTIVES LEGIS LATION .............................................................. ........................ 7 5.4 TRANSITION FOR REPORTABLE EVENTS IN PMCF CLINICAL INVESTIGATIONS INITIATED UNDER DIRECTIVES LEGISLATION .............................................................. .......................................... 8 6 REPORT BY WHOM ................................................ ............................................................... ............................................................... ..................................................... 8 7 REPORT TO WHOM ................................................ ............................................................... ............................................................... ..................................................... 8 8 REPORTING TIMELINES ........................................... ............................................................... ............................................................... .................................................... 8 8.1 REPORT BY SPONSOR TO NCA S............................................................... ............................................................... ............................................................... .............................. 8 8.2 REPORT BY THE INVESTIGATOR TO THE SPONSOR .............................................................. ............................................................... ............................................................... ........ 9 9 CAUSALITY ASSESSMENT .......................................... ............................................................... ............................................................... .................................................. 9 10 REPORTING FORM ................................................ ............................................................... ............................................................... .................................................... 11 10.1 COMPLETION GUIDELINES : FORM HEADER .............................................................. ............................................................... ............................................................... .............. 11 10.2 COMPLETION GUIDELINES : EVENT DETAILS .............................................................. ............................................................... ............................................................... .............. 13 11 REFERENCES .................................................... ............................................................... ............................................................... ......................................................... 16 12 APPENDIX – CLINICAL INVESTIGATION SUMMARY SAFETY REPORTING FORM .............................................................. ............................................................... .......... 16 Page 3 of 16 1 Introduction Safety reporting in clinical investigations of medical devices shall be performed in line with the requirements of the Regulat ion (EU) 2017/745 – Medical Device Regulation (MDR) Article 80(2): The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of th e following by means of the electronic system referred to in MDR Article 73: a) any serious adverse event that has a causal relationship with t he investigational device, the comparator or the investigation procedure or where such causal relationshi p is reasonably possible; b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention ha d not occurred, or circumstances had been less fortunate; c) any new findings in relation to any event referred to in points a) and b). The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the spon sor may submit an initial report t hat is incomplete followed up by a complete rep ort. Upon request by any Member State in which the clinical investig ation is being conducted, the sponsor shall provide all informa tion referred to in paragraph 1. For post-market clinical follow up (PMCF) investigations of CE- marked devices1 used within the intended use covered by the CE-marking, report ing requirements of MDR Article 80(5) and (6) apply. This means tha t the vigilance provisions laid down in Articles 87 to 90 and i n the acts adopted pursuant to Article 91 shall apply for PMCF clinical investigat ions. However, this guidance document is still relevant for PMC F clinical investigations as the reporting of serious adverse events where a causal relat ionship to the preceding investigational procedure has been est ablished shall follow the reporting procedures of clin ical investigations as outlined in Article 80. 1.1 Safety reporting in the absence of Eudamed Since the electronic system referred to in Article 73 (Eudamed) will not be available and fully functional at the Date of appl ication of the MDR this guidance outlines the procedures for safety reporting in clinic al investigations in the absence of Eudamed. This document defines Serious Ad verse Event (SAE) reporting mod alities and includes a summary tabulation reporting format. 1 The PMCF investigations referred to in MDR Article 74(1). Page 4 of 16 2 Scope 2.1 Clinical investigation s of medical devices The reporting modalities and format set out in this guidance ap ply to:  Pre-market clinical investigations covered by Articles 62 and 74(2) of the MDR conducted with: a) Non-CE marked devices, b) CE marked devices used outside the intended use(s) covered by t he CE-marking. c) The term pre-market clinical inv estigation may also include som e studies covered by MDR Article 82. As MDR Article 82 allows member states to define national requi rements for such clinical investigations, sponsors are encourag ed to check with the applicable NCA2 whether this guidance or other reporting procedures should be applied. In situations where a clinical investigation has started using a non-CE marked device, and the right to bear the CE marking ha s been obtained before the end of the clinical investigation, the SAE reporting continues until completion of the investigation, according to the clinical investigation plan and these guidelines apply throughout the SA E reporting period. For pre-market clinical investigations involving CE marked comp arator devices used within their intended purpose, SAEs occurri ng in or to subjects that are in the comparator arm of an investigation sha ll also be reported in accordance with these guidelines. Note: SAEs concerning CE marked devices which meet the vigilanc e reporting criteria also need to be handled under the post-mar ket surveillance/vigilance system.  Those Post-Market Clinical Follow Up (PMCF) investigations that involve procedures additional to those performed under th e normal conditions of use of the device, and where those additional pro cedures imposed by the clinical investigation plan are invasive o r burdensome, covered by MDR Article 74(1). For these clinical in vestigations the safety reporting for events pertaining to MDR Article 80(6) follow the Serious Adverse Event reporting process only, and ar e outlined in this guidance. Events pertaining to MDR Article 8 0(5) are reported following the vigilance process only and are outside t he scope of this guidance.  Note that other post-market clinical investigations may be subj ect to safety reporting requirements in line with this guidance due to national requirements following MDR Article 82, but there is no such general requirement. Sponsors are encouraged to check wit h the applicable NCA whether this guidance or other reporting procedu res should be applied.  Due to the transitional provisions in MDR Article 120(11) this guidance also covers clinical investigations which have started to be conducted in accordance with Article 10 of Directive 90/385/EEC (AIMDD) o r Article 15 of Directive 93/42/EEC (MDD) prior to 26 May 2021. These investigations may continue to be conducted after date of appli cation of the MDR, but the reporting of serious adverse events and device deficiencies shall be carried out in accordance with the MDR re quirements from 26 May 2021 and onwards. 2.2 Medical devices used in clinical trials of medicinal products ( drug trials)  A CE-marked device which is used outside its intended purpose, or a non-CE marked device in a clinical drug trial would implic itly have to be assessed for safety and performance and the study shall foll ow both MDR (Chapter VI) and the applicable legislation for cli nical drug trials. This guidance document is then relevant for compliance with the MDR regarding safety reporting. 2 For the purpose of this guidance," NCAs" encompasses the Natio nal Competent Authorities of the EEA, Switzerland and Turkey. Page 5 of 16  If a drug-device study (or a drug trial) is not undertaken to a ssess the safety or performance of a device used in the study, the reporting requirements of MDR Article 80 do not apply, as long as the dev ice is CE marked and used within its intended purpose. This gui dance is not applicable, but the vigilance re porting provisions of MDR apply in those situations, as for any commercially available device. Sponsors should make sure that the device manufacturer is notified about any incidents related to the device and the legal manufacturer of the device is responsible for the subsequent vigilance reporting. 3 Definitions 3.1 Investigational device A device that is assessed in a clinical investigation (MDR Article 2(46)) Note: An investigational device can be a non-CE marked device o r a CE marked device. The definition in MDR Article 2(46) does not differentiate between different regulatory statuses of devices. However, the reporting requirements are different depending on whether the c linical investigation is done for purposes described in Article 62, 74 or 82. The definition is understood to cover also the devices i nvestigated in PMCF investigations, even if they are not subject to notification pe r Art 74.1. 3.2 Adverse Event (AE) Any untoward medical occurrence, unintended disease or injury o r any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinic al investigation, whether or not related to the investigational device. (MDR Article 2(57)) Note: a. This definition includes events that are anticipated as well as unanticipated events b. This definition includes events occurring in the context of a c linical investigation related to the investigational device, th e comparator or the procedures3 involved. 3.3 Serious Adverse Event (SAE) Any adverse event that led to any of the following: a) death, b) serious deterioration in the health of the subject, that result ed in any of the following: i. life-threatening illness or injury, ii. permanent impairment of a body structure or a body function, iii. hospitalisation or prolongation of patient hospitalisation, iv. medical or surgical intervention to prevent life-threatening il lness or injury or permanent impairment to a body structure or a body function, v. chronic disease, c) foetal distress, foetal death or a congenital physical or menta l impairment or birth defect (MDR Article 2(58)) 3.4 Device deficiency Any inadequacy in the identity, quality, durability, reliabilit y, safety or performance of an i nvestigational device, includin g malfunction, use errors or inadequacy in information supplied by the manufacturer. 3 For the purpose of safety reporting all activities related to the use of a medical device may be considered procedures Page 6 of 16 (MDR Article 2(59)) 4 Reporting method A new template for the Summary Reporting Form should be used fo r all studies from 26 May 2021. The tabular format featured in the Appendix needs to be filled in/updated for each reportable event or for new findings/updates to already reported events. It shall be tr ansmitted to all NCAs where the clinical investigation is being performed. For more details on how to complete the form refer to section 10. Reporting form . 4.1 Transition to reporting via Eudamed Once Eudamed is available and fully functional the obligations and requirements that relate to performing safety reporting via Eudamed shall apply from the date corresponding to six months after the date of pub lication of the notice referred t o in Article 34(3) of the MDR. 4.1.1 Ongoing events at time of transition to Eudamed It is acknowledged that at the time of transition to reporting via Eudamed, there will be ongoing events for which initial rep orts have been made according to the procedures described in this document. For the se reportable events follow-up and final reports will be submit ted to the NCAs by the same procedure, but all new reportable events shall be ente red in Eudamed. Whether retrospective uploading of previous event reports to Eu damed will be possible is not clear at the time this guidance i s issued. 4.2 Overview of formats to be used b y sponsors when reporting to NC As Under directives legislation Until May 25th, 2021: The tabular format from MEDDEV 2.7/3 Appe ndix I should be used Transition period From May 26th, 2021 and until Eudamed is available The Tabular format of this guidance (Appendix- Summary Reporting Form) should be used. When Eudamed is available but not yet mandatory and until the timepoint when Eudamed becomes mandatory Either the Tabular format of this guidance (Appendix- Summary Reporting Form) or the Eudamed web form can be used. Note: Once the shift to Eudamed reporting has been made for a s pecific clinical investigation, Eudamed should continue to be used for reporting all new events and updates to those events throughout the remai nder of the clinical investigation. From the timepoint when Eudamed is mandatory* *From the date corresponding to six months after the date of publication of the notice referred to in Article 34(3) of the MDR. Web form via Eudamed shall be used for all new events, and upda tes to those events. The Tabular format of this guidance (Appendix- Summary Reporting Form) can be used only to transmit follow-up reports/final repo rts to the NCAs on events which were in itially reported in this format . 4.3 Collecting reports from investigators The format in which sponsors wish to receive single event repor ts from investigators will be up to the sponsor to design and t hey may be adapted to an individual clinical investigation. When sponsors design s uch reporting forms, they should consult this guidance document to e ns ure al l relevant details are captured in the reports from the investiga tor, so that the sponsors can fu lfil their reporting obligation s. Page 7 of 16 5 Reportable events For the purpose of this guidance and based on the definitions a bove, the following events are considered reportable events in accordance with MDR Art. 80(2): a) any serious adverse event that has a causal relationship with t he investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention ha d not occurred, or circumstances had been less fortunate; c) any new findings in relation to any event referred to in points a) and b). Serious adverse events related to a CE marked device which is p art of the investigation procedure (for example a CE-marked imp lanting tool used in combination with a non-CE marked investigational device) are reportable per MDR Article 80(2) if there is a causal, (or rea sonably possible) relationship to the device, the comparator or the investigation procedure. The reporting procedures described in this guide sh ould then be followed in addition to the normal vigilance reporting procedur es for CE marked devices. All causality assessments should be made using the guidance in section 9. Only causality level 1 (i.e. “not related”) is exclu ded from reporting. If either the sponsor or the investigator has assigned a higher ca usality level than "not related", the event should be reported. 5.1 Exceptions for PMCF investigatio ns according to MDR Article 74. 1 Following Article 74.1 the SAE reporting for these PMCF clinica l investigations is governed b y Articles 80(5) and 80(6). This means that the provisions o f vigilance laid down in Articl es 87-90 and acts adopted pursuant to Article 91 shall apply. H owever, the SAEs where a causal relationship between the serious adverse event a nd the preceding investigational procedure has been established shall follow the reporting procedures of clinical investigations as outlined in Article 80. For the purpose of this guidance reportable events in PMCF clin ical investigations are thus those serious adverse events where a causal relationship between the serious adverse event and a preceding investigation al procedure has been established. “Preceding investigational procedure” shall be understood as a procedure which is imposed by th e Clinical Investigation Plan a nd which has taken place before (or coincided in time) with the serious adverse ev ent. This includes but is not limited to the burdensome or inva sive procedure(s) which defines whether the study is subject to notification requ irements following MDR article 74(1). 5.2 Reportable events occurring in Third Countries Reportable events occurring in Third Countries4 in which a clinical investigation is performed under the same clinical investigation plan have to be reported in accordance with this guidance to the NCA (s) of the European countries in which the clinical investigati on is being conducted.  The NCA shall start receiving the reportable events occurring i n Third Countries as soon as the clinical investigation is auth orised to start in that Member State.  Events occurring in Third Countries after the participating Eur opean sites have closed shall continue to be reported. 5.3 Transition period for reportable events in pre-market clinical investigations initiated und er directives legislation It is acknowledged that the MDR implies changes to the reportin g requirements compared to the directives’ requirements where a ll SAEs should be reported regardless of relatedness. Under MDR sponsors are n o longer obliged to report SAEs that are “not related” to the c linical investigation 4 Countries other than Switzerland, Turkey and those belonging t o the EEA. Page 8 of 16 procedures or the investigational device. At the date of applic ation for MDR there will be ongoing events for clinical investi gations initiated under directives legislation. As from the 26th of May 2021 sponsors are no longer expected to submit follow-u p reports to NCAs for events that have been deemed “not related“ (see section 9 of this document for guidan ce on causality assessment). For ongoing events that have a cau sality assessment other than “not related” follow up reports will still have to b e provided. To facilitate the transition and give time for sponsors to upda te Clinical Investigation Plans and study procedures in clinica l investigations a sponsor may continue to report all SAEs t o NCAs until Eudamed reporting is mandatory (see section 4.1 Transition to reporting via Euda med). This applies only to studies which have started to be conducted5 in accordance with Article 10 of Directive 90/385/EEC or Artic le 15 of Directive 93/42/EEC prior to 26 May 2021. 5.4 Transition for reportable events in PMCF clinical investigation s initiated under dire ctives legislation In case of PMCF studies which required SAE reporting according to the Pre-MDR national legislations, MDR article 80 (5) and 80 (6) shall apply from May 26th, 2021. 6 Report by whom Reportable events have to be reported by the sponsor of the cli nical investigation, which could be the manufacturer, the legal representative or another person6 or entity,. 7 Report to whom Reportable events must be reported at the same time to all NCAs where the clinical investigation has commenced using the summary tabulation featured in the Appendix. A list of clinical investigation contact points within the NCAs is published at the Commission's homepage. For the purpose of this guidance, an investigation is considere d to have commenced in an individual Member State: • For investigations under the directives: When the sponsor is au thorized to start the investigation in accordance with the noti fication procedures in that Member State. • For investigations started under the MDR: When the sponsor is a uthorized to start the investigation in that Member State in ac cordance with the provisions laid out in the MDR. Member States may also require separate reporting to the Ethics Committee(s). 8 Reporting timelines 8.1 Report by sponsor to NCAs. The sponsor must report to all NCAs where the clinical investig ation is authorised to start: • For all reportable events as described in section 5 which indic ate an imminent risk of death, serious injury, or serious illne ss and that requires prompt remedial action for other patients/subjects, us ers or other persons or a new finding to it: Immediately, but not later 5 For the purpose of safety reporting this is defined as “Author ised to start in the individual Member State in line with appli cable directives legislati on, regardless of whether any subjects have been recruited in the Member State or not.” 6 Contact person established by the sponsor in line with Article 62(2) if accepted by Member State. Page 9 of 16 than 2 calendar days after awareness by sponsor of a new report able event or of new information in relation with an already re ported event. This includes events that are of significant and unexpected nat ure such that they become alarming as a potential public health hazard. It also includes the possibility of multiple deaths occurring at s hort intervals. These concerns may be identified by either the NCA or the manuf acturer. • Any other reportable events as described in section 5 or a new finding/update to it: Immediately, but not later than 7 calendar days following the date of awareness by the sponsor of the new repor table event or of new information in relation with an already r eported event. In some cases, a different periodicity or different modalities may be agreed between the participating NCAs and the sponsor ac cording to the investigation’s design and to the pathology under clinical inve stigation. This would allow implementation of adequate provisio n for clinical investigations in which SAE frequency is expected to be high du e to the natural progression of the disease (e.g. palliative on cology). 8.2 Report by the investigator to the sponsor The sponsor shall implement and maintain a system to ensure tha t the reporting of the reportable events as defined under chapt er 5 will be provided by the investigator to the sponsor immediately, but no t later than 3 calendar days after investigation site study per sonnel’s awareness of the event. 9 Causality assessment The relationshi p between the use of the medic al device7 (including the medical - surgical procedure) and the occurrence of each adverse event shall be assessed and categorized. D u r i n g c a u s a l i t y a s s e s s m e n t a c t i v i t y , c l i n i c a l j u d g e m e n t s h a l l be used and the relevant documents, such as the Investigator’s Brochure, the Clinical Investigation Plan or the Risk Analysis Report shall b e consulted, as all the foreseeable serious adverse events and the potential risks are listed and assessed there8. The presence of confounding factors, such as concomitant medi cation/treatment, the natural history of the underlying disease, other concurrent illness or risk factors shall also be c o n s i d e r e d . The above considerations apply also to the serious adverse even ts occurring in the comparison group. For the purpose of harmonizing reports, each SAE will be classi fied according to four different levels of causality: 1. Not related 2. Possible 3. Probable 4. Causal relationship The sponsor and the investigators will use the following defini tions to assess the relationship of the serious adverse event t o the investigational device, the comparator or the investigation procedure. 1. Not related: Relationship to the device, comparator or procedur es can be excluded when: - the event has no temporal relationship with the use of the inve stigational device, or the procedures related to application of the investigational device; 7 Intended as both investigational device and comparator. 8 For a comparator device, the Operator’s Manual could be a rele vant document. Page 10 of 16 - the serious adverse event does not follow a known response patt ern to the medical device (if the response pattern is previously known) and is biologically implausible; - the discontinuation of medical device application or the reduct ion of the level of activation/exposure - when clinically feasi ble - and reintroduction of its use (or increase of the level of acti vation/exposure), do not impact on the serious adverse event; - the event involves a body-site or an organ that cannot be affec ted by the device or procedure; - the serious adverse event can be attributed to another cause (e .g. an underlying or concurrent illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); - the event does not depend on a false result given by the invest igational device used for diagnosis9, when applicable; In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, depending on the t ype of device/procedures and the serious adverse event. 2. Possible: The relationship with the use of the investigational device or comparator, or the relationship with procedures, is w eak but cannot be ruled out completely. Alternative causes are also pos sible (e.g. an underlying or concurrent illness/ clinical condi tion or/and an effect of another device, drug or treatment). Cases where re latedness cannot be assessed, or no information has been obtain ed should also be classified as possible. 3. Probable: The relationship with the use of the investigational device or comparator, or the relationship with procedures, seem s relevant and/or the event cannot be reasonably explained by ano ther cause. 4. Causal relationship: the serious adverse event is associated with the investigational device, co mparator or with procedures beyond reasonable doubt when: - the event is a known side effect of the product category the de vice belongs to or of similar devices and procedures; - the event has a temporal relationship with investigational devi ce use/application or procedures; - the event involves a body-site or organ that o the investigational device or procedures are applied to; o the investigational device or procedures have an effect on; - the serious adverse event follows a known response pattern to t he medical device (if the response pattern is previously known) ; - the discontinuation of medical device application (or reduction of the level of activation/exposure) and reintroduction of its use (or increase of the level of activation/exposure), impact on th e serious adverse event (when clinically feasible); - other possible causes (e.g. an underlying or concurrent illness / clinical condition or/and an effect of another device, drug o r treatment) have been adequately ruled out; - harm to the subject is due to error in use; - the event depends on a false result given by the investigationa l device used for diagnosis10, when applicable; In order to establish the relatedness, not all the criteria lis ted above might be met at the same time, depending on the type of device/procedures and the serious adverse event. 9 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment a nd incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious dis ease. In other cases, the patient might not receive an effectiv e treatment (thereby missing out on the benefits that treatment would confer) or might not be diagnosed with the correct disease or condition. 10 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment a nd incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious dis ease. In other cases, the patient might not receive an effectiv e treatment (thereby missing out on the benefits that treatment would confer), or might not be diagnosed with th e correct disease or condition. Page 11 of 16 The sponsor and the investigators will distinguish between the serious adverse events related to the investigational device an d those related to the procedures (any procedure specific to the clinical investig ation). An adverse event can be related both to procedures and the investigational device. Complications caused by concomitant treatments not impo sed by the clinical investigation plan are considered not relat ed. Similarly, several routine diagnostic or patient management procedures are applied to patients regardless of the clinical investigation p lan. If routine procedures are not imposed by the clinical investigation plan, complications caused by them are also considered not related. In some particular cases the event may not be adequately assess ed because information is insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators will make the maximum effort to define and categorize the event a n d a v o i d these situations. Where an investigator assessment is not avail able and/or the sponsor remains uncertain about classifying the serious adverse event, the sponsor should not exclude the relatedness; the even t should be classified as “possible” and the reporting not be d elayed. Particular attention shall be given to the causality evaluation of unanticipated serious adverse events. The occurrence of una nticipated events related could suggest that the clinical investigation places su bjects at increased risk of harm than was to be expected before hand. 10 Reporting form The reporting form template for the summary SAE tabulation is g iven in the Appendix of this document. The reporting form is study specific and covers only a given cl inical investigation, defined by a distinct clinical investigat ion plan. English is the recommended language for the reporting form. The report form ca n be modified in any applicable software (not only Microsoft Ex cel) but the file needs to be compatible with Microsoft Excel when sent to the participating NCAs. The template form contains inserted filters and functionality t o facilitate use of preferred terminology in the reporting. The se are important for the analysis and should be maintained. Sponsors who generate the excel report file by automated proces ses may implement other technical features in their systems for e x c e l f i l e generation to ensure the preferred terms listed in metadata are used. The table gives a cumulative overview of the reportable events per clinical investigation and will be updated and transmitted to participating NCAs each time a new reportable event or a new finding to an al ready reported event is to be reported. More detailed informati on has to be provided on request of an NCA, if so requested by using the ind ividual study specific reporting form (see further section 4.3 Collecting reports from investigators ). 10.1 Completion guidelines: Form header 10.1.1 EUDAMED/CIV-ID The union-wide Single Identification Number mentioned in MDR Ar ticle 70(1) will not be possible to generate until Eudamed for MDR is fully functional. For the transition period, clinical investigations will get tracking numbers (CIV-ID) upon registration in the Eud amed2 database which is performed by the NCA upon receipt of an application. This CI V ID is provided to the sponsor during the NCA’s handling of th e initial application for the clinical investigation and should be entered on the saf ety reporting form. The CIV ID should already be available for a clinical investiga tion started under the directives’ legislation, where it should be indicated on the MEDDEV 2.7/3 reporting form etc. Sponsors who are not aware of the CIV ID of their clinical inv estigations are invited to cont act the concerned NCA to get this information. Page 12 of 16 10.1.2 Title of Clinical Investigation The identifying title of the Clinical Investigation. The title indicated here should be consistent with other title entries (s uch as in clinical investigation application form, clinical inves tigation plan cover page etc). 10.1.3 CIP number/code The unique identification code or short name assigned to the sp ecific clinical investigation pl an by the Sponsor (numeric, alp hanumeric or acronym) should be indicated. 10.1.4 Contact person Name, address, e-mail and telephone number should be provided f or the person who is sponsor’s point of contact in case NCA hav e follow up questions regarding submitted safety report forms. 10.1.5 MS+NCA Reference numbers For each participating Member State indicate the country code11 and the NCA’s national reference number for the clinical inves tigation. Example: SE 5.1-20YY-XXXXXX DK 20YYXXXXXX 10.1.6 No. of subjects enrolled to date total Indicate the total number of subjects who have been enrolled (p er date of report) in the clinical investigation globally. 10.1.7 No. of subjects enrolled to date per country List all countries where the clinical investigation has been au thorised by date of report and indicate the number of subjects who have been enrolled in the clinical investigation (per date of report) in each coun try. 10.1.8 Device type Indicate the type of device(s) assessed in the clinical investi gation (e.g. pacemaker, coronary stent, hip implant). 10.1.9 Reference Member State Indicate the name of the Member State which drew the unique EUD AMED/CIV ID (normally the first Member State receiving an appli cation for the clinical investigation). Once the coordinated assessment pr ocedure (per MDR Article 78) is up and running, the coordinatin g Member State should be indicated here. 10.1.10 No. of investigational devices used to date total Indicate the total number of investigational devices which have been used (per date of report) in the clinical investigation g lobally. 10.1.11 No. of investigational devic es used to date per country List all countries where the clinical investigation has been au thorised by date of report and indicate the number of investiga tional devices which have been used in the clinical investigation (per date of repor t) in each country. 10.1.12 Date of report Indicate the date when the report is compiled for transmission to NCAs. Format DD/MM/YYYY. 11 Use ISO-3166-1 alpha-2 codes, i.e.two-letter country codes as defined in ISO 3166-1 Page 13 of 16 10.2 Completion guidelines: Event details Each unique reportable event is presented in a separate line. U pdates to a previously reported event should be made by changin g the information in the same line, and clearly identified according to the princ iples described below. Any new information added in the form should be highlighted in bold and/or colour. This includes any new lines added and any c hanges made to the information in an already existing line. In the initial report, in any given line, no fields shall be le ft intentionally blank. To meet this requirement, preliminary i nformation should be filled in, despite the need of further updating. 10.2.1 Status The sponsor shall identify the new/updated information in the s tatus column as: A = added = new reportable event; M = modified = new finding/update to an already reported event; U = unchanged. 10.2.2 Date Sponsor received report of SAE/DD Indicate the date when the sponsor was first notified by the in vestigation site about the event. This date is checked for comp liance with reporting timelines as outlined in section 8 Reporting timelines . Format DD/MM/YYYY. 10.2.3 Country code Indicate the country code 11 for the country in which the subject associated with the event has been enrolled. 10.2.4 Investigation site Name identifying institution or site where the clinical investi gation is carried out. 10.2.5 Subject ID code The study specific subject ID code, i.e. the link between study data and the actual subject identity (which is not to be provi ded in this form). 10.2.6 SAE ID code The investigator, sponsor or manufacturer should assign a uniqu e ID to each SAE that has occurred, This number shall remain un changed throughout all other alterations of the particular SAE-reportin g due to ongoing assessment. 10.2.7 Date of procedure/First use Indicate the date of the relevant procedure or the date when th e subject was exposed to the dev ice for first use. Format DD/MM /YYYY. 10.2.8 Date of event onset The date when the first signs of an event were noticed may be d ifferent (earlier) than the date when the event fulfilled the s eriousness criteria (see further the definition in section 3.3 Serious Adverse Even t (SAE)). The date when the event became an SAE should be repor ted as Date of event onset. In case of Device Deficiencies which did not lead to an SAE, the date the DD was discovered should be indicated. Format DD/MM/YYYY. 10.2.9 SAE or DD Choose one option from SAE(Seriou s Adverse Event) or DD (Device Deficiency). Do not add other options. Page 14 of 16 10.2.10 Age The subject’s age at date of event onset should be indicated. In cases where exact date of birth is not available as a basis for age calculation, it is acknowledged that an approximate age at date of event onset could be calculated based on the age at enrollment. Normally the Age should be indicated in Years, although for pae diatric/neonatal populations it may be more relevant to indicat ed age in months, weeks or days. When a different unit than years is used, the un it should be indicated as appropriate. 10.2.11 Patient gender Choose one option from the following list (do not add other opt ions):  Female  Male  Other  Unknown 10.2.12 Location of device For this field, it is the location of the device at the time th e report is submitted to NCA is of interest (i.e not at the tim e of investigator or sponsor awareness of the event). Changed location of the device is in i tself not a reason to provide an updated report. However, whene ver an update/final report is provided for other reasons, it is relevant to update this field if the device for example has reached the sponsor by then. Choose one option from the following list (do not add other opt ions):  Investigational/study site  Sponsor  Subject  Manufacturer  Remains implanted  Discarded  Unknown  Other 10.2.13 Classification of event Choose one option from the following list of consequence charac teristics (do not add other options):  Death  Life-threatening illness or injury  Permanent impairment/ Chronic disease  Hospitalization  Medical or surgical intervention  Foetal distress, fœtal death or congenital physical or mental o r birth defect  Not applicable (Note that this option is only to be selected in case of reportable Device deficiencies that did not lead to an SAE) Page 15 of 16 It is acknowledged that for a specific event two or more option s may be equally applicable, e.g. ” Hospitalization” and “medica l intervention”. The highest-ranking classification should be indicated, using the f ollowing ranking order: 1) Death , 2) life threatening, 3) foeta l distress, 4) permanent impairment, 5) Medical or surgic al intervention 6) hospitalizat ion. 10.2.14 Description of event Provide a description of the event in free text. Below is a non -exhaustive list of items that could be relevant to cover:  Nature of the observed symptoms  Duration and severity of the symptoms  Date of onset of first signs of the event (before it became a S AE)  Medical background of the patient  Medical care of the patient  Comments on the event in relation to already known safety data Use of standardised terminology corresponding to relevant IMDRF codes is encouraged. 10.2.15 Action/treatment /outcome Provide information in free text on actions taken, treatment(s) administered and the outcome. 10.2.16 Relationship to procedure Choose one option from the foll owing list of causality levels ( for explanatory texts see sect ion 9 Causality assessment):  Not related  Possible  Probable  Causal Please report the assessments by sponsor and investigator in th e respective columns. 10.2.17 Relationship to device Choose one option from the foll owing list of causality levels ( for explanatory texts see sect ion 9 Causality assessment)  Not related  Possible  Probable  Causal Please report the assessments by sponsor and investigator in th e respective columns. 10.2.18 Unanticipated SADE Choose option Yes or No An Unanticipated Serious Adverse Device Effect12 is an effect which by its nature, incidence, severity or outco me has not been identified in the current risk assessment. Procedure s associated with the use of a device should be addressed in the risk assessment, which make s it possible to 12 An adverse device effect is an adverse event related to the us e of an investigational device. A serious adverse device effect is an adverse device effect that has resulted in any of the consequence characteristics of a serious adverse eve nt. Page 16 of 16 determine whether the procedure related SAEs are Unanticipated Serious Adverse Device Effect or not. SAEs related to procedure s imposed by the clinical investigation plan but not with the use of the dev ice should not be considered Serious Adverse Device Effects. 10.2.19 Investigation arm Choose one option from the following list:  Test group  Comparison group  Blinded  Not applicable Note: For some study designs it might be more relevant to add n ame of device; i.e. in a clinical investigation with several te st groups it might be useful to differentiate which investigational device that the s ubject has been exposed to. 10.2.20 Event status Choose one option from the following list (do not add other opt ions):  Resolved  Resolved with Sequelae  Ongoing  Death 10.2.21 Date of event resolution Add date in format DD/MM/YYYY. If event status is “Ongoing” ent er Not Applicable. 11 References 1. R e g u l a t i o n ( E U ) 2 0 1 7 / 7 4 5 o f t h e E u r o p e a n P a r l i a m e n t a n d o f t h e council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC No 178/2002 and Regulation (EC) No 1 223/2009 and repealing Council Directives 90/385/EEC and 93/42/ EEC. 2. Council Directive 90/385/EEC of 20 June 1990 on the approximati on of the laws of the Member States relating to active implantable medical devices, last amended by Directive 2007/47/EC. 3. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, last amended by Directive 2007/47/EC. 4. Codes for the representation of names of countries and their su bdivisions – Part 1: Country codes (ISO 3166-1) published by In ternational Organisation for Standardization (ISO). 12 Appendix – Clinical Investigation Sum mary Safety Reporting Form

08 MDCG 2020-8 Guidance on PMCF Evaluation Report Template.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-8 1 MDCG 2020-8 Post-market clinical follow-up (PMCF) Evaluation Report Template A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-8 2 Post-market clinical follow-up (PMCF) Evaluation Report Template A guide for manufacturers and notified bodies Medical Device Medical Device Coordination Group Document MDCG 2020-8 3 Contents Introduction ........................................................................................................................................................................................................................................... 4 Post-market clinical follow-up evaluation report Template ............................................................................................................................................................ 4 Section A. Manufacturer contact details ....................................................................................................................................................................................... 5 Section B. Medical Device description and specification .......................................................................................................................................................... 5 Section C. Activities undertaken related to PMCF: results ..................................................................................................................................................... 7 Section D. Evaluation of clinical data relating to equivalent or similar devices .................................................................................................................... 7 Section E. Impact of the results on the technical documentation ............................................................................................................................................ 7 Section F. Reference to any common specification(s), harmonized standard(s) or guidance document(s) applied ...................................................... 9 Section G. Conclusions .................................................................................................................................................................................................................. 9 Medical Device Medical Device Coordination Group Document MDCG 2020-8 4 Introduction The Medical Device Regulation (EU) 2017/745 (MDR) considers the post-market clinical follow-up (PMCF) as a continuous process that updates the clinical evaluation and that shall be addressed in the manufacturer’s post-market surveillance plan. The MDR reinforces the PMCF process by the manufacturer, devoting part B of Annex XIV to it and providing a set of requirements for developing a PMCF plan and its evaluation report, necessary to its implementation. The manufacturer shall analyse the findings coming from the activities foreseen in the PMCF plan and document the results in this PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation. The conclusions of the PMCF evaluation report shall be taken into account to update eventually the clinical evaluation, the risk management documentation, the post market surveillance plan and the SSCP, if applicable. The purpose of the present templates is to guide manufacturers in complying with the requirements of the MDR with respect to the compilation of the PMCF evaluation report. This would assist manufacturers in a harmonised and complete presentation of post market clinical data and facilitate the activity of notified bodies and competent authorities in finding the information in an organized format. Post-market clinical follow-up evaluation report Template Post-market clinical follow- up (PMCF) plan corresponding to the present evaluation report PMCF plan number and version: Post-market clinical follow- up (PMCF) Evaluation Report PMCF report number: PMCF report date: PMCF report version: Revision history Rev Revision date Description of change Revised by Medical Device Medical Device Coordination Group Document MDCG 2020-8 5 Section A. Manufacturer contact details Legal manufacturer name: Address: SRN: Person responsible for regulatory compliance: E-mail: Phone: Fax: Authorised representative (if applicable): Address: Contact person: E-mail: Phone: Fax: Section B. Medical Device description and specification Refer to section B from PMCF plan, if there are no changes. If there are changes from PMCF plan, please fill in the different requested fields highlighting those changes. Product or trade name: Model and type: General description of the device: Medical Device Medical Device Coordination Group Document MDCG 2020-8 6 Intended purpose1 Intended users Basic UDI-DI: Intended patient population: Medical condition(s)2: Indications: Contraindications: Warnings: List and description of any variants and/or configurations covered by this plan: List of any accessories covered by this plan: Certificate number (if available): CND code(s)3: Class: Classification rule: Expected lifetime4 Novel product ☐ yes ☐ no Novel related clinical procedure: ☐ yes ☐ no Explanation of any novel features: 1 Intended purpose means the use for which a device is intended according to the data supplied by the manufacturer on the label in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (MDR, Article 2(12)). 2 It refers to the clinical condition that is to be diagnosed, prevented, monitored, treated, alleviated, compensated for, replaced, modified or controlled by the medical device. 4 The expected lifetime is to be defined during the design input phase by considering the current state of the art for a specific intended use and indication of a device. Medical Device Medical Device Coordination Group Document MDCG 2020-8 7 Section C. Activities undertaken related to PMCF: results In this section the manufacturer shall report all the activities described in section C of the PMCF plan which have been performed, all the collected clinical data obtained from those completed activities, as well as any justification of deviations from the plan. The discussion shall include the analysis of the findings, whether positive or negative and also the potential impact on the different documents (clinical evaluation report, risk management file, SSCP, etc…) initially reviewed during the conformity assessment. It is expected for each activity performed, a description in different subsections, related to the type of activities (device registry, PMCF studies, real world evidence, surveys about the use of device, etc…), and for each subsection, a description about the quality of data collected.5 Section D. Evaluation of clinical data relating to equivalent or similar devices In this section the manufacturer shall report all the clinical data collected relating to an equivalent device or selected similar device(s), provide an analysis and conclusions, and whether changes of the state of the art, or newly identified hazards would have an impact on the devices benefit-risk determination, the clinical evaluation and/or the PMCF plan. Product name of equivalent / similar device Results discussed References used to get the results (publications, part of technical documentation from this equivalent / similar device) Section E. Impact of the results on the technical documentation 5 For the analysis and assessment of the clinical data collected, some parts of section 9.3.1 from Meddev 2.7/1 rev.4 could be used to assess the quality of data. Medical Device Medical Device Coordination Group Document MDCG 2020-8 8 In this section, the manufacturer shall discuss the aggregate results coming from each PMCF activity planned and performed, described in section C, but also results coming from equivalent and/or similar device, described in section D, which are considered to impact the technical documentation and at least the following documents shall be considered: 1. Clinical evaluation report - CER (date and version) ☐ No relevant information from the clinical evaluation report have been considered. If applicable, it is expected from manufacturer to describe why some information that might have an impact on the CER have not been considered. Relevant information analyzed and monitored: - - Analysis of the outcome is to be reported in the updated clinical evaluation report. 2. Risk management file (date and version) ☐ No relevant information from the risk management file have been considered If applicable, it is expected from manufacturer to describe why some information that might have an impact on the risk management file have not been considered. Relevant information analyzed and monitored: - - - Medical Device Medical Device Coordination Group Document MDCG 2020-8 9 Analysis outcome to be reported in the risk management file updated: - - Section F. Reference to any common specification(s), harmonized standard(s) or guidance document(s) applied In this section the manufacturer should point out whether the collected clinical data related the device in question still confirm adherence to applied common specifications and/or applied harmonized standards, and/or guidances listed in the PMCF plan. Common Specification(s) applied (Title, date and version) Harmonised standard(s) applied (Title, date and version) Guidance(s) followed (Title, date and version ) Section G. Conclusions In this section, it is expected that the manufacturer shall provide an overall conclusion of the findings and relate them to the aims of the PMCF plan. The conclusions shall be taken into account in the following clinical evaluation and in the risk management. Finally, this conclusion shall highlight if any need for preventive and/or corrective measures has been identified. The conclusion may also give input to the next PMCF plan. Medical Device Medical Device Coordination Group Document MDCG 2020-8 10

07 MDCG 2020-7 Guidance on PMCF Plan Template.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-7 1 MDCG 2020-7 Post-market clinical follow-up (PMCF) Plan Template A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-7 2 Post-market clinical follow-up (PMCF) Plan Template A guide for manufacturers and notified bodies Medical Device Medical Device Coordination Group Document MDCG 2020-7 3 Contents Introduction ........................................................................................................................................................................................................................................... 4 Post-market clinical follow-up plan Template .................................................................................................................................................................................. 5 Section A. Manufacturer contact details ....................................................................................................................................................................................... 5 Section B. Medical Device description and specification .......................................................................................................................................................... 6 Section C. Activities related to PMCF: general and specific methods and procedures ........................................................................................................ 7 Section D. Reference to the relevant parts of the technical documentation .......................................................................................................................... 9 Section E. Evaluation of clinical data relating to equivalent or similar devices .................................................................................................................... 10 Section F. Reference to any applicable common specification(s), harmonized standard(s) or applicable guidance document(s) ............................. 11 Section G. – Estimated date of the PMCF evaluation report .................................................................................................................................................. 12 Medical Device Medical Device Coordination Group Document MDCG 2020-7 4 Introduction The Medical Device Regulation (EU) 2017/745 (MDR) considers the post-market clinical follow-up (PMCF) as a continuous process that updates the clinical evaluation and that shall be addressed in the manufacturer’s post-market surveillance (PMS) plan. The MDR reinforces the PMCF process by the manufacturer, devoting part B of Annex XIV to it and providing a set of requirements for developing a plan, necessary to implement PMCF. A PMCF plan shall specify the methods and procedures set up by the manufacturer, to proactively collect and evaluate clinical data from the use in or on humans of a CE marked medical device, placed on the market or put into service within its intended purpose, as referred to in the relevant conformity assessment procedure. The aim of the PMCF plan is:  confirming the safety1 and performance, including the clinical benefit if applicable, of the device throughout its expected lifetime;  identifying previously unknown side-effects and monitor the identified side-effects and contraindications;  identifying and analysing emergent risks on the basis of factual evidence;  ensuring the continued acceptability of the benefit-risk ratio, referred to in Section 1 and 9 of Annex I in the MDR;  identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct. The PMCF plan shall be part of the post-market surveillance plan. The findings of the PMCF shall be analysed by the manufacturer who shall document the results in a PMCF evaluation report. The PMCF evaluation report shall be part of the clinical evaluation report and the technical documentation. The adequateness of the PMCF plan and its application is subject to assessment by the notified body. The notified body’s assessment of the clinical evaluation shall also cover the manufacturer’s procedures and documentation of the PMCF, as well as the justification in relation to non-performance of PMCF. The purpose of the present template is to guide manufacturers in complying with the requirements of the MDR with respect to the compilation of the PMCF plan. This would assist manufacturers in a harmonised and complete presentation of post market clinical data and facilitate the activity of notified bodies and competent authorities in finding the information in an organised format. 1 The confirmation of the safety includes the acceptability of identified risks and particularly residual risks. Medical Device Medical Device Coordination Group Document MDCG 2020-7 5 Post-market clinical follow-up plan Template PMCF plan number: PMCF plan date: PMCF plan version: Revision history Rev Revision date Description of change Revised by Section A. Manufacturer contact details Legal manufacturer name: Address: SRN: Person responsible for regulatory compliance: E-mail: Phone: Fax: Authorised representative (if applicable): Address: Contact person: E-mail: Phone: Fax: Medical Device Medical Device Coordination Group Document MDCG 2020-7 6 Section B2. Medical Device description and specification Product or trade name: Model and type: General description of the device: Intended purpose3: Intended users Basic UDI-DI: Intended patient population: Medical condition(s)4: Indications: Contraindications: Warnings: List and description of any variants and/or configurations covered by this plan: List of any accessories covered by this plan: Certificate number (if available): CND code(s)5: Class: Classification rule: 2 MDR, Annex II, 1,1. 3 Intended purpose means the use for which a device is intended according to the data supplied by the manufacturer on the label in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (MDR, Article 2(12)). 4 It refers to the clinical condition that is to be diagnosed, prevented, monitored, treated, alleviated, compensated for, replaced, modified or controlled by the medical device 5 Per article 26 of MDR. Medical Device Medical Device Coordination Group Document MDCG 2020-7 7 Expected lifetime:6 Novel product: ☐ yes ☐ no Novel related clinical procedure: ☐ yes ☐ no Explanation of any novel features: Section C. Activities related to PMCF: general and specific methods and procedures In this section it is expected to describe the different activities that will be conducted in post-market, including general and specific methods / procedures to conduct in relation to the product covered by the scope of PMCF, also the aim of each activity described and the rational for the appropriateness of the chosen general and specific methods to achieve those objectives as well as the known limitations of the planned activities such as for example incomplete follow up, missing data and so on. The timelines of those activities shall be also defined quarterly or at least yearly. Here are some examples of different activities related to PMCF:  A manufacturer device registry (specific for the type of device or the group of the medical devices the product belongs to) can be indicated together with a description and a summary of the plan. A pre-specification of what quality and quantity data – based on the risk of the device(s) and the associated accessories – to be collected and analysed shall be included. Any possible evaluation of suitable national public registries with clinical data on the manufacturer’s own device and/or on similar devices could be specified in this section, identifying the expected quantity and quality of data to be gathered and the search protocols to be adopted.  PMCF studies planned could be indicated in this section, together with a summary of the plan including the design, sample size, the endpoints, the inclusion/exclusion criteria (e.g. extended follow up of patients included in the pre-market clinical investigations, new clinical investigations within the intended use, retrospective studies). In case of implantable devices and class III devices where clinical investigations have not been performed pursuant to Article 61 (4), the PMCF plan shall include post market studies to confirm the safety and performance of the device.  Planned Real-world evidence (RWE) analyses could be indicated in this section, together with a summary of the plan including the design, sample size, the endpoints, and analysis population. The real-world data (RWD) from which these analyses are based on should be of sufficient quality and come from reliable data sources.  Surveys planned to collect information about the use of the concerned medical device could be described. Each activity will be developed in a different subsection (e.g. C.1, C.2, …), and for which the manufacturer will: 6 The expected lifetime is to be defined during the design input phase by considering the current state of the art for a specific intended use and indication of a device. Medical Device Medical Device Coordination Group Document MDCG 2020-7 8  Define where the need of conducting the PMCF activity is coming from (requested by notified body, clinical evaluation report, PMS, risk management report, previous PMCF report, etc…)  Provide the description of activity, and if it is a general or specific procedure / method.  Define the aim of this activity: o confirming the safety of the medical device o confirming the performance of the medical device o identifying previously unknown side-effects (related to the procedures or to the medical devices). o monitoring the identified side-effects and contraindications o identifying and analysing emergent risks o ensuring the continued acceptability of the benefit-risk ratio o identifying possible systematic misuse or off-label use of the device  Describe the different procedures which will be used as part of PMCF: o screening of scientific literature and other sources of clinical data o post-market studies o collecting data in registries o survey from health care professional o survey from patients/users o review of case reports which may reveal misuse or off-label use  Describe the rationale for the appropriateness of the chosen methods/procedures, including: o the justification for sample size, timescales and endpoints o justification for comparator, on the basis of intended purpose and state of the art o justification of the study design on the basis of all of the above, and why it is sufficient to ensure representative patient populations and provide for adequate controls on sources of bias (an evaluation of the potential sources of bias should form part of this) o a statistical justification for the expected quality of outcomes, and justification for why this is satisfactory in light of the residual risks. This is an important consideration. For example, retrospective surveys with no justification other than “this should demonstrate the expected quality of evidence that we require,” but without showing a statistical rationale, are not acceptable.  Provide the timelines of the activity. A detailed and adequately justified time schedule for PMCF activities, such as the analysis of PMCF data and reporting, shall be described. Medical Device Medical Device Coordination Group Document MDCG 2020-7 9 A summary table of the different PMCF activities foreseen by the manufacturer is provided below: Number of activity Description of activity Aim of the activity Rationale and known limitations of the activity Timelines of the activity Section D. Reference to the relevant parts of the technical documentation In this section the manufacturer is required to include references to the relevant information from the clinical evaluation report and from the risk management file, which need to be analysed, followed up, and evaluated in this plan. As an alternative, the manufacturer is required to state that there is no relevant information from the clinical evaluation report and/or from the risk management file to be considered in this plan. Clinical Evaluation Report (date and version) Relevant information to be further analysed and monitored: - - - Risk Management File (date and version) Relevant information to be further analysed and monitored: Medical Device Medical Device Coordination Group Document MDCG 2020-7 10 - - - ☐ No relevant information from the clinical evaluation report to be considered in this plan ☐ No relevant information from the risk management file to be considered in this plan Section E. Evaluation of clinical data relating to equivalent or similar7 devices The manufacturer shall gather in this section information regarding equivalent / similar devices for which clinical data will be further evaluated and presented in the PMCF report. Please note that PMCF data intended to demonstrate continuing safety and performance should be sourced from the device under evaluation. Data from equivalent or similar devices may be used, for example to update the information relating to the state of the art, to identify and further assess relevant safety outcomes etc. The selected devices shall be consistent throughout the technical documentation. Indicate whether the selected device is demonstrated to be equivalent or is a similar device. For each device listed, a clear reference to the pertinent parts of the CER can be made. The following items of each equivalent and/or similar devices would be at least provided, in a table format: 7 Section 5, MDCG 2020-5 Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies. Medical Device Medical Device Coordination Group Document MDCG 2020-7 11 Product name of equivalent / similar device Intended purpose Intended users Intended patient population Medical condition Indication Reference to clinical data evaluation in the CER ( date, version and location in the text) Section F. Reference to any applicable common specification(s), harmonized standard(s) or applicable guidance document(s) Common specification(s) to comply with, if applicable: (Title, date and version) Harmonised standards to apply, if applicable (Title, date and version) Guidance on PMCF, if applicable Medical Device Medical Device Coordination Group Document MDCG 2020-7 12 (Title, date and version) Section G. – Estimated date of the PMCF evaluation report When the manufacturer plans to have the first report. The timelines shall be defined quarterly or at least yearly.

06 MDCG 2020-6 Guidance on Sufficient Clinical Evidence for Legacy Devices.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-6 MDCG 2020-6 Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 2 of 22 Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC A guide for manufacturers and notified bodies Page 3 of 22 Table of contents 1. Definitions ...................................................................................................................................................... 4 1.1. Terms defined in MDR Article 2 .................................................................................. 4 1.2. Additional terms not defined in MDR Article 2 ............................................................ 4 2. Reference documents ............................................................................................................................... 6 3. Scope ................................................................................................................................................................ 6 4. Introduction and context ......................................................................................................................... 7 5. General aspects ............................................................................................................................................ 8 6. Guidance on specific aspects of clinical evaluation for legacy devices ........................... 10 6.1. Annex XIV Part A Section 1a: Establish or update a clinical evaluation plan .............. 10 6.2. Annex XIV Part A Section 1b: Identify available clinical data .................................... 11 6.2.1. Pre-market sources of clinical data ...................................................................... 12 6.2.2. Post-market sources of clinical data ..................................................................... 12 6.3. Annex XIV Part A Section 1c: Appraisal of the clinical data ...................................... 12 6.4. Annex XIV Part A Section 1d: Generation of new clinical data .................................. 13 6.5. Annex XIV Part A Section 1e: Analysis of the clinical data ........................................ 14 Appendix I - Sections of MEDDEV 2.7/1 rev. 4 which are still relevant under the MDR for the application of this guidance ................................................................................................................. 18 Appendix II – Clinical Evaluation Plan for Legacy Devices .............................................................. 19 Appendix III – Suggested hierarchy of clinical evidence for confirmation of conformity with relevant GSPRs under the MDR ........................................................................................................ 20 Page 4 of 22 This guidance document is not legally binding. It has been put together following contribution from national competent authorities, industry and relevant stakeholders and it should therefore be recognised as best practice. It also intends to support a harmonised approach with respect to clinical data providing sufficient clinical evidence necessary to demonstrate conformity with the relevant General Safety and Performance Requirements (GSPR) across European Union Member States. 1. Definitions 1.1. Terms defined in MDR Article 2 The following terms are used as defined in the Medical Device Regulation (EU) 2017/745 (MDR):  ‘performance’;1  ‘risk’;2  ‘intended purpose’3  ‘benefit-risk determination’;4  ‘clinical evaluation’;5  ‘clinical investigation’;6  ‘clinical data’;7  ‘clinical evidence’;8  ‘clinical performance’;9 It should be noted that clinical performance may arise from either ‘direct or indirect medical effects’ ‘leading to a clinical benefit for patients’; see comments for relevance to clinical benefit below  ‘clinical benefit’.10 It should be noted that clinical benefits may be either direct or indirect; for example devices such as guidewires may assist other medical devices in achieving their intended purpose, without having a direct therapeutic or diagnostic function themselves.  ‘generic device group’.11 1.2. Additional terms not defined in MDR Article 2 Additional terms which are not explicitly defined in Article 2 of the MDR, but which are essential to evaluation of benefit-risk and clinical evaluation conclusions: 1 MDR, Article 2(22). 2 MDR, Article 2(23). 3 MDR, Article 2(12). 4 MDR, Article 2(24). 5 MDR, Article 2(44). 6 MDR, Article 2(45). 7 MDR, Article 2(48). 8 MDR, Article 2(51). 9 MDR, Article 2(52). 10 MDR, Article 2(53). 11 MDR, Article 2(7). Page 5 of 22  ‘legacy devices’: this is considered to include all devices previously CE marked under the European Medical Devices Directive 93/42/EEC (MDD) or Active Implantable Medical Devices Directive 90/385/EEC (AIMDD)  ‘well-established technology’: this terminology is used in Article 52(5) and Article 61(8) of the MDR, but is not defined in these articles. The term is not restricted to the devices listed in Article 61(6b); Article 61(8) explicitly states that this includes devices similar to the exempted devices listed in Article 61(6b), which might be added to that list in future. The common features of the devices which are well- established technologies are that they all have: o relatively simple, common and stable designs with little evolution; o their generic device group has well-known safety and has not been associated with safety issues in the past; o well-known clinical performance characteristics and their generic device group are standard of care devices where there is little evolution in indications and the state of the art; o a long history on the market. Therefore, any devices that meet all these criteria may be considered “well- established technologies”.  ‘scientific validity’, ‘scientifically valid’: this terminology is used in the MDR in reference to clinical data planning, evaluation and conclusions12. Clinical evaluations must follow a “defined and methodologically sound procedure”13, for which expectations of scientific validity are implicit. Embedded in the term ‘scientific validity’ are concepts including adequacy of study design and controls for bias, appropriateness and relevance of research questions, adequacy of sample sizes and statistical analyses, completeness of data, adequacy of follow up period, and appropriateness of conclusions on the basis of objective evidence. Section 9.3.1 of MEDDEV 2.7/1 rev. 4 provides guidance for the evaluation of methodological quality and scientific validity under the MDD/AIMDD which are equally valid under the MDR which can be considered to apply when referencing ‘scientific validity’ in this guidance.  ‘level of clinical evidence’: this terminology is used in the MDR with respect to requirements for demonstration of conformity with the relevant GSPR and overall benefit-risk14. It is understood to encompass the amount and quality of evidence (i.e. its characterisation by quality, quantity, completeness and statistical validity, etc.) required to demonstrate safety, performance and the benefit-risk conclusion of a medical device. It should not be confused with the term ‘levels of evidence’ (as used in evidence-based medicine) which is used to rank study designs, and is only a part of the concept ‘level of clinical evidence’. Regarding the assessment of the level of clinical evidence for the device in question, see sections 6.3 and 6.5d of this document.  ‘state of the art’: IMDRF/GRRP WG/N47 provides the following definition: Developed stage of current technical capability and/or accepted clinical practice in regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience. 12 MDR Annex XV, Chapter I, Article 2(2.1) and (2.6). 13 MDR Article 61(3). 14 MDR Article 61(1), Annex IX section 5.1. Page 6 of 22 Note: The state-of-the-art embodies what is currently and generally accepted as good practice in technology and medicine. The state-of-the-art does not necessarily imply the most technologically advanced solution. The state-of-the-art described here is sometimes referred to as the “generally acknowledged state-of- the-art  ‘intended use’: The MDR defines ‘intended purpose’, but not ‘intended use’. ‘intended use’ should be considered to have the same meaning as ‘intended purpose’.  ‘indication’, ‘indication for use’: refers to the clinical condition that is to be diagnosed, prevented, monitored, treated, alleviated, compensated for, replaced, modified or controlled by the medical device. It should be distinguished from ‘intended purpose/intended use’, which describes the effect of a device. All devices have an intended purpose/intended use, but not all devices have an indication (e.g. medical devices with an intended purpose of disinfection or sterilisation of devices).  ‘similar device’: devices belonging to the same generic device group. The MDR defines this as a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics15. 2. Reference documents This document provides facilitative guidance to the requirements of MDR Chapter VI and Annex XIV, and references the following MDD/AIMDD guidance documents:  MEDDEV 2.7/1 rev. 4: Clinical Evaluation: A Guide for Manufacturers and Notified Bodies under Directives 93/42/EEC and 90/385/EEC  MEDDEV 2.12/2 rev 2: Post Market Clinical Follow-Up Studies: A Guide for Manufacturers and Notified Bodies 3. Scope This document seeks to provide guidance for clinical data providing sufficient clinical evidence necessary to demonstrate conformity with the relevant GSPR, as per Article 61(1) MDR, for legacy devices CE marked with respect to Directives 93/42/EEC (MDD) or 90/385/EEC (AIMDD). This document aims to provide guidance for manufacturers and notified bodies to prepare for the conformity assessment procedure according to the MDR. This document does not provide comprehensive guidance with respect to the process or methodology relating to clinical evaluation. It is general and not restricted to any particular device technology or risk class. Following on from the principles described in Section 3 however, special attention is given to those described in Article 61(6). 15 MDR, Article 2(7). Page 7 of 22 4. Introduction and context This section is intended to provide an introduction and context, and not to modify the interpretation of the MDR. MDR Article 61(1) states: Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III. The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV. MDR Article 61(4) states that clinical investigations shall be performed for Class III and implantable devices, but distinct exemptions from this requirement are identified both in this article and in Articles 61(5) and 61(6). The common theme of these exempted devices is that they have been previously marketed (Article 61(6)) or have been demonstrated to be equivalent to devices previously marketed (Article 61(5)). Article 61(6a and b) further distinguishes between legacy devices (Article 61(6a)) which have been previously marketed under 93/42/EEC or 90/385/EEC and a specific subset of well-established technologies (WET) (Article 61(6b)). The following should be noted:  all such exemptions from clinical investigations require that the clinical evaluation is based on “sufficient clinical data”;  the basic clinical evaluation requirements for the legacy devices described in Article 61(6a) and the devices of Article 61(6b) are the same: “sufficient clinical data” and compliance to common specifications where these exist. The distinction between the two is that the devices listed in Article 61(6b) are not explicitly required to have had prior certification under the Directives to be exempted from the requirement for clinical investigations that otherwise apply to Class III and implantable devices;  both the Directives and the MDR require the quantity and quality of clinical data to be sufficient to demonstrate safety, performance and the acceptability of the benefit-risk ratio: both the Directives and the MDR require clinical evidence to be sound and the conclusions derived from this evidence to be scientifically valid. Article 61(10)16 allows for the use of non-clinical data for demonstration of conformity with GSPRs: Without prejudice to paragraph 4,where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed 16 See MDCG guidance on the CEAR template for notes related to use of Article 61(10). Page 8 of 22 appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. Article 61(10) cannot be applied to Class III or implantable devices. In exceptional cases Article 61(10) may be applied for all other device classifications. 5. General aspects “Sufficient clinical evidence” is not defined in the MDR. The definition of “clinical evidence” itself contains the word ”sufficient” but it is related to the amount and quality of the clinical data and the clinical evaluation results which “allow a qualified assessment of whether the device is safe and achieves the intended clinical benefits when used as intended by the manufacturer”.17 Sufficient clinical evidence is also mentioned in the MDR Article 61 where it is provided that the confirmation of conformity with the relevant GSPR shall be based on sufficient clinical evidence. Therefore, “sufficient clinical evidence” is understood as “the present result of the qualified assessment which has reached the conclusion that the device is safe and achieves the intended benefits”. It is important to note that clinical evaluation is a process where this qualified assessment has to be done on a continuous basis. Compared to Directives 93/42/EEC and 90/385/EEC, MDR provides greater detail and additional requirements with respect to the process of clinical evaluation, for the purpose of confirmation of conformity with relevant GSPR. The generation of clinical data and their evaluation providing sufficient clinical evidence is part of a lifecycle approach to medical devices. The MDR reinforces a number of important factors which are relevant to clinical evaluation. This includes:  Consideration of available alternative treatment options is required for the confirmation of the acceptability of the benefit-risk ratio.18  The acceptability of the benefit-risk ratio must be based upon clinical data providing sufficient clinical evidence including where applicable relevant data from post-market surveillance.19  The term “clinical evidence” is introduced and the level of clinical evidence must be specified and justified by the manufacturer, taking the characteristics of the device and the intended purpose into account.20  The incorporation of post market surveillance (PMS) data in particular the post-market clinical follow-up (PMCF) data into the process of clinical evaluation.21 Manufacturers are required to establish a post-market surveillance plan in accordance with Annex III of the MDR and the clinical data arising from this PMS shall be incorporated into the clinical evaluation.  The definition of equivalence is now included in the text of the MDR,22 and the process to demonstrate equivalence is defined23. 17 MDR, Article 2(51). 18 MDR, Article 61(3)(c). 19 MDR, Article 61(1) and Annex III. 20 MDR, Article 61(1). 21 MDR, Article 61(1) and (11). 22 MDR, Annex XIV, Part A, section 3. 23 MDCG 2020-5 Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies. Page 9 of 22  A definition of “clinical data” is provided.24 When it comes to the first MDR conformity assessment of a legacy device the pre-market and post-market clinical data generated for the purpose of MDD/AIMDD can be taken into account. As requirements and guidance developed over time, it is not necessarily the case that the clinical data used for conformity assessment under the Directives is clinical data providing sufficient clinical evidence for the purpose of MDR requirements. Legacy devices which have been placed on the market have been subjected to conformity assessment and therefore are presumed to have been supported by clinical data25. Post- market clinical data together with the clinical data generated for the conformity assessment under the MDD/AIMDD will be the basis of the clinical evaluation process for legacy devices under the MDR. During the period of validity of the MDD/AIMDD certificates, the MDR requirements for the PMS apply from the MDR date of application. Legacy devices are therefore not exempted from the additional requirements in MDR concerning PMS, including PMCF. PMS data and clinical evaluation plans and reports need to be produced and updated. The MDR compliant clinical evaluation for a legacy device must contain the identification of available clinical data as well as their appraisal / analysis / evaluation and shall lead to a demonstration of conformity to the MDR GSPR based on clinical data providing sufficient clinical evidence as part of a lifecycle approach. The European Commission guidance MEDDEV 2.12/2 regarding PMCF studies notes different instances where a PMCF study may have been justified:26  Route chosen for clinical evaluation : where CE marking for legacy devices was based upon equivalence, PMCF studies may have been necessary. The European Commission guidance MEDDEV 2.12/2 regarding PMCF also notes that in the case that clinical evaluation was based exclusively on clinical data from equivalent devices for initial conformity assessment, the certifying notified body shall verify that PMCF studies have been conducted,27 in accordance with the relevant provisions of the Directives.28  Device related factors : There are a number of device-related factors where PMCF studies may have been necessary.29 When assessing the conformity of legacy devices under the MDR, it is important to verify whether PMCF studies considered necessary under the MDD/AIMDD (and where applicable, during the transition period, under the MDR), have been appropriately conducted, and results are taken fully into account for in the clinical evaluation for the conformity assessment under MDR. Guidance on the general process of conducting clinical evaluation is also available in the MEDDEV 2.7/1 rev. 4. This guidance was written with respect to the MDD and AIMDD to provide practical guidance on several scientific and clinical aspects that are relevant for conducting clinical evaluation. However only the text of the MDR is authentic in law, sections relevant to the MDR are listed in Appendix I to this document. 24 MDR, Article 2(48). 25 Except where non-clinical testing were demonstrated to be adequate (MDD, Annex X, 1.1(d); AIMD, Annex 7, 1.5). 26 MEDDEV 2.12/2, section 5 https://ec.europa.eu/growth/sectors/medical-devices/current-directives/guidance_en 27 MEDDEV 2.12/2, section 8. 28 Annex II.4, Annex II.7, Annex III, Annex V.6 and Annex VI.6 of Directive 93/42/EEC and Annex II.4, Annex II.7, Annex III and Annex V.6 of Directive 90/385/EEC. 29 MEDDEV 2.12/2, section 5. Page 10 of 22 6. Guidance on specific aspects of clinical evaluation for legacy devices Sections 6.1 – 6.5 below provide guidance on each stage of the clinical evaluation process of MDR Annex XIV Part A Section 1. 6.1. Annex XIV Part A Section 1a: Establish or update a clinical evaluation plan30 Manufacturers are required to document a clinical evaluation plan to meet the requirements of MDR Annex XIV Section 1a. Premarket elements of the plan as described in the final indent of MDR Annex XIV Section 1a (first-in-man studies, feasibility and pilot studies) are not generally relevant to legacy devices which are unchanged in design or indications. However, the context for the plan as described in indents 1-7 and the basis for the PMCF as described in indent 8 of MDR Annex XIV Section 1a are considered relevant and necessary for demonstration of compliance to the MDR. Appendix II of this guidance document suggests a minimum content for clinical evaluation plans for legacy devices. Further advice regarding specific sub-indents of MDR Annex XIV Section 1a are provided below. a. Identification of the relevant GSPRs (indent 1 of MDR Annex XIV Section 1a): clinical evaluation planning under the Directives required an identification of the relevant Essential Requirements (ER) for which demonstration of conformity required clinical data. The manufacturer should conduct an analysis with respect to the GSPRs of the MDR, to determine if additional data to support the clinical evidence are required to meet additional MDR requirements. This could be achieved either through a gap analysis with respect to new MDR requirements, or by creation of an entirely new analysis for the MDR. As noted in Section 3, Article 61(10) cannot be applied to Class III or implantable devices, but may be applied to some or all requirements for confirmation of conformity with relevant GSPRs for all other device classifications if adequately justified. b. Specification of the intended purpose, target groups, indications, contraindications (indents 2-3 of MDR Annex XIV Section 1a): Appendix A3 of MEDDEV 2.7/1 rev. 4 lists additional information to Annex II of the MDR about device description that can be relevant for planning clinical evaluations. The manufacturer needs to ensure that inputs for the clinical evaluation plan are in line with the device’s “label, instructions for use, promotional or sales materials or statements”31 and with the device’s updated risk management documents. c. Detailed description of intended clinical benefits with relevant and specified clinical outcome parameters (indent 4 of MDR Annex XIV Section 1a): MEDDEV 2.7/1 rev. 4 Appendix A7.2 Section b provides relevant additional information with respect to the definition of clinical benefits. MEDDEV 2.7/1 rev. 4 Appendix A7.2 Section c provides relevant information with respect to the quantification of benefits and determination of relevant outcome parameters, which may be useful for clinical evaluation planning. d. Specification of qualitative and quantitative aspects of clinical safety and performance (indents 5-7 of MDR Annex XIV Section 1a): The level of clinical evidence required for the device under evaluation needs to be determined by the manufacturer and verified by the notified body. The level of clinical evidence shall 30 MDR, Annex XIV, Part A, section 1. 31 MDR, Article 2 (12). Page 11 of 22 be appropriate in view of the characteristics of the device and its intended purpose.32 The proposed level of clinical evidence should take into account the specification of methods to be used for examination of qualitative and quantitative aspects of clinical performance and clinical safety with clear reference to the determination of residual risks and side-effects. MEDDEV 2.7/1 rev. 4 appendix A6 describes examples of studies that lack scientific validity for the demonstration of adequate clinical performance and/or clinical safety. MEDDEV 2.7/1 rev. 4 section 9.3.2 also provides relevant guidance. It also has to take into account the intended clinical benefits to patients with relevant and specified clinical outcome parameters as well as an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device.33 For medical devices which have been subject to conformity assessment according to Directives, it should be possible to provide a clear justification for the level of clinical evidence required to reach a demonstration of conformity based on clinical data providing sufficient clinical evidence at the end of the data analysis stage. Manufacturers should identify benefits and risks of the device under evaluation, take into account available alternative treatment options and a clinical assessment of residual risks associated with the device before justifying the level of clinical evidence. As an outcome of this step, it should be possible to conclude if the device is one which has a clearly positive benefit–risk determination, when alternatives are considered, or a marginal one. Special attention is required, with respect to devices with a marginal benefit-risk, at both the stage of initial conformity assessment and when designing the post-market surveillance or clinical follow-up of the device. According to the MDR, parameters to be used to “ determine…. the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device” need to be based on the state of the art in medicine.34 Section 8.2. of MEDDEV 2.7/1 rev. 4 indicates how data on the current state of the art in medicine can be identified. 6.2. Annex XIV Part A Section 1b: Identify available clinical data35 It is important to identify all available sources of clinical data from both the pre-market and post-market phases. This will include all of the clinical data which is generated and held by the manufacturer as well as clinical data for equivalent or similar devices36. Clinical data is defined in the MDR and the sources of data are specified in Article 2(48). Sections 6.2.1 and 6.2.3 below provide additional guidance with respect to the use of these data sources for legacy devices. It should be noted that, apart from devices for which Article 61(10) may be applied, the MDR requires confirmation of conformity with the relevant GSPRs to be based on clinical data as defined in Article 2(48). However, other types of data may provide supportive or clarifying information: this may include data derived through evaluation of state of the art, 32 MDR, Article 61(1). 33 MDR, Annex XIV, Part A, section 1 (a) 5th indent. 34 MDR, Annex XIV, Part A, section 1. 35 Guidance with respect to identification of clinical data is provided in section 8 and Appendix A4 and A5 of MEDDEV 2.7/1 rev. 4. 36 Section 5, MDCG 2020-05 Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies. Page 12 of 22 evaluation of clinical data for similar devices (as described in Section 1.2 of this document), usability or simulated use testing, etc. A summary of considerations related to use of clinical and non-clinical data sources is provided in Appendix III of this document. 6.2.1. Pre-market sources of clinical data For the purpose of legacy devices, pre-market sources of clinical data may include:  Clinical investigation reports of the device concerned;  Clinical investigation reports or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated in accordance with the MDR;  Reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated;  Other pre-market data, e.g. case reports on experience with the use of the device in question, such as compassionate or humanitarian exceptional use reports. Note that this kind of pre-market data may be more prone to bias, compared to those listed above. It should be noted that MDR Article 2(48) provides a narrower definition of what constitutes clinical data sources as compared to the Directives which allow unpublished reports on other clinical experience to contribute to the clinical evaluation. Such data sources may provide informative context for the clinical evaluation of legacy devices. 6.2.2. Post-market sources of clinical data Post-market sources of clinical data refer to data collected following the initial CE marking under the Directives (or prior to introduction of a new indication or design variant). This may include:  PMS clinical data, complaint and incident reports;  PMCF studies, including post-market clinical investigations;  Independent clinical studies conducted using the device37;  Device registries;  Data retrieved from the literature. For well-established technologies the clinical evaluation can be based on data coming from similar devices, under the conditions detailed in paragraph 6.5 (e). With respect to legacy devices, when clinical data from equivalent devices is used, equivalence must be demonstrated according to the requirements of the MDR.38,39 6.3. Annex XIV Part A Section 1c: Appraisal of the clinical data The clinical data sets should be subject to an appraisal with respect to their relative contribution to the overall clinical evaluation. It is important to perform analysis of the methodological quality of data obtained from different sources to identify and assess the level of evidence, bias, other inherent weakness or other possible shortcomings. Clinical investigations, other sources of clinical data and post-market sources of clinical data can be of variable methodological quality and therefore an appraisal of the design of 37 Including for example devices used during clinical trials of pharmaceutical substances, or accessories to other medical devices, where the device is clearly identified. 38 MDR, Annex XIV and Article 2(48). 39 MDCG 2020-5 Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies. Page 13 of 22 these studies is important. Examples of studies that lack scientific validity for demonstration of adequate clinical performance and / or clinical safety can be found in Appendix A6 General principles of clinical evaluation of MEDDEV 2.7/1 rev. 4. The use of vigilance data, in general is appropriate for identification of any new risks, events in subpopulations, examining trends in PMS reports etc. With respect to the utilisation of post-market surveillance data for the purpose of conformity assessment, it is important to recognise that uncontrolled sources of clinical data – for example complaint or incident report data – cannot always provide reliable data with respect to the incidence of risks and cannot provide an estimate of uncertainty i.e. a confidence interval. Due to limitations of complaints reporting, the use of estimates such as [number of incidents or complaints] / [number of device sales] cannot generally be considered sufficient to provide proof of safety; their use should be limited to cases where data from pre-market or post-market clinical investigations or PMCF studies are not deemed appropriate. Additional information on the use of information derived from vigilance data, device registry data, case series, patient dossiers and other use data can be found in section 9.3.1 (c) of MEDDEV 2.7/1 rev. 4. Clinical data appraisal should be conducted using verified/validated assessment tools. Examples include methodological quality assessment tools developed by medical researchers and scientists to assess published clinical data such as Appendix F of IMDRF MDCE WG/N56 on Clinical Evaluation, Cochrane Collaboration’s tool for Randomized Controlled Trials (RTC), MINORS (Methodological index for non-randomized studies), Reisch tool (for non-randomized interventional studies), Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Their detailed description, the inclusive list of major components of each tool is included in the paper by Zeng X, Zhang Y, Kwong JS et al. “The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review”40. This list is not exhaustive. Additional validated tools may become available in the future. 6.4. Annex XIV Part A Section 1d: Generation of new clinical data Legacy devices following the MEDDEV 2.12/2 guidance for PMCF should normally have collected data on the devices themselves in the post-market phase. In the event that the postmarket data on the device itself (including PMCF) is not adequately comprehensive to provide sufficient clinical evidence, and the demonstration of equivalence is no longer possible under the definition of equivalence in the MDR, new data may need to be generated prior to CE-marking under the MDR. In general, there shall be sufficient clinical evidence to confirm safety, performance and the acceptability of the benefit-risk determination in relation to the state of the art for the legacy devices prior to CE-marking under the MDR, and such demonstration should not rely on new PMCF studies started under the MDR to bridge gaps (e.g. indications not supported by clinical evidence). Where other evidence, for example results of pre-clinical testing etc. as described in MDR Article 61(10), is used for confirmation of safety and performance, PMCF studies may be undertaken to confirm these conclusions. 40 J Evid Based Med. 2015 Feb;8(1):2-10. doi: 10.1111/jebm.12141. Review. https://www.ncbi.nlm.nih.gov/pubmed/25594108 Page 14 of 22 6.5. Annex XIV Part A Section 1e: Analysis of the clinical data The aim of this stage is the determination if all clinical data collected and appraised, as described in previous stages, demonstrate together conformity with relevant GSPR. In order to determine the benefit-risk ratio, it is necessary to identify the benefits and risks associated with the device and the alternatives (if any). Practical guidance is available in section 10 of MEDDEV 2.7/1 rev. 4.41 Demonstration of compliance with the GSPR, relevant for the device in question have to be based on:  The usage of reliable, justified and sound analytical methods (where applicable qualitative, quantitative, or both);  Results of performed comprehensive analysis;  Identification of any missing data and/or gaps;  Determination of PMCF needs. a. Clinical benefits Clinical benefit means “the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health”.42 The type of clinical benefit associated with a device depends upon the device under evaluation and its intended purpose. Examples of clinical benefits and their quantification can be found in Appendix A7.2 letters (b) and (c) of MEDDEV 2.7/1 rev. 4. It should be noted that while direct clinical benefits should be supported by clinical data, indirect clinical benefits may be demonstrable by other evidence such as:  pre-clinical and bench test data (eg compliance to product standards or common specifications);  real world data such as registries, information deriving from insurance database records, etc;  data from another device that is used with the subject device which does have direct clinical data (eg, data from a stent used to justify safety and performance of a guidewire). A determination of the level of clinical evidence required to demonstrate an indirect clinical benefit should be made on the basis of a thorough risk assessment and evaluation of short, medium and long term clinical risks (for example, a guidewire, although used transiently, may have long term clinical risks if it leads to vessel dissection). b. Risks Risk means the combination of the probability of occurrence of harm and the severity of that harm.43 The MDR requires manufacturers to establish, document, implement and maintain a system for risk management.44 The standard ISO 1497145 provides such a process for managing risks associated with medical devices, as part of an ongoing, 41 This chapter includes references to the MDD, MDR requirements should be used instead, ie. reference to ‘Essential requirements’ should be replaced by GSPR and reference to PMCF should be replaced by the relevant MDR requirements, i.e. in Annex XIV, part B. 42 MDR, Article 2(53). 43 MDR, Article 2(23). 44 MDR, Article 10(2). 45 Medical devices — Application of risk management to medical devices. Page 15 of 22 lifecycle approach. The Annex I of the MDR require that manufacturers reduce risks as far as possible, and to do this, manufacturers must estimate and evaluate the risks associated with, and occurring during, the intended use and during reasonably foreseeable misuse.46 The determination as to which risks require the generation of clinical data to support either the probability and severity of a particular harm, or the effectiveness of a risk control measure, is one which must be reached upon a case by case basis,47 and the decision as to when it is necessary to generate further clinical data is not addressed by ISO 14971 and should be an output of the process of clinical evaluation. Considerations on aspects of risk evaluation, and considerations on the number of patients needed to obtain sufficient data can be found in Appendix A7 of MEDDEV 2.7/1 rev. 4. c. Benefit-risk determination, state of the art, alternative treatment options The MDR requires that any risks which may be associated with the use of the device are “compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art”48 and that the determination of the acceptability of the benefit-risk ratio is “ based on the state of the art in medicine ”.49 It is important to remember that a medical device may be used for an indication for which there are many alternative medical options. This may include the use of medicinal products, other medical devices, other medical or allied health professional interventions, a combination of any of these or no intervention. As such, in order to determine a benefit- risk ratio, up-to-date alternatives must be considered for legacy devices. The appropriateness and relevance of an alternative treatment option depends upon a wide range of factors, including the nature of the healthcare system and patient preferences. To help to describe alternatives, it is necessary to describe the ‘state of the art’ for the treatment of the indicated clinical condition taking alternative treatments into account. The state of the art in this context can be taken to mean the generally accepted most effective treatment option, for the intended purpose relevant to the device under consideration. Occasionally, this may be subject to differences of opinion between clinical evaluators as to what is the state of the art, and where such differences exist, these should be described and taken into account insofar as is possible. In such cases, a thorough evaluation of the results from published clinical studies of high methodological quality shall be taken into account. Moreover, where applicable, particular attention shall be paid to therapy guidelines grounded on principles of evidence based medicine. Novel and innovative device technology may be subject to a rapidly evolving state of the art for a particular indication, and where this exists, it should also be noted. Aspects that influence the acceptability of benefits and risks can be found in Appendix A7.2 letter (e) and in Appendix A7.4 of MEDDEV 2.7/1 rev. 4. 46 MDR, Annex I, Chapter 1, section 3(c). 47 ISO14971:2007, page v, notes that an individual’s perception of risk can depend upon a range of factors including their cultural background, the socio-economic and educational background of the society concerned, the actual and perceived state of health of the patient, and many other factors. 48 MDR, Annex I, Chapter 1, Section 1. 49 MDR, Annex XIV, Part A, Section 1(a). Page 16 of 22 d. The level of clinical evidence available to demonstrate conformity based on clinical data providing sufficient clinical evidence The MDR requires that the level of clinical evidence is justified and specified by the manufacturer. The required level of clinical evidence has to be identified, specified and justified by the manufacturer during the clinical evaluation process. This level has to be appropriate to demonstrate conformity with the relevant GSPR. To reach a determination of sufficiency, when considering the available level of clinical evidence, the manufacturer may use widely available and validated tools when examining clinical data. These tools are methodological quality assessment tools developed by medical researchers and scientists to assess published clinical data.50 Examples of these tools include the Cochrane Collaboration´s tool for RCT or NOS checklist for analytical studies (see Footnote 40). See MEDDEV 2.7.1 rev 4, Section 9.3.2 ‘How to determine the relevance of a data set for the clinical evaluation’, for further information. e. Lack of clinical data providing sufficient clinical evidence Manufacturers should conduct a gap analysis with respect to the MDR requirements. If data gaps have been identified, there are different possibilities to bridge those gaps. While controlled clinical investigations might be the preferred method for collecting clinical data as part of the PMCF studies for some products, there are other possibilities to gather relevant clinical data in the field in order to close the clinical data gap. Other alternatives include, but are not limited to systematic reviews of clinical data published in the literature, evaluation of results from PMCF studies such as clinically relevant scientifically sound questionnaires51 or registries. Scientifically sound studies will normally include (note, this is not a complete list):  Clearly stated research question(s), objective(s) and related endpoints;  An evaluation of potential sources of bias or study distortion, and the impact of these factors on the potential validity of results;  Design with an appropriate rationale and statistical analysis plan;  A plan for an analysis of the data and for drawing appropriate conclusion(s). If there is not sufficient supportive clinical evidence with regard to the declared intended purpose52 including the indications and claims as appropriate, manufacturers shall narrow the intended purpose of the device under evaluation until it is supported by the available clinical evidence. As noted in Section 4, some legacy devices may have limited clinical data, particularly if they were marketed prior to the publication of the Directives. In some cases, it may be necessary for the manufacturer to undertake PMCF to generate new data for these legacy devices prior to CE marking under the MDR, whereas in other cases, particularly for low risk standard of care devices where there is little evolution in the state of the art, it may be possible to demonstrate conformity with the relevant GSPRs with a more limited clinical data set. Devices previously certified under the Directives might not be considered to have sufficient clinical data for certification under the MDR. Reasons may include: 50 The suggested tools may also be relevant for unpublished data. 51 Clinically relevant and where possible validated. 52 MDR, Article 2(12). Page 17 of 22  changes in the state of the art  data arising from PMS may identify new risks or provide additional clarity with respect to indications and contraindications  devices previously certified under Quality System annexes of the Directive may not have been sampled prior to an application for MDR certification, and the clinical evidence therefore not subject to Notified Body scrutiny  the MDR introduces new requirements on the use of equivalence, which may reduce the overall volume of data available for demonstration of conformity with the relevant GSPRs  the MDR has a more explicit definition of what constitutes clinical data, which may remove some data sources previously used Although the Directives indicate that data shall be collected in the post-market phase for all devices53, in practise the data collected may not meet MDR criteria, if the devices were considered standard of care and were not associated with safety concerns. Stable, well- established technologies that perform as intended and are not associated with safety concerns, and where there has been no innovation, are less likely to be the subject of research, and therefore literature data may be limited or non-existent. In some cases, it may be necessary for the manufacturer to undertake PMCF to generate new clinical data for these devices prior to certification under the MDR, even if they are well-established and have been on the market for several decades, to enable an evaluation of their safety and clinical performance in relation to an evolving state of the art. In exceptional cases, particularly for low risk standard of care devices where there is little evolution in the state of the art, and the device is identified as belonging to the group of ‘well-established technologies’ (see section 1.2 and Appendix III in this document) a lower level of clinical evidence may be justified to be sufficient for the confirmation of conformity with relevant GSPRs. This may be supported by clinical data from the PMS provided that there has been a quality management system in place to systematically collect and analyse any complaints and incident reports, and that the collected data support the safety and performance of the device. 53 MDD, Annex II(3.1) indent 7, Annex IV(3), Annex V(3.1) indent 8, Annex VI(3.1) indent 8, Annex VII(4). Page 18 of 22 Appendix I - Sections of MEDDEV 2.7/1 rev. 4 which are still relevant under the MDR for the application of this guidance The identified sections of MEDDEV 2.7/1 rev. 4 are considered relevant to MDR as they contain helpful information regarding how to perform activities associated with clinical evaluation:  6.4. Who should perform the clinical evaluation?  8. Identification of pertinent data (Stage 1)  9. Appraisal of pertinent data (Stage 2)  10. Analysis of the clinical data (Stage 3). This chapter includes references to the MDD, MDR requirements should be used instead  A3. Device description - typical contents  A4. Sources of literature  A5. Literature search and literature review protocol, key elements  A6. Appraisal of clinical data - examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety  A7.2. Conformity assessment with requirement on acceptable benefit/risk profile  A7.3. Conformity assessment with requirement on performance  A7.4. Conformity assessment with requirements on acceptability of undesirable side-effects  A10. Proposed checklist for the release of the clinical evaluation report. Page 19 of 22 Appendix II – Clinical Evaluation Plan for Legacy Devices54 A modified Clinical Evaluation Plan for legacy devices should include at least:55  An identification of the GSPR that require support from relevant clinical data.  A specification of the intended purpose of the device.56  A clear specification of intended target groups with clear indications and contra- indications.  A detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters.  A strategy to identify, analyse and assess alternative treatments57.  A specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects;  An indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device.  An indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non- viable animal or human tissues, are to be addressed.  A strategy and methodology to identify, analyse and appraise all relevant available clinical data in light of the changed definition for clinical data.  Evidence for equivalence, if clinical data from an equivalent device is included in the clinical evaluation.  A definition of the required level of clinical evidence, which shall be appropriate in view of the characteristics of the device and its intended purpose.58 59 60  A strategy and methodology to systematically collect, summarise and assess post market surveillance data to demonstrate continuing safety and performance, and to what extent complaints with regards to safety and performance have been observed with the legacy devices.61 54 MDR, Annex VII, 4.11. 55 Appendix A3 of MEDDEV 2.7/1 rev. 4 lists information that can be relevant for planning clinical evaluations. The manufacturer needs to make sure that input for the clinical evaluation plan are in line with the device’s “label, instructions for use, promotional or sales materials or statements” and with the device’s updated risk management documents. 56 In order to fully identify the intended purpose(s) of a legacy device, the manufacturer needs to consider the data that is foreseen on the label, in the instructions for use or in promotional or sales materials or statements that are foreseen for the device. Typical elements of the intended purpose can be found in Appendix A3 of MEDDEV 2.7/1 rev. 4. 57 MDR, Article 61(3)(c). 58 MDR, Article 61(1). 59 The proposed level of clinical evidence should take into account the specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects. 60 To determine the level of clinical evidence it is necessary to identify benefits and risks of the device under evaluation and to take into account available alternative treatment options, and a clinical assessment of failure modes associated with the device. 61 MDR Article 83 and MDR Annex III. Page 20 of 22 Appendix III – Suggested hierarchy of clinical evidence for confirmation of conformity with relevant GSPRs under the MDR Sources of pre- and post- market clinical data are described in Sections 6.2.1 and 6.2.2 of this document. Reference is also made to clinical evidence which may provide contextual, supportive or clarifying information for demonstration of conformity with the relevant GSPRs. A suggested hierarchy of evidence and considerations to apply is provided in the table below, ranked roughly in order from strongest to weakest (some variations may apply dependent on the device, GSPR for which evidence is required, and quality of individual data sources): Rank Types of clinical data and evidence Considerations / comments 1 Results of high quality62 clinical investigations covering all device variants, indications, patient populations, duration of treatment effect, etc This may not feasible or necessary for certain well-established devices with broad indications (eg Class IIb legacy sutures, which could be used in every conceivable patient population) 2 Results of high quality clinical investigations with some gaps Gaps must be justified / addressed with other evidence in line with an appropriate risk assessment, and clinical safety, performance, benefit and device claims. Assuming the gaps can be justified, there should be an appropriate PMCF plan to address residual risks. Otherwise, manufacturers shall narrow the intended purpose of the device until sufficient clinical data has also been generated. 3 Outcomes from high quality clinical data collection systems such as registries63 Is there sufficient evidence of the quality of the data collected by the registry64, 65? Are the devices adequately represented? Are the data appropriately stratified? Are the endpoints appropriate to the safety, performances and endpoints identified in the clinical evaluation plan? 4 Outcomes from studies with potential methodological flaws but where data can still be quantified and acceptability justified66 Many literature sources fall into this category, due to limitations such as missing information, publication bias, time lag bias, etc. This applies equally to publications in the peer-reviewed scientific literature. However, for legacy devices 62 Refer to data appraisal considerations described in Section 6.3 of this guidance. 63 Please note that the Considerations / Comments listed in point 2 also apply to these studies. 64 http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-170316-methodological-principles.pdf 65 http://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-160930-principles-system-registries.pdf 66 Please note that the Considerations / Comments listed in point 2 also apply to these studies. Page 21 of 22 where no safety or performance concerns have been identified, these sources can be sufficient for confirmation of conformity to the relevant GSPRs if appropriately appraised and the gaps are identified and handled. High quality surveys may also fall into this category. Class III legacy devices and implantable legacy devices which are not well-established technologies should have sufficient clinical data as a minimum at level 4. Those devices which are well-established technologies may be able to confirm conformity with the relevant GSPRs via an evaluation of cumulative evidence from additional sources as listed below. Reliance solely on complaints and vigilance is not sufficient. 5 Equivalence data (reliable / quantifiable) Equivalence must meet MDR criteria. It is normally expected that manufacturers should gather data on their own devices in the post-market phase, therefore reliance on equivalence should be duly justified, and linked to appropriate PMCF or proactive PMS. 6 Evaluation of state of the art, including evaluation of clinical data from similar devices as defined in Section 1.2 of this document This is not considered clinical data under the MDR, but for well-established technologies only can be considered supportive of confirmation of conformity to the relevant GSPRs. Data from similar devices may be also important to establish whether the device under evaluation and similar devices belong to the group of devices considered as “well established technologies” (WET). See section 1.2 in this document for the criteria for WET. Data from similar devices may be used, for example, to demonstrate ubiquity of design, lack of novelty, known safety and performance profile of a generic group of devices, etc. 7 Complaints and vigilance data; curated data This falls within the definition of clinical data under MDR Article 2(48), but is not generally considered a high quality source of data due to limitations in reporting. It may be useful for identifying safety trends or performance issues. High volume data collected within a robust quality system may provide supportive evidence of device safety. 8 Proactive PMS data, such as that derived from surveys This falls within the definition of clinical data under MDR Article 2(48), but is not generally considered a high quality source of data due limitations associated with sources of bias and quality of data collection. It may be useful for Page 22 of 22 identifying safety concerns or performance issues. 9 Individual case reports on the subject device This falls within the definition of clinical data under MDR Article 2(48), but is not considered a high quality source of data due to limitations in generalising findings to a wider patient population, reporting bias, etc. It may provide supportive or illustrative information with respect to specific claims. 10 Compliance to non-clinical elements of common specifications considered relevant to device safety and performance Common specifications which address clinical investigation or data requirements directly would rank higher in this hierarchy. Common specifications may address clinically relevant endpoints through non-clinical evidence such as mechanical testing for strength and endurance, biological safety, usability, etc. 11 Simulated use / animal / cadaveric testing involving healthcare professionals or other end users67 This is not clinical data, but may be considered evidence of confirmation of conformity to relevant GSPRs, particularly in terms of usability, such as for accessories or instruments. 12 Pre-clinical and bench testing / compliance to standards62 Pre-clinical and bench testing may address clinically relevant endpoints through non-clinical evidence such as mechanical testing for strength and endurance, biological safety, usability, etc. 67 This may be of interest in the case of application of Article 61(10).

mdcg_clinical_evaluationtemplate_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 0 MDCG 2020-13 Clinical evaluation assessment report template July 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and a representative of the European Commission chairs it. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 1 Contents Introduction ............................................................................................................................... ....... 3 Scope ......................................................................................................................... ..................... 3 Approach to Template .......................................................................................................... ........... 4 Template CEAR ................................................................................................................. ............. 6 Section A: Administrative particulars (notified body, manufacturer, product and clinical evaluation report reference) .................................................................................................. ....... 6 Section B: Reviewers involved in the notified body assessment of the clinical evaluation ........... 7 Section C: Device description, classification, clinical evaluation plan, information materials supplied by the manufacturer, common specifications and harmonised standards applied, equivalence and state of the art .............................................................................................. ..... 8 Section D: Clinical literature review.......................................................................................... .. 15 Section E: Clinical investigations and related documentation .................................................... 18 Section F: PMS, PMCF and the plan for updates ...................................................................... 20 Section G: IFU, SSCP, labelling and other information supplied with the device ....................... 21 Overall Conc lusions: .......................................................................................................... ........ 24 Specific Considerations ....................................................................................................... .......... 25 Section I: Clinical evaluation c onsultation procedure for certain class III and class IIb devices (Article 54) .................................................................................................................. ............... 25 Section J: Where demonstration of conformity based on clinical data is not deemed appropriate (Article 61(10)) .............................................................................................................. ............. 28 Section K: The voluntary clinical consultation on the clinical development strategy (Article 61(2)) .............................................................................................................................. ..................... 30 Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 2 List of acronyms CEAR Clinical Evaluation Assessment Report CECP Clinical Evaluation Consultation Procedure CER Clinical Evaluation Report CIP Clinical Investigation Plan EUDAMED European Databank on Medical Devices IFU Instructions for Use MDR Medical Device Regulation (Regulation (EU) 2017/745 on me dical devices) PMCF Post-Market Clinical Follow-up PMS Post-Market Surveillance PSUR Post-Market Surveillance Update Report SRN Single Registration Number SSCP Summary of Safety and Clinical Performance TDAR Technical Documentation Assessment Report UDI-DI Unique Device Identification Device Identifier Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 3 Introduction A c l i n i c a l e v a l u a t i o n a s s e s s m e n t r e p o r t ( C E A R ) i s a r e p o r t u s e d b y t h e n o t i f i e d b o d y t o c l e a r l y d o c u m e n t t h e conclusions of its assessment of the clinical evidence presente d by the manufacturer in the clinical evaluation report (CER) and the related clinical evaluation that was conducted – a core requirement of the Medical Device Regulation (EU) 2017/745 (MDR). The clinical evaluation must be a part of the manufacturer's qu ality management. It should also be aligned with and reflected in other aspects of the technical documentation, such as: • The interface of the clinical eva luation with the risk manageme nt process and its appraisal and analysis of the pre- clinical and clinical evaluation and their relevance for the de m o n s t r a t i o n o f c o n f o r m i t y w i t h t h e r e l e v a n t requirements in Annex I. 1 • Post-market surveillance including any corrective and preventiv e actions involving the device. • Post-market clinical follow-up pl an and where appropriate the p ost-market clinical follow-up report. • Instructions for use, which provide adequate information on int ended purpose, proper use and warnings about risks to patients and healthcare practitioners. As part of its conformity assessment activities the notified bo dy shall examine, validate and verify that manufacturers' procedures and documentation adequately address the requirement s relating to the technical documentation 2 and clearly document its assessment3. The notified body shall review the clinical evidence presented by the manufacturer in the clinical evaluation report and the related clinical evaluation that was conducted, which i ncludes4:  Assessing the suitability of using data from claimed equivalent devices, taking into account factors such as new indications and innovation. The notified body shall clearly doc ument its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity. For any characteristic of the device claimed as innovative by the manufacturer or for new indication s, the notified body shall assess to what extent specific claims are supported by specific pre-clinical and clin ical data and risk analysis.  Verifying that the clinical evidence and the clinical evaluatio n are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. That verification shall include consideration of the adequacy of the benefit-risk determination, the risk management, the instructions for use, the user training and the manufacture r's post-market surveillance plan, and include a review of the need for, and the adequacy of, the PMCF plan prop osed, where applicable.  Considering the clinical evaluation and the benefit-risk determ ination, and whether specific milestones need to be defined to allow the notified body to review updates to the cli nical evidence that result from post-market surveillance and PMCF data. The outcome of this assessment must be clearly documented in th e CEAR. 5 A harmonised CEAR template provides a standardised method for documenting the notified body’s assessm ent of the manufacturer’s clinical evaluation and related documents. CEARs in this format will also support specific additional requirements such as the clinical evaluation consultation procedure6 and reviews by designating authorities.7 Scope This template applies to MDR Annexes IX section 4 and Annex X s ection 3. It also applies to assessments of technical documentations on a sampling basis for class IIa/IIb devices in accordance with Annex IX sections 2.3 and 3.5 and 1 MDR, Annex VII Section 4.5.1 and 4.5.5 2 MDR, Annexes II and III 3 MDR Annex VII Section 4.5.5 and 4.6 4 MDR, Annex IX Sections 4.4 to 4.7 5 MDR, Annex IX 4.8 6 MDR, Article 54 7 MDR, Article 45 Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 4 Section 10 of Annex XI(A).8 Aspects related to the clinical evaluation assessment are also laid down in Section 4.5.5 an d oth er r ele van t s ecti on s of A n n e x V II. It als o ap p lies to m ed ical d e vice s fo r wh ich clin ical d at a is n o t d ee med appropriate,9 to demonstrate conformity with Annex I, and the demonstration of an adequate justification for this.10 Approach to Template Please note that the explanatory text under each heading provid es brief descriptions of the type of information which will be included by the notified body, however it is not an all -inclusive list and further detail may be required depending upon the device or the intended purpose for which it will be us ed. This template represents the minimum content for a CEAR and needs to be incorporated into the process and proced ures of the notified body.11 The CEAR shall also make a recommendation to support a final review and a final decision to be taken by the notified body. Any non-compliances identified during the assessment of the asp ects described in the relevant sections of the template, as well as the appropriate follow up actions taken by the manufacturer to close them need to be documented. This template may be used by the notified body to d ocument the non-compliance/deficiencies and queries raised during the assessment and the assessment of resp onses received. It is important to note that the completed CEAR may not necessarily contain comprehensive inform ation regarding the non-compliance/deficiencies, which were raised by the notifie d body during the course of the assessment. The CEAR shall document the outcome12 and the conclusions13 of the assessment. Designating authorities shall assess whether the clinical evalu ation assessment was conducted appropriately, considering the assessment, procedures, associated documentatio n and the conclusions; 14 Designating authorities will have access to the complete ‘audit trail’ of the notified body. Expert panels who are conducting a clinical evaluation consulta tion procedure shall assess the CEAR, however they may not have access to the complete conformity assessment for t he device and associated procedures and documentation. To enable the expert panel work, the CEAR shall provide sufficient information with respect to the clinical evidence provided by the manufacturer, in particular c oncerning the benefit-risk determination, the consistency of that evidence with the intended purpose, includi ng the medical indication or indications and the PMCF plan.15 Expert panels may also request the notified body to present it s conclusions regarding the clinical evaluation assessment report.16 It is only once all the non-compliances have been closed out th at the relevant tick-box should be completed to signal t h a t t h e a s s e s s m e n t i s p o s i t i v e . I n t h e r a r e e v e n t t h a t t h e r e i s one or more open minor non-compliances at the conclusion of the assessment stage, this must be clearly descri bed in the template, together with appropriate follow- u p a c t i o n s t o c l o s e t h e m , a n d e x p e c t e d c o m p l e t i o n t i m e l i n e s t o be followed by the manufacturer under the supervision of the notified body. The sections covered in Annex I of this template are generally applicable depending on the type of assessment. The sections covered in Annex II may be applicable, depending upon the device under evaluation. All applicable sections should be completed, relevant conclusions reached and correspon ding boxes ticked for the report to be complete . The CEAR should be signed-off by the relevant personnel in acco rdance with the quality management system of the notified body. When making available the CEAR to third parties, the notified body should treat the personal data within 8 MDCG 2019-13 9 Article 61(10) 10 Based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intende d and the claims of the manufacturer. 11 MDR, Annex VII Section 4.6 12 MDR, Annex IX Section 4.8 13 MDR, Annex VII Section 4.6 14 MDR, Article 45(3) 15 MDR, Annex IX Section 5.1(c) 16 MDR, Annex IX Section 5.1(b) Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 5 it as per its procedures for the management of personal data, i n compliance with Regulation (EU) 2016/679 General Data Protection Regulation. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 6 Template CEAR Section A: Administrative particulars (notified body, manufactu rer, product and clinical evaluation report reference) Medical device name model and type: ☐ Basic UDI-DI(s) (if available): ☐ Certificate number (if applicable): Project number: Risk Class: Applicable code(s) per Commission Implementing Regulation (EU) 2017/2185: Manufacturer(s) name and SRN: Authorised representative (if applicable) name and SRN: Notified body: Notified body number: E-mail contact of NB: Telephone contact of NB: Parts of this template which have been applied General considerations 17 ☐ Section A: Administrative particulars ☐ Section B: Reviewers involved ☐ Section C: Device description, classification, clinical evaluation plan, information materials supplied by the manufacturer, common specifications and harmonised standards applied, equivalence and state of the art ☐ Section D: Clinical literature review ☐ Section E: Clinical investigations and related documentation ☐ Section F: PMS and PMCF ☐ Section G: IFU, SSCP, labelling and other information supplied with the device ☐ Section H: Summary of all available data and conclusions ☐ Overall Conclusions Specific Considerations Type of assessment: ☐ Initial conformity assessment ☐ Assessment of changes18 and update of the clinical evaluation19 ☐ Re-certification assessment ☐ Assessment of technical documentation for class IIa / IIb devices on a sampling basis Intended purpose: Check of clinical evaluation report authors ☐ CER dated and signed ☐ CVs provided for CER author(s) Comments: Confirm CVs are up to date Confirm CER authors have full range of required expertise represented (e.g. research methods, information 17 These must be completed in all cases 18 MDR, Annex IX Section 4.10 19 For example in accordance with Annex VII, Section 4(10) Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 7 According to Annex / section: Insert the Annex and section management, regulatory requirements, device technology, diagnosis and management of conditions to be treated) CVs are considered acceptable: ☐ ☐ Section I: Clinical evaluation consultation procedure for certain class III and class IIb devices (Article 54) ☐ Section J: Where demonstration of conformity based on clinical data is not deemed appropriate (Article 61(10)) ☐ Section K: The voluntary clinical consultation on the clinical development strategy (Article 61(2)) Technical file identification number and technical documentatio n assessment report (TDAR) reference if available or any other references that allow the correlation between TDAR and CEAR: Documents assessed: For example, clinical evaluation report, clinical investigation plan, clinical investigation re port, ethics committee approval , Competent Authority approval, post market surveillance data, publications. Include the title, version number/reference and date of the doc uments. When the CER has been updated verify that this update correspon ds to the most recently updated PMS/PMCF reports and any condit ions set on the first certification, if applicable. Note that references to the technical documentation should be m ade in order to ensure document control. Section B: Reviewers involved in the notified body assessment o f the clinical evaluation Provide the name or the employee code of the personnel with rel evant clinical expertise (as per 3.2.4 of annex VII): Relevant clinical expertise: Have additional reviewers been involved? Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 8 ☐Yes ☐No Provide a justification: Additional reviewers assigned to review the clinical evaluation Number of additional reviewers Names of additional reviewers: Separate the internal and external clinical reviewers. You may use employee codes Specific aspects assessed (by each additional reviewer): For example, rationale for the design and chosen statistical methodology of clinical i nvestigation etc. Competence area / codes: List of relevant MDR codes or area this person is authorised to, according to the Authorisation Matrix, as of Annex VII, 3.3.2) Relevant expertise: Section C: Device description, classification, clinical evaluat ion plan, information materials supplied by the manufacturer, c ommon specifications and harmonised standards applied, equivalence and state of the art Device description Describe the device and comment on the intended purpose, includ ing:  The intended patient population and medical conditions to be di agnosed, treated and/or monitored.  A general description of the key functional elements: its parts /components (including software if appropriate), its formulatio n, its composition, its functionality and, where relevant, its qualitative and quantitative composition.  The principles of operation of the device and its mode of actio n; explanation of any novel features. Classification List the applicable classifica tion rule(s) and indents. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 9 Device configurations/variants included in this application: Include the manufacturers description of the sizes, differences in design features, different configurations etc. Include an image of the device where possible. If applicable, include the manufacturers description of the dev ice history and/or changes in the device since its last assessm ent. Where relevant, include the manufacturers description of the re ason for differences in design variants with illu strative image s where possible. Accessories or compatible devices: Describe any accessories or compatible devices if any or state, “none”). Include component devices in case of system/procedure pack. If the use of accessories or compatible devices has an impact o n clinical safety or performance or the scope or validity of th e clinical evaluation, identify this here. If it is necessary to understand the usage of the device, inclu de images or other relevant inf ormation such as diagrams. Previous generations of the device and similar devices (if appl icable): Verify that the manufacturer has provided:  an overview of the previous generation or generations of the de vice produced by the manufacturer, where such devices exist.  an overview of identified similar devices available on the Unio n or international markets, where such devices exist, including length of time on the market, sales volume etc. Non-compliances identified and resolved for this section may be briefly described in this box Device details, intended purpose and classification are: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Clinical evaluation plan Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 10 Briefly summarise the manufacture r’s clinical evaluation plan a nd confirm that it meets the requirements of Annex XIV Part A S ection 1a, highlighting the areas which require particular attention for this assessment:  an identification of the general safety and performance require ments that require support from relevant clinical data;  a specification of the intended purpose of the device;  a clear specification of intended target groups with clear indi cations and contra-indications;  a detailed description of intended clinical benefits to patient s with relevant and specified clinical outcome parameters;  a specification of methods to be used for examination of qualit ative and quantitative aspects of clinical safety with clear re ference to the determination of residual risks and side- effects;  an indicative list and specification of parameters to be used t o determine, based on the state of the art in medicine, the acc eptability of the benefit-risk ratio for the various indication s and for the intended purpose or purposes of the device;  an indication how benefit-risk issues relating to specific components such a s use of pharmaceutical, non-viable animal or human tissues, ar e to be addressed; and  a clinical development plan indi cating progression from explora tory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmat ory investigations, such as pivotal clinical investigations, and a PMCF as referred to in P art B of Annex XIV of MDR, with an indication of milestones and a description of potential acceptance criteria. A detailed description of the clinical development plan is not required for the purpose of this template unless there are spec ific concerns. Add the manufacturer’s reference and version and date of the cl inical evaluation plan. Clinical performance Summarise the clinical data to d emonstrate the ability of the d evice, resulting from any direc t or indirect medical effects wh ich stem from its technical or functional characteristics, incl uding diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical bene fit for patients, when used as intended by the manufacturer. Describe the clinical benefits. Safety Does the clinical evaluation adequately addresses the qualitati ve and quantitative aspects of clinical safety with clear refer ence to the determination of residual risks and undesirable sid e- effects and the confirmation of the relevant safety and perform ance requirements provided for in Annex I? Summarise the clinical data regarding safety, and also describe residual risks and any undesirable side- effects. Does the clinical evaluation spec ify the methods to be used for examination of qualitative and quantitative aspects of clinica l safety with clear reference to the determination of residual risks and undesirable side-effects? If relevant, briefly summarise any significant complaint, trend s or vigilance issues associated w ith earlier device iterations , which may be equivalent or similar devices, and explain wheth er or not they have any impact on the clinical evaluation assessme nt. Non-compliances identified and resolved for this section may be briefly described in this box Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 11 The clinical evaluation plan is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Common specifications, harmonised standards or other solutions applied Are there common specifications relevant to the device under ev aluation? Have they been complied with? If not: 20  Explain any deviations and how t hese might affect the validity of the clinical evaluation and its conclusions, and any equival ence claims.  Confirm that the manufacturer has adopted solutions that ensure a level of safety and performanc e that is at least equivalent thereto in accordance with Article 9(3). Are there harmonised standards relevant to the clinical evaluat ion of the device under evaluation? Have they been applied? If partially applied add the manufacturers justification and co nfirm that the manufacturer has adopted solutions that ensure a level of safety and performanc e required by the Regulation (EU) 2017/745. If there are deviations explai n any deviations and how these mi ght affect the validity of the clinical evaluation and its conc lusions, and any equivalence claims. Is the most up-to-date revision being used by the manufacturer? (state which revision was used) Are there other solutions that have been applied? Describe any standards, guidance or other solutions that have b een applied, and the manufacturers justification Non-compliances identified and resolved for this section may be briefly described in this box 20 Excluding devices listed in Annex XVI which must comply with th e relevant common specifications in accordance with Article 9(4 ). Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 12 The application of CS, harmonised standards or other solutions is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. The demonstration of equivalence Is the clinical evaluation based upon clinical investigation(s) or other studies reported in scientific literature, of a devic e for which equivalence to the device in question can be demonstrated? State Yes / No Device(s) to which equivalence has been claimed: Is the clinical evaluation based upon reports published in peer reviewed scientific literature on a device for which equivalen ce to the device in question can be demonstrated? State Yes / No If yes, specify the source(s) of the data, if it is the device in question, or an equivalent device, or both. Device(s) to which equivalence has been claimed: Device which is most relevant: Assessment of equivalence 1. Equivalence rationales: Indicate which devices are/are not equivalent, and confirm that data relating to devices which are not equivalent have been ex cluded from the analysis of clinical data for the purposes for demonstrating safety and performance. If equivalence has been claimed to more than one device, each d emonstration of equivalence can only be based on a single devic e. Each equivalent device must meet all three equivalence criteria (clinical, technical, biological). 2. Are the devices equivalent in accordance with Section 3 of Anne x XIV including technical, biologi cal and clinical characterist ics? State Yes / No Identify any differences in these parameters, and verify why th ese are not expected to adversely affect the safety and perform ance of the medical device under evaluation. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 13 Non-compliances identified and resolved for this section may be briefly described in this box The demonstration of equivalence is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Access to data Comment on the manufacturer’s access to data, relating to devic es with which they are claiming equivalence in order to justify their claims of equivalence. For implantable and Class III device s, if equivalence is claime d with a device marketed by another manufacturer, confirm that there is a current valid contract between the two manufacturers allowing ongoing access to the technical document ation in accordance with Article 61 (5) of the MDR. Has the original clinical evaluat ion been performed in complian ce with the requirements of Regulation 2017/745, and has the ma nufacturer of the second device provided clear evidence thereof? State Yes / No Confirm that access to data is sufficient to provide the manufa cturer with enough information about the equivalent devices to support equivalence claims, in cluding any testing which may have been undertaken to confirm equivalence of specifications/p erformance/etc. Any other limitations with re spect to equivalent devices: Comment on any other limitations with respect to the equivalent devices or manufacturer’s equivalence claims, and the extent t o which these limitations impact the manufacturer’s clinical evaluation and conclusions. Non-compliances identified and resolved for this section may be briefly described in this box Manufacturer demonstration of equivalence and access to data is : Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 14 Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. State of the art Benchmark devices, state of the art and other available treatme nt options: Describe the alternative availabl e treatment options identified by the manufacturer which could offer comparable safety and pe rformance for the same treatment indications / patient populations, etc. Briefly describe how benchmarks for safety and performance have been identified by the manufacturer in terms of the state of t he art. Benchmarks will norma lly be based on aggregate data from several devices considered to have acceptable performance (e.g. systematic reviews or registry analysis); if individual d evices are selected as benchmarks for safety and performance, a suitable rationale should be provided. Confirm that the manufacturer's description of the state of the art is based upon an appropriate literature search (see sectio n D)? For devices previously marketed, is the description of the stat e of the art still accurate? Can the device still be considered to be state of the art? Safety, performance and benefit-risk claims - requirements in t erms of the state of the art: What performance and safety endpoints has the manufacturer iden tified? In light of the outcomes achievable with benchmark products and other treatment options, are these endpoints appropriate and c linically relevant? Have surrogate endpoints been adequately justified? Has the manufacturer adequately described an indicative list an d specification of parameters used to determine, based on the s tate of the art in medicine, the acceptability of the benefit- risk ratio for the various indications and for the intended pur pose or purposes of the device? Non-compliances identified and resolved for this section may be briefly described in this box Manufacturer demonstration of state of the art is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 15 Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Novelty Include the manufacturer’s explanation of any novel features of the device and/or the related clinical procedures and their pu rpose. What is the possible clinical or health impact in terms of bene fit/risk? Is novelty adequately addressed? ☐ Section D: Clinical literature review With respect to the search criteria of the literature review, does it: ☐ Address all device sizes, variants, model and accessories? ☐ Address the same clinical condition? Further information regarding literature search methods is avai lable in MEDDEV 2.7/1 revision 4, section A5. Searches for the device in question, equivalent devices and oth er devices (for example to support a description of the state o f the art) should be described separately. With respect to the selection criteria of the literature review, does it relate to both below: ☐ The device under evaluation or to a device demonstrated to be equivalent? ☐ The state of the art or alternative available treatment option ? The clinical evaluation should c learly describe the selection c riteria with respect to the regulatory purpose to which it will apply. The CER should clearly differentiate between the two ty pes of data referenced above. If the data does not relate to either of the above, provide a rationale with respect to its inclusio n. Literature search protocol21 Provide a brief summary of the literature search strategy appli ed, commenting on: 21 For general guidance on a literat ure search, see MEDDEV 2.7/1 r evision 4, A5. Literature search and literature review protocol , key elements. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 16 • The adequacy of search terms: for example, it should be suffici ently broad to establish benchmarks, determine the general stat e of the art, determine potential risk, adverse events, undesirable side-effects, etc. Note that a search which is restricted to the manufacturer’s ow n product or the name of their chosen equivalent could miss imp ortant information and therefore is not acceptable. • Databases used (to minimize bias multiple databases should be u sed). • Acceptability of inclusion and exclusion criteria. • Both favourable and unfavourable data included. • Strategies for avoiding duplication of data (for example, acros s different publications or between manufacturer and published data). • Literature search and review protocol (i.e. how did the manufac turer test this protocol to ensure comprehensive identification of relevant data / demonstrate that all relevant data has been retrieved?). • Any deviations from the manufacturer’s literature search protoc ol. • Overall conclusions regarding the adequacy of search methods, l ikelihood of having retrieved all relevant data, and methods us ed to avoid bias. Comment if systematic search and review methods such as the fol lowing have been used: • PICO (patient characteristics, type of intervention, control, a nd outcome queries). • Cochrane Handbook for Systematic Reviews of Interventions. • PRISMA (The Preferred Reporting Items for Systematic Reviews an d Meta-Analyses) Statement. • MOOSE Proposal (Meta-analysis Of Observational Studies in Epide miology). • Other (specify or describe). Literature searc h documentation: ☐ Literature search protocol provided ☐ Literature search reports provided ☐ Full list of retrieved articles provided ☐ Full list of excluded articles provided, with reasons for excl usion ☐ Full text copies of relevant documents available Comments: Provide rationale if any of the above has not been provided. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 17 Nota bene: • A literature search and other retrieval of data should be carri ed out based on a search protocol. The search protocol should d ocument the planning of the search before execution. • Once the searches have been executed, the adequacy of the searc hes should be verified and a literature search report should be compiled to present details of the execution, any deviations from the literature search protocol, and the results of the search. • It is important that the literature search is documented to suc h degree that the methods can be appraised critically, the resu lts can be verified, and the search reproduced if necessary. • Abstracts lack sufficient detail to allow issues to be evaluate d thoroughly and independently, but may be sufficient to allow a first evaluation of the relevance of a paper. Copies of the full text papers and documents should be obtained for the a ppraisal stage. • The literature search protocol(s), the literature search report (s), and full text copies of relevant documents using URL links , become part of the clinical evidence and, in turn, the technical documentation for the medical device. Non-compliances identified and resolved for this section may be briefly described in this box Literature search protocol and outputs are: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Data appraisal: Provide a brief summary of the manufacturer’s data appraisal me thods (i.e. how they determine whether the data from a given st udy or other source of data is of sufficient quality and relevance to be included in the clinical evaluation. This inclu des evaluation of criteria incl uding study design, sources of b ias, peer review, relevance to subject device, etc. Retrieved s tudies and data sets should be weighted on the basis of scientific qua lity and relevance to the scope and objectives of the clinical evaluation for the subject devices). Justify the acceptability of the appraisal in terms of: • Methodological quality and scient ific validity of articles retr ieved and evaluated appropriately. • Relevance of the information to the clinical evaluation determi ned and documented. • Contribution of each data set to the clinical evaluation weight ed according to systematic criteria. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 18 Non-compliances identified and resolved for this section may be briefly described in this box Data appraisal is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Section E: Clinical investigations and related documentation Has the manufacturer conducted clinical investigation(s)? State Yes / No Has the manufacturer conducted pre-market or post-market clinic al investigations? Provide detail If the manufacturer has not conducted clinical investigation: What is the rationale? Why is this acceptable / unacceptable? Has the manufacturer provided a c opy of all clinical investigat ion reports? State Yes / No Were all clinical investiga tions publicly registered? State Yes / No Have been verified that clinical investigations conducted with respect to Regulation (EU) 745/ 2017 publicly registered on EUDA MED? State Yes / No Provide the EUDAMED single regist ration number where available. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 19 Did the clinical investigations result in a publication in a sc ientific journal? State Yes / No If yes, does the clinical investigation report reflect the resu lts of clinical investigation(s) or other studies reported in s cientific literature, or reports published in peer reviewed sci entific literature on other clinical experience? If there are any diffe rences describe these and summarise the rationale provided by t he manufacturer. Has the manufacturer provided all Competent/Regulatory Authorit y correspondence (from all countries, including outside of EU) State Yes / No Are the conclusions drawn by the manufacturer, based upon the r esults of the clinical investiga tion, valid in the light of the approved clinical investigation plan? Provide detail If clinical investigations not performed under Regulation (EU) 745/2017 were not publicly registered or published:  Confirm that a rationale was provided.  Confirm that the SSCP and where relevant the IFU (for example w ith respect to the description of clinical benefits) adequately provide information for the intended user and if relevant, the patient. Clinical Investigation Plan (CIP) reference CIP complies with MDR, Annex XV, and EN ISO 14155 Annex A State Yes / No CIP scope and study design Adequacy of CIP scope and study design for demonstration of saf ety, performance and benefit risk of subject devices:  Study design.  Devices identified.  Patient population.  Patient numbers.  Objectives and endpoints.  Length of follow up and intervals.  Study locations.  Overall conclusions. Non-compliances identified and resolved for this section may be briefly described in this box Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 20 Manufacturer clinical investigati ons and related documentation are: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Section F: PMS, PMCF and the plan for updates Documents reviewed, where relevant: ☐ PMS Plan ☐ PMS Report (where relevant) ☐ PMCF Plan ☐ PMCF Report (where relevant) ☐ PSUR (if available) Include references to the above documents. The demonstration of equivalence and the link to post-market cl inical follow-up Describe how the manufacturer will verify the presumption that there would be no clinically significant difference in the safe ty and clinical performance of the device under evaluation compared with the equivalent device by post market surveillance or post market clinical follow-up? Is there a post-market clinical follow-up planned? State Yes / No Is this an implantable or class III device for which clinical i nvestigations have not been perfo rmed in accordance with Articl e 61(4)? State Yes / No For these devices the PMCF plan should include post market clin ical studies to demonstrate the safety and performance of the d evice. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 21 Clinical evaluation updates: Identify when updates to the clinical evaluation report shall b e assessed during the surveillance and post certification monit oring activities and which frequency should be considered. Provide further detail taking into account the manufacturer's P MCF plan and the post-market surveillance plan. Non-compliances identified and resolved for this section may be briefly described in this box The PMS, PMCF and the plan for updates are: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Section G: IFU, SSCP, labelling and other information supplied with the device Information materials supplied by the manufacturer and the inst ructions for use: Describe what has been reviewed – IFU, promotional materials (i f available), SSCP, labelling etc. In case several documents ha ve been assessed, identify answers to the questions below for each of the documents.22 22 Note that the SSCP requires a separate validation report. Comments on appropriateness of PMS/PMCF Plan: If no PMCF is planned, has the manufacturer provided an accepta ble justification for not conducting a PMCF? State Yes / No Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 22 Intended purpose: Does the clinical evidence support this? Intended patient population: Who is the intended patient population? Does the clinical evidence support this? Are all the appropriate/relevant restrictions, warnings or cont raindications in place? Intended users: Is the device to be used by healthcare professionals or lay use rs? Does the IFU provide all the appropriate/relevant informati on for the intended user? Has the manufacturer taken into account the technical knowledge , experience, education, training and use environment, where ap plicable, and the medical and physical conditions of intended users (design for lay, professional, disabled or other users). Is any training for users required as a risk control measure? I f not, is this justified with respect to the risk management fi le and the clinical evaluation? Limitations: Has the manufacturer adequately/clearly described any limitatio ns for the device use? Does the device require any specific limitations? Contraindications: Have contraindications been adequately/clearly described? Are any further contraindications necessary? Warnings and precautions: Have warnings, precautions and/or measures to be taken in the e vent of malfunction of the device or changes in its performance that may affect safety been adequately descried? Does the information supplied by the manufacturer adequately/cl early provide the safety and performance information relevant t o the user, or any other person, as appropriate/relevant? Is the estimation of associated risks and residual risk adequat e? Is this estimation quantitative (i.e. a percentage rate or r ate with a confidence interval) or qualitative? Is the descript ion appropriate for patients and users? Is the information provided to the end user written in a clear and understandable way (instruction s of use, indications, and w arnings)? Is the IFU and other information materials supplied by the manu facturer aligned with the other parts of the technical document ation? Consider: • the clinical evaluation (the dev ice description used for the cl inical evaluation, other content s of the clinical evaluation re port). • the available clinical data (such as the public registration an d results of clinical investigations, publications, PMCF studie s, etc.). Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 23 • PMS report or PSUR. • the risk management file. Non-compliances identified and resolved for this section may be briefly described in this box IFU, promotional materials, labelling are: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Section H: Summary of all available data and conclusions Has the manufacturer conducted clinical investigation(s) for th e device under evaluation? State Yes / No Has the manufacturer demonstrated equivalence with respect to s ection 3 of Annex XIV of the MDR? State Yes / No If the manufacturer conducted CIs, does clinical data from clin ical investigations of the device under evaluation adequately d emonstrate compliance with the relevant general safety and performance requirements? State Yes / No Has the reliability of the sourc e of clinical investigation dat a been assured through monitoring activities and verification o f the application of appropriate clinical research standards? State Yes / No If the manufacturer demonstrated equivalence with respect to se ction 3 of Annex XIV of the MDR does the data from an equivalen t device demonstrate compliance with Annex I? State Yes / No Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 24 Provide a summary of safety data (with reference to the relevan t section of the CER). Provide a summary of performance data (with reference to the re levant section of the CER) Does the clinical data provide su fficient clinical evidence to:23 • Demonstrate compliance with the relevant general safety and per formance requirements? State Yes / No, and provide additional i nformation if relevant • Support the intended purpose, the claims and the information in the IFU and SSCP? State Yes / No, and provide addi tional information if relevant What are the remaining unanswered questions regarding the devic e under evaluation? Describe these with respect to the plan for PMS / PMCF Overall Conclusions: Benefit-risk conclusions: Summarise the clinical benefits. D escribe them briefly in relat ion to the meaningful and measu rable patient relevant clinical outcomes, including outcome(s) related to diagnosis. Describe their positive impact on patient management or public health. Summarise the risks with clinical relevance (e.g uncertainties or limitations of clinical data, undesirable side-effects, pote ntial for misuse, etc) and provide a short description (e.g. in cidence, severity, duration, vulnerable patient subgroups, dose-response relationship where relevant, etc). Discuss the impact of risks (as described above) in relation to the clinical benefits taking into account the factors describe d and in particular the uncertain ties in relation to available clinical data. Have all the risks that could have a significant impact on the benefit-risk analysis' been identified in the clinical evaluati on? Is there alignment between the risk management and clinical eva luation? 23 For legacy products, see MDCG 2020-6 Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 25 State Yes / No Describe how the clinical benefits outweigh the risks also cons idering the current state of the art. Have all deficiencies/non-compliances been raised and satisfact orily addressed in the course of this clinical evaluation asses sment? State Yes / No Is it possible to follow the changes that have been made to add ress them? Overall conclusion on the assessment of the manufacturer's clin ical evaluation including a clinical judgement of the opinion p rovided by any external expert. Make a clear recommendation to the notified body's decision mak er in regards to the conclusions of this assessment for the pur pose of granting certification, stating in addition: • whether the post-market surve illance plan, including the PMCF p lan, is adequate. • specific milestones to be set for further review of the up to d ate clinical evaluation by the notified body. • considerations to define the period of certification. • additional conditions on the cer tification to be considered. Sufficient information are prov ided to demonstrate acceptabilit y of benefit-risk conclusions and confirm that the relevant MDR requirements are met : ☐ Specific Considerations Section I: Clinical evaluation consultation procedure for certa in class III and class IIb devices (Article 54) Is the procedure required by Article 54(1) to be applied? State Yes / No Provide further information where necessary with respect to thi s justification If this procedure is not to be applied, with respect to Article 54(2) what is the reason? 24 24 See MDCG 2019-3, Interpretation of Article 54(2)b Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 26 (a) renewal of a certificate issued under the MDR; ☐ (b) the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose , and the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not adversely affect the benefit-risk ratio of the device; ☐ Provide a summary of the modification(s) that have been made to the device? Provide a summary of the manufacturer’s rationale demonstrating that the benefit-risk ratio of the device is not adversely aff ected. Has the clinical data been provided to support the conclusions of the manufacturer regarding the benefit-risk of the modified device with respect to the previous version? For legacy devices, verify:  that the modifications do not adversely affect the benefit-risk ratio.  that the device in question had a valid certificate under the D irectives.  in case the certificate has been withdrawn, suspended 25 or expired, if there is an impact on compliance with the gener al safety and performance requirements, and  that there is no pending assessment of changes for the device o r outstanding non-compliance.  the description of modifications provided and assess if these m odifications are limited only to those needed in order to compl y with the new legal requirements introduced by the MDR. Note: limitations of the intended purpose of the device should not trigger the consultation procedure in accordance to Art. 54 . (c) the principles of the clinical evaluation of the device typ e or category have been addressed in a CS referred to in Articl e 9 and the notified body confir ms that the clinical evaluation of the manufacturer for this device is in compliance with the rele vant CS for clinical evaluation of that kind of device. ☐ Relevant scientific panel and associated competence area(s) Indicate your opinion on the r elevant scientific and associated competence area(s) for the device under assessment: Medical area(s) Associated competence-related areas Orthopaedics, traumatology, rehabilitation, rheumatology Joint replacements (hip, knee, shoulder) Spinal devices Non-articulating devices, rehabilitation Other 25 The devices for which the certificates were withdrawn or suspe nded due to lack of compliance wi th essential requirements will require a clinical evaluation consultation procedure as this adversely affects the benefit-risk ratio of the device. Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 27 Circulatory system: cardiovascular / lymphatic system Prosthetic heart valves and devices for heart valve repair Cardiovascular stents (metallic and bioresorbable) and vascular prostheses Active implantable cardiac devic es and electrophysiological dev ices Structural interventions and new devices (e.g. LAA/PFO occluder s, heart failure devices) Cardiac surgery including extracorporeal membrane oxygenation, cardiopulmonary bypass devices, artificial hearts (and left ventricular assist devices) Other Respiratory, anaesthesiology, intensive care Respiratory and anaesthetic devices Neurology Central and peripheral nervous system devices Implants for hearing and vision (sensory recovery) Neurosurgical devices Other Endocrinology and diabetes Endocrinology and diabetes (e.g. insulin delivery systems and c losed-loop systems, continuous glucose monitoring) Implantable systems General and plastic surgery, dentistry Surgical implants and general surgery Plastic surgery and wound care Maxillofacial surgery Dentistry (devices for dentistry (oral surgery, implantology, d ental materials incl.)) Other Obstetrics & gynaecology including reproductive medicine Devices for obstetrics and gynaecology Gastroenterology & hepatology Devices for gastroente rology and hepatology Nephrology & urology Devices for nephrology and urology Ophthalmology Devices for ophthalmology Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 28 Provide further information necessary with respect to this just ification Conclusion for certain class III and IIb devices to be consider ed by the expert panel Novel aspects See section C, subsection ‘Novelty’ Benefit-risk determination See section H and the Overall Conclusion sections Consistency of clinical evidence with intended purpose and PMCF Provide an assessment of the consistency of the clinical eviden ce with: (a) the intended purpose, including medical indication(s), (b) the post-market clinical follow-up (PMCF) plan. Section J: Where demonstration o f conformity based on clinical data is not deemed appropriate (Article 61(10)) Has the manufacturer claimed that the demonstration of conformi ty with general safety and performance requirements based on cl inical data is not deemed appropriate in accordance with Article 61(10)? State Yes / No Nota bene : A clinical evaluation is still required and the above informa tion and evidence-based justifica tion shall be presented in the clinical evaluation report. Has the manufacturer provided a justification for reliance upon Article 61(10)? State Yes / No If yes, describe the evidence which the manufacturer is relying on, w ith respect to:  Performance evaluation  Bench testing Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 29  Pre-clinical evaluation Consider:  Has any available clinical data for the device or an equivalent device been searched for and/or identified by the manufacturer ? If yes –was the identified clinic al data integrated in the clin ical evaluation. This should include an evaluation of clinical data identified f rom the literature, and an appraisal of their relevance to the device under evaluation.  Is clinical data available for si milar devices, does this provi de information with relevant to the safety and performance of t he device under evaluation? Has the manufacturer conducted an appropriate search of scienti fic literature? If clinical data for similar devi ces is available – this should be included in the CER and evaluated and may be of particular relevance to post-market surveillance / PMCF planning.  The results of the manufacturer's risk management Are the results of the manufacturer's risk management supportiv e of the use of non-clinical testing methods?  Consideration of the specifics of the interaction between the d evice and the human body Is the device under assessment part of a system or stand-alone? Is there sufficient information regarding this interaction avai lable from sources other than clinical data?  The clinical performance intended What is the intended performance? Is it reasonable to rely upon non-clinical data for the proposed intended performance?  The claims of the manufacturer The manufacturer should not make any claims which are not suppo rted by clinical data. Overall conclusion Non-compliances identified and resolved for this section may be briefly described in this box The justification of the manufacturer for reliance upon Article 61(10) is: Compliant with the applicable requirements of the MDR: ☐ Include any relevant comments Compliant with the applicable requirements of the MDR with the exception of the minor non-compliance below: ☐ Medical Devices Medical Devices Coordination Group Document MDCG 2020-13 30 Add a clear description of any remaining minor non-compliance t ogether with required follow-up actions to close them and timel ines for their completion to be followed by the manufacturer. Section K: The voluntary clinical consultation on the clinical development strategy (Article 61(2)) Expert Panel consultation reference: Expert Panel recommendations: Have the views of the expert panel been given due consideration by the manufacturer? Has this been included in the clinical evaluation report? Is there any divergence between the manufacturers clinical deve lopment strategy and the views of the expert panel? If yes – wh at is the justification for this? Is this acceptable? Explain why.

MDCG 2020-1.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-1 MDCG 2020-1 Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software March 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 1 of 21 Guidance on Clinical Evaluation/ Performance Evaluation of Medical Device Software March 2020 Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software Page 2 of 21 Table of Contents 1. Purpose ............................................................................................................................................ 3 2. Scope ............................................................................................................................................... 3 3. Background ..................................................................................................................................... 4 3.1. Abbreviations ........................................................................................................................... 5 3.2. Formats used within this document........................................................................................... 5 3.3. Definitions ............................................................................................................................... 5 4. General principles of the MDSW CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) process ....................................................................................................................................... 9 4.1. Introduction ............................................................................................................................. 9 4.2. Determination of the valid clinical association / scientific validity .......................................... 12 4.3. Technical Performance /Analytical Performance .................................................................... 12 4.4. Clinical Performance .............................................................................................................. 13 4.4.1. Clinical investigations and clinical performance studies .................................................. 14 4.4.2. Where demonstration of conformity based on clinical data is not deemed appropriate ..... 15 4.5. Final analysis and conclusion of the clinical evaluation (MDR) / performance evaluation (IVDR) .............................................................................................................................................. 15 4.6. Continuous update of the clinical evaluation (MDR) / performance evaluation (IVDR)........... 15 Annex I – Methodological principle for generation of CLINICAL EVIDENCE ........................................ 17 Annex II – Examples of CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) strategies ........................................................................................................................................... 18 a) MDSW intended to analyse sleep quality data .................................................................... 18 b) MDSW intended for image segmentation ............................................................................ 19 c) MDSW intended to detect inflammatory bowel diseases (IBD) .......................................... 20 d) Active devices containing MDSW to enable their intended purpose .................................. 21 e) MDSW which provides an additional user-interface to control an insulin pump ............... 21 f) MDSW intended to analyse exhaled CO2 in a life-sustaining device in order to control ventilator settings ......................................................................................................................... 21 Page 3 of 21 1. Purpose The purpose of this guidance is to provide a framework for the determination of the appropriate level of CLINICAL EVIDENCE required for MEDICAL DEVICE SOFTWARE (MDSW) to fulfil the requirements set out in Regulation (EU) 2017/745 – Medical Devices Regulation (MDR) and Regulation (EU) 2017/746 – In Vitro Diagnostic Medical Devices Regulation (IVDR).1 In order to promote global convergence, this document takes into account certain concepts outlined in International Medical Device Regulators Forum (IMDRF) guidance documents (such as N41).2 2. Scope This guidance should be applied to MDSW. For the purpose of this guidance, MDSW is software that is intended to be used, alone or in combination, for a purpose as specified in the definition of a “medical device” in the medical devices regulation or in vitro diagnostic medical devices regulation. It should be noted that software can be associated3 with another medical device, by driving or influencing its use. The guideline MDCG 2019-11 clarifies that software which is driving or influencing is covered by the medical devices regulations4 either as a part/component of a device or as an accessory for a medical device. Software developers should refer to MDCG 2019-11 for guidance on the appropriate qualification and classification of software prior to such software being introduced into the market. The same principles of CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) apply to all MDSW. Conceptually, the following models of software can be understood (whereas combinations may be possible, refer to Table 1): a) Software for which the manufacturer claims a specific medical intended purpose. Such software has a CLINICAL BENEFIT and requires CLINICAL EVIDENCE within its own conformity assessment. b) Software for which the manufacturer does not claim any medical intended purpose. Such software is intended to drive or influence a medical device. The CLINICAL EVIDENCE is provided within the context of the driven or influenced device and is therefore out of the scope of this document. It should be recognised that the concept of a CLINICAL BENEFIT for MDSW may deviate from that which applies in the case of pharmaceuticals or other medical devices, since the benefit of MDSW may lie in providing accurate medical information on patients, where appropriate, assessed against medical information obtained through the use of other diagnostic options and technologies, whereas the final clinical outcome for the patient is dependent on further diagnostic and/or therapeutic options which could be available. 1 Depending on the device in question, the level of Clinical Evidence may differ and shall be assessed on a case by case basis. 2 International Medical Device Regulators Forum – IMDRF/SaMD WG/N41FINAL:2017 – Guidance on Software as a Medical Device (SaMD): Clinical Evaluation 3 Associated medical device may be software or hardware. 4 The use of “The Medical Devices Regulations” from here on out refers to both Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR. Page 4 of 21 Model of Software CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) - scope MDSW (with independent intended purpose and claimed CLINICAL BENEFIT) MDSW only MDSW (with intended purpose and claimed CLINICAL BENEFIT related to driving or influencing a medical device for a medical purpose) MDSW and the driven or influenced medical device Notes 1,2 Software driving or influencing the use of a medical device (with no independent intended purpose or independent claimed CLINICAL BENEFIT ) Driven or influenced medical device including the software (component or accessory) Table 1 Different MDSW and CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) requirements Note 1: If a software is driving/ influencing more than one medical device, an independent CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) is required for each foreseen and clinically viable software – device combination. Note 2: Out of scope of this guidance (See MDCG 2019-11 for examples). 3. Background Article 61 (1) of the MDR and Article 56 (1) of the IVDR state the following: ‘The manufacturer shall specify and justify the level of CLINICAL EVIDENCE necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of CLINICAL EVIDENCE shall be appropriate in view of the characteristics of the device and its intended purpose.’ Article 2 (51) of the MDR and Article 2 (36) of the IVDR define ‘ CLINICAL EVIDENCE ’ as: ‘clinical data and CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended CLINICAL BENEFIT (S), when used as intended by the manufacturer.’ In order to provide guidance relating to the level of CLINICAL EVIDENCE required for MDSW and as set out in recital (5) of the MDR and IVDR, this guidance takes into account internationally converged principles adopted by an international group of regulators, IMDRF ( http://www.imdrf.org ). Adoption of these principles provides European regulators an initial framework when further developing MDR/ IVDR- specific regulatory approaches and expectations for regulatory oversight. While this document describes a converged approach to CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) for MDSW , it should be read in conjunction with other documents that aim to provide Page 5 of 21 horizontal guidance for the CLINICAL EVALUATION of medical devices or PERFORMANCE EVALUATION of in vitro diagnostic medical devices.5 Note: Please be advised that this document is subject to revision upon the publication of the aforementioned horizontal guidance. Clinical expertise and judgments are required at every step of the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR), including literature search and appraisal. Each indication and claimed CLINICAL BENEFIT that is part of the intended purpose should be assessed individually and have the supporting CLINICAL EVIDENCE . Systematic and explicit approach for the appraisal of supporting data allows achieving confident, scientifically substantiated conclusions and facilitates transparency of these judgments. 3.1. Abbreviations GSPR General Safety and Performance Requirements IMDRF International Medical Device Regulators Forum IVDR In Vitro Diagnostic Medical Devices Regulation; EU 2017/746 MDCG Medical Device Coordination Group MDR Medical Devices Regulation; EU 2017/745 MDSW Medical Device Software PMCF Post Market Clinical Follow -up PMPF Post Market Performance Follow -up PMS Post Market Surveillance RWE Real-World Evidence SaMD Software as a Medical Device SOTA State-of-the-Art SSCP Summary of Safety and Clinical Performance SSP Summary of Safety and Performance 3.2. Formats used within this document Cursive A note to a text CAPITALIZED Terms defined in this document or the Regulations subscript References 3.3. Definitions The definitions elaborated within this section and utilised within this document are intended to apply solely to Medical Device Software (MDSW) according to the MDR and IVDR. 5 These guidance documents are under development and will be published on the Commission’s Medical Devices website. Page 6 of 21 CLINICAL BENEFIT Article 2 (53) MDR defines CLINICAL BENEFIT as the positive impact of a device on the health of an individual, expressed in the terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health; whereas Article 2 (37) IVDR defines CLINICAL BENEFIT as the positive impact of a device related to its function, such as that of screening, monitoring, diagnosis or aid to diagnosis of patients, or a positive impact on patient management or public health.6 Source: EU 2017/745 (MDR), Article 2 (53); EU 2017/746 (IVDR), Article 2 (37) and IVDR recital (64) CLINICAL DATA (MDR) Information concerning safety or performance that is generated from the use of a device and is sourced from the following: - clinical investigation(s) of the device concerned, - clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated, - reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated, - clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up; Source: EU 2017/745 (MDR) (IVDR) Clinical Data, in particular: - from relevant peer-reviewed scientific literature and available consensus expert opinions or positions from relevant professional associations relating to the safety, performance, clinical benefits to patients, design characteristics, scientific validity, clinical performance and intended purpose of the device and/or of equivalent or similar devices; or - other relevant clinical data available relating to the safety, scientific validity, clinical performance, clinical benefits to patients, design characteristics and intended purpose of similar devices, including details of their similarities and differences with the device in question - clinically relevant information coming from post-market surveillance, in particular the post-market performance follow-up; Source: Adopted from EU 2017/746 (IVDR) Annex XIV (2.4) and Annex VII (4.10) and (4.1 1) 6 IVDR recital (64) states : It should be recognised that the concept of clinical benefit for in vitro diagnostic medical devices is fundamentally different from that which applies in the case of pharmaceuticals or of therapeutic medical devices, since the benefit of in vitro diagnostic medical devices lies in providing accurate medical information on patients, where appropriate, assessed against medical information obtained through the use of other diagnostic options and technologies, whereas the final clinical outcome for the patient is dependent on further diagnostic and/or therapeutic options which could be available. Page 7 of 21 CLINICAL DEVELOPMENT PLAN (MDR) A plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations and a PMCF with an indication of milestones and a description of potential acceptance criteria. Source: EU 2017/745 (MDR), Annex XIV, part A CLINICAL EVALUATION (MDR) A systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including CLINICAL BENEFITS , of the device when used as intended by the manufacturer. Source: EU 2017/745 (MDR), Article 2 (44) CLINICAL EVIDENCE Clinical data and CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended CLINICAL BENEFIT (S), when used as intended by the manufacturer. Source: EU 2017/745 (MDR), Article 2 (51)); EU 2017/746 (IVDR), Article 2 (36) CLINICAL INVESTIGATION (MDR) Any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device. Source: EU 2017/745 (MDR), Article 2 (45) CLINICAL PERFORMANCE Article 2 (52) MDR defines clinical performance as the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a CLINICAL BENEFIT for patients, when used as intended by the manufacturer; whereas Article 2 (41) IVDR defines clinical performance as the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user. Source: EU 2017/745 (MDR), Article 2 (52); EU 2017/746 (IVDR), Article 2 (41) CURATED DATABASE / CURATED REGISTRY For the purpose of this document, a curated database /curated registry is any kind of structured repository such as a traditional database, an ontology or an XML file, that is created and updated with a great deal of human effort through the consultation, verification, and aggregation of existing sources, and the interpretation of new (often experimentally obtained) raw data. GENERALISABILITY Generalisability refers to the ability of a MDSW to extend the intended performance tested on a specified set of data to the broader intended population. Page 8 of 21 HUMAN FACTORS ENGINEERING Human factors engineering refers to the a pplication of knowledge about human behaviour, abilities, limitations, and other characteristics to the design of and interactions with a MDSW to achieve adequate USABILITY . PERFORMANCE EVALUATION (IVDR) An assessment and analysis of data to establish or verify the SCIENTIFIC VALIDITY , the ANALYTICAL and, where applicable, the CLINICAL PERFORMANCE of a device. Source: EU 2017/746 (IVDR), Article 2 (44) PERFORMANCE STUDY (IVDR) A study undertaken to establish or confirm the analytical or CLINICAL PERFORMANCE of a device. Source: EU 2017/746 (IVDR), Article 2 (42) REAL-WORLD PERFORMANCE Information on real -world device use and performance from a wider patient population than a controlled study. Source: Definition derived from IMDRF/SaMD WG/N41FINAL:2017 STATE-OF-THE-ART Developed stage of current technical capability and/or accepted clinical practice in regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience. Note: The STATE-OF-THE-ART embodies what is currently and generally accepted as good practice in technology and medicine. The state-of-the-art does not necessarily imply the most technologically advanced solution. The STATE-OF-THE-ART described here is sometimes referred to as the “generally acknowledged STATE-OF- THE-ART” Source: Modified from IMDRF/GRRP WG/N47 FINAL:2018 TECHNICAL PERFORMANCE (MDR) /ANALYTICAL (IVDR)) PERFORMANCE Capability of a MDSW to accurately and reliably generate the intended technical/analytical output from the input data. Source: IMDRF/SaMD WG/N41FINAL:2017 Source: EU 2017/746 (IVDR) Article 2 (40) USABILITY For the purpose of this document, usability refers to the c haracteristic of the user interface that establishes effectiveness, efficiency and ease of user learning and user satisfaction. VALID CLINICAL ASSOCIATION (MDR) / SCIENTIFIC VALIDITY (IVDR) Means the association of an MDSW output with a clinical condition or physiological state. Source: Derived from IMDRF/SaMD WG/N41FINAL:2017 Source: EU 2017/746 (IVDR), Article 2 (38) Page 9 of 21 4. General principles of the MDSW CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) process 4.1. Introduction CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) is an ongoing process, conducted throughout the life cycle of a MDSW. It is a structured, transparent, iterative and continuous process which is part of the quality management system for a device. Software that qualifies as a MD or an IVD is subject to the same general CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) principles, laid down in the applicable guidelines and regulatory documents, as other MDs/ IVDs, such as: - Establishing and maintaining a CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) plan and criteria applied to generate the necessary CLINICAL EVIDENCE based on the characteristics of the device; - Identification of the relevant data pertaining to performance and/ or safety of the device and any remaining unaddressed issues or gaps in the data; - Appraisal of the relevant data in terms of quality and its contribution to the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR); - Analysis of the available data and its relevance with regard to demonstrating conformity with the relevant General Safety and Performance Requirements (GSPRs); - Documenting the relevant data, their assessment and the CLINICAL EVIDENCE derived therefrom, in the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) report; - Updating the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) and its documentation throughout the life cycle of the MDSW concerned with data obtained from implementation of the manufacturer's Post Market Clinical Follow-up / Post Market Performance Follow-up (PMCF /PMPF) plan. These methodological principles are depicted in Figure 1. Figure 1 Overview of the stages of the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) Page 10 of 21 The requirements for CLINICAL EVALUATION and PERFORMANCE EVALUATION are outlined in Article 61 of the MDR (including Annex XIV) and Article 56 of the IVDR (including Annex XIII), respectively. While the definition of CLINICAL EVALUATION in the MDR and PERFORMANCE EVALUATION in the IVDR are not identical (see section 0), there is a shared expectation for providing sufficient CLINICAL EVIDENCE to demonstrate conformity with relevant GSPRs under the normal conditions of the device’s intended use. CLINICAL EVIDENCE should be sufficient and appropriate in view of the characteristics of the device, clinical risks and its intended purpose. The level of CLINICAL EVIDENCE necessary should be specified and justified by the manufacturer. Three key components should be taken into account when compiling CLINICAL EVIDENCE for every MDSW (Figure 1), and each is described below in further detail. VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY is understood as the extent to which, the MDSW’s output (e.g. concept, conclusion, calculations) based on the inputs and algorithms selected, is associated with the targeted physiological state or clinical condition. This association should be well founded or clinically accepted (e.g. existence of a scientific framework or sufficient level of evidence as further elaborated in section 4.2 of this document). The V ALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY of a MDSW should demonstrate that it corresponds to the clinical situation, condition, indication or parameter defined in the intended purpose of the MDSW. NOTE: The VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY seeks to establish that there are sound scientific principles underpinning the use of the MDSW in question. The information provided for the establishment of the V ALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY should put forward the case that the MDSW has an association with a clinical condition or physiological state. This association may not always be readily established. Thus, the C LINICAL PERFORMANCE can serve as an additional input to the VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY from a clinical perspective for the specific intended purpose (see Annex I). Example: MDSW that detects heart arrhythmia by analysing auscultation sound obtained by a digital stethoscope requires demonstrating VALID CLINICAL ASSOCIATION of the association between abnormal cardiac sounds and heart arrhythmia. Evidence supporting VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY can be generated e.g. through literature research, professional guidelines, proof of concept studies, or manufacturer’s own clinical investigations/clinical performance studies. Validation of the TECHNICAL PERFORMANCE / ANALYTICAL PERFORMANCE is the demonstration of the MDSW’s ability to accurately, reliably and precisely generate the intended output, from the input data. Evidence supporting T ECHNICAL PERFORMANCE / ANALYTICAL PERFORMANCE can be generated through verification and validation activities, e.g. unit-level, integration, and system testing or by generating new evidence through use of curated databases, curated registries, reference databases or use of previously collected patient data. Validation of the CLINICAL PERFORMANCE is the demonstration of a MDSW’s ability to yield clinically relevant output in accordance with the intended purpose. The clinical relevance of a MDSW’s output is a positive impact Page 11 of 21 - on the health of an individual expressed in terms of measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, prediction of risk, prediction of treatment response(s), or - related to its function, such as that of screening, monitoring, diagnosis or aid to diagnosis of patients, or - on patient management or public health. Evidence supporting C LINICAL PERFORMANCE can be generated by testing the MDSW under evaluation, or an equivalent device, in the target population and for the intended use. The applied methodology should be appropriate in light of the device characteristics and intended purpose and may include pre-clinical testing, a clinical investigation or a clinical performance study. Specifically, for MDSW not claiming C LINICAL BENEFITS that can be specified through measurable, patient-relevant clinical outcome(s), clinically relevant outputs are achieved through demonstrated predictable and reliable use and USABILITY (please refer to section 4.2 of this document). In addition, CLINICAL EVALUATION or PERFORMANCE EVALUATION of MDSW must consider the benefit- risk ratio in light of the STATE-OF-THE-ART related to practice of medicine for diagnosis, treatment or patient management. It is further expected that the assessment of MDSW considers all components of the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) (see Figure 1 and Annex 0). The three components described above do not represent a distinct stepwise approach but rather portray a methodological principle for the generation of CLINICAL EVIDENCE . To determine and justify the level of CLINICAL EVIDENCE , both amount and quality of supporting data should be evaluated. This assessment may be guided by the following non-exhaustive questions: Sufficient amount - Does the data support the intended use, indications, target groups, clinical claims and contraindications? - Have the clinical risks and analytical performance/ clinical performance been investigated? - Have relevant MDSW’s characteristics, such as the data input and output, the applied algorithms or type of interconnection been considered when generating the data to support the performance of the device? - What is the grade of innovation/ history on the market (how big is the body of scientific evidence)? - Other, as applicable. Sufficient quality - Were the type and the design of the study/ test appropriate to meet the research objectives? - Was the data set appropriate and actual (state of the art)? - Was the statistical approach appropriate to reach a valid conclusion? - Were all ethical, legal and regulatory considerations/ requirements taken into account? - Is there any conflict of interest? Page 12 of 21 - Other, as applicable. 4.2. Determination of the valid clinical association / scientific validity In the first step, the manufacturer should verify the association between the output of the MDSW (based on the inputs and algorithms selected) and the targeted physiological/ clinical condition, clinical situation or clinical parameter, as defined in the intended purpose of the MDSW. MDSW may include a multitude of clinical features governed by its intended purpose which require individual assessment. This association should be clinically accepted or well founded, which means accepted by the broad medical community and/or described in scientific (peer-reviewed) literature. VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY can be demonstrated through the use of existing CLINICAL PERFORMANCE DATA while taking into account the generally acknowledged STATE-OF-THE-ART. VALID CLINICAL ASSOCIATION / SCIENTIFIC VALIDITY may further be demonstrated by the creation of new CLINICAL PERFORMANCE DATA in the cases where existing data is not sufficient. For example, as a result of a gap analysis, the manufacturer could conclude that additional data may be required. Examples of existing data (in no particular order) - Technical standards - Professional medical society guidelines - Systematic scientific literature review - CLINICAL INVESTIGATION s/ CLINICAL PERFORMANCE STUDIES - Published CLINICAL DATA (e.g. Summary of Safety and Clinical Performance (SSCP) / Summary of Safety and Performance (SSP), Registries and databases from authorities) Examples of generating new evidence (in no particular order) - Secondary data analysis (Analysis of real-world data) - Perform CLINICAL INVESTIGATION / CLINICAL PERFORMANCE STUDY 4.3. Technical Performance /Analytical Performance The manufacturer should verify that the MDSW reliably, accurately and consistently meets the intended purpose in real-world usage. The relevant performance characteristics, as part of the GSPRs and linked to the analytical and / or clinical features, should be supported by evidence generated during verification and validation activities as part of good manufacturing practices for software, or by generating new evidence through the use of curated databases, curated registries, reference databases or use of previously collected patient data. Page 13 of 21 TECHNICAL PERFORMANCE / ANALYTICAL PERFORMANCE is confirmed by the examination and provision of objective evidence that the MDSW specifications conform to user needs and intended uses, and that the requirements implemented can be consistently fulfilled.7 For example, performance verification and validation in the intended computing8 and use environments9,10 can be characterised by the demonstration of - availability, - confidentiality, - integrity, - reliability, - accuracy (resulting from trueness and precision), - analytical sensitivity, - limit of detection, - limit of quantitation, - analytical specificity, - linearity, - cut-off value(s), - measuring interval (range), - GENERALISABILITY , - expected data rate or quality, - absence of inacceptable cybersecurity vulnerabilities, - HUMAN FACTORS ENGINEERING . Identification of gaps during the validation of the T ECHNICAL PERFORMANCE /ANALYTICAL PERFORMANCE could require generation of new evidence, for example, to demonstrate generalisability with real-life datasets or to extend the usability evaluation to omitted user groups. 4.4. Clinical Performance For the validation of a MDSW’s CLINICAL PERFORMANCE , the manufacturer should demonstrate that the MDSW has been tested for the intended use(s), target population(s), use condition(s), operating- and use environment(s) and with all intended user group(s). Section 4.1 of this document further provides context that validation of C LINICAL PERFORMANCE includes the assessment of clinical safety, effectiveness, performance and can support the demonstration of CLINICAL BENEFIT . Validation of the CLINICAL PERFORMANCE should be considered at each change of the software to a new release. If no validation is performed, a justification should be stated in the technical documentation. With a validation of C LINICAL PERFORMANCE , it is demonstrated that users can achieve clinically relevant outputs through predictable and reliable use of the MDSW. 7 Derived from Source: GHTF/SG3/N18:2010. 8 Computing environment: e.g., hardware, memory size, processing unit, time zone, network infrastructure) under which the software is to perform. 9 Use environment: actual conditions and setting in which users interact with the medical device. 10 Example on operating environments with distinct requirements are cloud or remote networks. Page 14 of 21 The manufacturer should consider the intended use(s), indication(s), desired clinical output(s) expressed as claims, leading to expected CLINICAL BENEFIT s as part of the CLINICAL PERFORMANCE validation. A MDSW may have multiple features with only some features claiming a specific CLINICAL BENEFIT . CLINICAL PERFORMANCE is only applicable to those features. Since MDSW can be modular in nature, validation of the C LINICAL PERFORMANCE is also permissible on module level when the functionality of the modules is independent of the other modules. This would allow the confirmation of a continuous benefit / risk acceptability only for the MDSW modules that have changed. In cases where the final combination of modules changes product indications and intended purposes, the performance of that final product configuration should also be evaluated. Validation of the C LINICAL PERFORMANCE can be characterised by the demonstration of applicable C LINICAL DATA to the MDSW in question, such as (non-exhaustive): - clinical/ diagnostic sensitivity, - clinical/ diagnostic specificity, - positive predictive value, - negative predictive value, - number needed to treat (average number of patients that need to be diagnosed/ treated in order to have an impact on one person), - number needed to harm (number of patients that need to be diagnosed/ treated in order have an adverse effect on one patient), - positive likelihood ratio, - negative likelihood ratio, - odds ratio, - USABILITY / user interface, - confidence interval(s). CLINICAL DATA can be obtained by one or multiple methods such as those referred to in GHTF/SG5/N7:2012 and IMDRF/SaMD WG/N41FINAL:2017. In addition to the considerations above, C LINICAL EVALUATION of class III and implantable devices (MDR), shall include data from a C LINICAL INVESTIGATION unless the conditions of Article 61(4), (5) or (6) of the MDR have been fulfilled. For MDSW falling under the IVDR, the evaluation of clinical performance requires the carrying out of clinical performance studies regardless of the classification of the device, unless due justification is provided for relying on other sources of clinical performance data. Relevant common specifications should be taken into account. 4.4.1. Clinical investigations and clinical performance studies The practical and achievable benefits of a C LINICAL INVESTIGATION / CLINICAL PERFORMANCE STUDY should be considered as part of determining what data are needed for demonstrating the safety and performance of a new or modified MDSW. The investigation or study should account for potential risks, should follow appropriate ethical requirements, and should be compliant with all relevant legal and regulatory requirements. Page 15 of 21 MDSW has specific characteristics that should be considered when setting up a clinical investigation or clinical performance study. If the MDSW is used for the determination of a patient’s future state (e.g. predisposition, prognosis, prediction) or if the output of the MDSW impacts clinical outcomes (e.g. treatment efficacy) or patient management decisions, then a prospective study may be required as part of the device’s CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR). In other situations, retrospective analysis may be more appropriate to generate the necessary data to support compliance with the GSPRs, as there is no impact on patient management and the research does not introduce any risks to the patients. Such an approach is only possible under condition that there is an adequate access to data sets of sufficient amount and quality and obtained from the target population. Formal requirements of MDR Articles 62 (1), 74 and 82 need to be met as far as appropriate for pre-market retrospective studies of MDSW falling under the MDR. 4.4.2. Where demonstration of conformity based on clinical data is not deemed appropriate In line with the provisions of MDR Article 61 (1) and IVDR Article 56(1), the level of CLINICAL EVIDENCE required should be appropriate in view of the device claims and characteristics. For medical devices, where the demonstration of conformity with GSPRs based on clinical data is not deemed appropriate (MDR Article 61 (10)), the manufacturer shall duly substantiate in the technical documentation why it is adequate to demonstrate conformity based on the results of non-clinical testing methods alone, including PERFORMANCE EVALUATION , bench testing and preclinical evaluation, and USABILITY assessment. The justification must be based on the output of the risk management process. This should include an evaluation of clinical STATE-OF-THE-ART, including alternative diagnostic and treatment options, including those identified from literature, and an appraisal of their relevance to the device under evaluation. The device / body interaction, the CLINICAL PERFORMANCE s intended, and the claims of the manufacturer should be specifically considered. A CLINICAL EVALUATION (MDR) is still required, and the above information and evidence-based justification should be presented in the clinical evaluation report. Similarly for IVDs, where due to specific device characteristics, demonstration of conformity with GSPRs based on clinical data is not deemed appropriate, a PERFORMANCE EVALUATION (IVDR) is still required and a justification shall be provided and documented in the Performance Evaluation Plan and the corresponding Performance Evaluation Report. 4.5. Final analysis and conclusion of the clinical evaluation (MDR) / performance evaluation (IVDR) The manufacturer should compile evidence, perform the benefit-risk analysis and document the CLINICAL or PERFORMANCE EVALUATION and its output in the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) report. 4.6. Continuous update of the clinical evaluation (MDR) / performance evaluation (IVDR) The safety, effectiveness and performance of the MDSW should be actively and continuously monitored by the manufacturer. Page 16 of 21 Such data may include, but is not limited to post-market information such as complaints, PMCF/ PMPF data, REAL-WORLD PERFORMANCE data, direct end-user feedback or newly published research / guidelines and should be subject to the CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) principles depicted in Figure 1. The unique level of connectivity of MDSW facilitates access to REAL-WORLD PERFORMANCE data, which can be used for multiple purposes, including, but not limited to - timely detection and correction of malfunctions; - detection of systematic misuse; - understanding user interactions; - to conduct ongoing monitoring of CLINICAL PERFORMANCE ; - to improve effectiveness; - develop the claims in the CLINICAL DEVELOPMENT PLAN (MDR) or future releases. MDSW can be released for CE marking with initially claimed and validated CLINICAL BENEFITS . Monitoring of REAL-WORLD PERFORMANCE data can help formulate hypotheses about future MDSW functionalities and intended use(s). Page 17 of 21 Annex I – Methodological principle for generation of CLINICAL EVIDENCE Page 18 of 21 Annex II – Examples of CLINICAL EVALUATION (MDR) / PERFORMANCE EVALUATION (IVDR) strategies The high-level examples provided here are for guidance purposes only and aim to provide general indications on how to develop a CLINICAL EVALUATION / PERFORMANCE EVALUATION strategy. The strategy presented in each example is not a confirmation of the pathway for a CLINICAL EVALUATION / PERFORMANCE EVALUATION of the device, as other factors need to be considered. Moreover, the proposed pathway reflects the specific intended purpose, or the healthcare context or situation, in which the device is used as described in the example itself. Any change to the intended purpose or the healthcare context / situation in which that same device is used might result in a different approach. Data source Examples Peer-reviewed, relevant scientific literature - Existing data from studies conducted with the subject device or equivalent device CLINICAL INVESTIGATION / CLINICAL PERFORMANCE STUDIES - Prospective or retrospective studies - Existing manufacturer data - Data from equivalent devices - Data from curated databases/registries/reference databases - Data from outside the EU with justification on applicability Published experience gained by routine diagnostic testing - REAL-WORLD PERFORMANCE DATA - Data obtained from PMPF/ PMCF a) MDSW intended to analyse sleep quality data An independent MDSW intended to take into account accelerometer and microphone data to determine quality of sleep and to estimate the expected success rate of CPAP (continuous positive airway pressure) treatment for sleep apnoea. The Manufacturer claims that the MDSW - determines the quality of sleep that impacts the general well-being. - monitors quality of sleep in patients with sleep disorders such as sleep apnoea (using phone sensors/wearable devices) - estimates the expected success rate of CPAP therapy. Valid Clinical Association To establish VALID CLINICAL ASSOCIATION , review literature. - Objective quality of sleep is measured by sleep duration, efficiency and fragmentation. It is further well-established that quality of sleep impacts general well-being such as concentration, risk-factors for cardiovascular disease, mood, cognitive abilities, etc. Page 19 of 21 - It is not well-established that the success of CPAP therapy can be predicted by monitoring the quality of sleep. - Address the association of accelerometer and microphone data to established quality of sleep parameters (e.g. sleep duration, efficiency and fragmentation). The VALID CLINICAL ASSOCIATION has been not established without gaps for prediction of success of CPAP therapy, which requires generation of missing clinical data. Technical Performance - Confirm with verification and validation tests that the app can reliably and reproducibly calculate sleep quality scoring. - Confirm compatibility between the MDSW and the device equipped with the sensors to ensure data can be utilised in the intended way. Clinical Performance - In addition to the USABILITY assessment, the manufacturer would perform a retrospective study on previously obtained data to confirm that success of CPAP therapy can be predicted based on the quality of sleep. b) MDSW intended for image segmentation An independent MDSW intended to allow automatic detection of organs and anatomical structures (such as the aorta) in CT scans with the accuracy of a radiologist. The Manufacturer claims that the MDSW: - detects abdominal aortic aneurisms on abdominal CT scans, - detects compression fractures on vertebrae, - detects liver cysts. Valid Clinical Association To establish VALID CLINICAL ASSOCIATION , review literature. - The normal shape and size of anatomy is well established. - Segmentation techniques on cross-sectional images correlates well with the actual size and shape. The VALID CLINICAL ASSOCIATION has been established without gaps identified. Technical Performance - Confirm with verification and validation tests the basic technical performance such as display, modification, window levelling of images, measurements including confirmation of accuracy, sensitivity and reliability of the MDSW as per the expected performance. Page 20 of 21 Clinical Performance - USABILITY assessment including the intended user groups in conjunction with the VALID CLINICAL ASSOCIATION and validation of T ECHNICAL PERFORMANCE results has been determined as sufficient to demonstrate conformity with relevant GSPRs. - In cases where data is available, a retrospective analysis can be performed. In cases where data does not represent the variability of input parameters, for the CLINICAL PERFORMANCE of the segmentation algorithm, the missing data could be generated in a prospective CLINICAL INVESTIGATION . c) MDSW intended to detect inflammatory bowel diseases (IBD) Self-testing independent MDSW intended for the semi-quantitative detection of calprotectin from a faecal sample. Reagents are added to the sample resulting in a colour change. The sample is then photographed on a smartphone, and the image is evaluated by an MDSW application (app) running on the phone. The MDSW app detects the colour change in the sample and interprets the concentration of calprotectin. The test is intended as an aid in monitoring and staging of patients with inflammatory bowel disease (IBD). Manufacturer’s claims that the MDSW app - aids in monitoring and staging the disease level of patients with inflammatory bowel diseases (IBD). - aids in differentiation between IBD and functional bowel disorders. - helps patients avoid unnecessary clinical visits. Scientific Validity To establish S CIENTIFIC VALIDITY, review literature. - The SCIENTIFIC VALIDITY could address how the calprotectin level corresponds to the IBD level and stages. Furthermore, it should address, whether calprotectin levels are suitable to differentiate between IBD and functional bowel disorders. - It is well-established that calprotectin concentration in faecal matter can be reliably measured in test strips by change of colour. - The colour intensity is directly representative of the concentration of calprotectin. Analytical Performance - Confirm the MDSW app can detect reliably and accurately the colour of the test strip compared to human observation, taking into account environmental factors. Clinical Performance - The manufacturer should assess the initial performance and feasibility by creating CLINICAL PERFORMANCE metrics, taking into account sensitivity, specificity and confidence intervals. - Any claims regarding CLINICAL BENEFIT should be supported by sufficient clinical performance data. - USABILITY should be confirmed by the manufacturer. Page 21 of 21 d) Active devices containing MDSW to enable their intended purpose Active devices, such as diagnostic or therapeutic devices, that include MDSW which drives the device in a way that, without the software it would not be able to fulfil its intended purpose. This software does not perform a medical purpose on its own. The CLINICAL EVALUATION of the MDSW should not be performed independently but should be performed together with the driven device. e) MDSW which provides an additional user-interface to control an insulin pump A MDSW intended to virtualise controls of an insulin pump additionally on a smartphone app by connecting to it. As the software is driving the insulin pump, it is not performing a medical purpose on its own, nor is it creating information on its own for medical purposes. The CLINICAL EVALUATION of the MDSW app should not be performed independently but should be performed together with the driven insulin pump. f) MDSW intended to analyse exhaled CO2 in a life-sustaining device in order to control ventilator settings The MDSW uses physiological data of the patient (e.g. exhaled CO 2, blood oxygen saturation) to control a ventilation device (e.g. frequency, volume and pressure). The MDSW allows the device to maintain the pre-set value at a desired target (defined by the clinician) without periodic user adjustments needed. This MDSW is part of a closed-loop system. The CLINICAL EVALUATION should not be limited to the MDSW and should include pre-clinical and clinical investigations, encompassing the entire closed-loop system.

mdcg_2019_9_sscp_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-9 1(24) MDCG 2019-9 Summary of safety and clinical performance A guide for manufacturers and notified bodies August 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2019-9 2(24) MDCG 2019-9 Summary of safety and clinical performance A guide for manufacturers and notified bodies August 2019 Table of contents Introduction .............................................................................................................................. ...............................3 Abbreviations .............................................................................................................................. ...........................3 General requirements and recommendations for the SSCP ..........................................................................4 Validation and uploading of the SSCP ...............................................................................................................7 Guidance for each of the required sections of the SSCP document ...........................................................10 1. The identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN .........................................................................................................................10 2. The intended purpose of the device and any indications, contraindications and target populations .............................................................................................................................. ..................11 3. A description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intended to be used in combination with the device .............................................................................................................................. ....................11 4. Information on any residual risks and any undesirable effects, warnings and precautions ......12 5. The summary of clinical evaluation as referred to in Annex XIV, and relevant information on post-market clinical follow-up .................................................................................................................15 6. Possible diagnostic or therapeutic alternatives ...............................................................................18 7. Suggested profile and training for users ...........................................................................................19 8. Reference to any harmonised standards and CS applied .............................................................19 9. Revision history .............................................................................................................................. ......19 References .............................................................................................................................. .............................20 Appendix: Template for the SSCP ....................................................................................................................21 Medical Device Medical Device Coordination Group Document MDCG 2019-9 3(24) Introduction The Regulation (EU) 2017/745 on medical devices (1) requires that the manufacturer shall draw up a summary of safety and clinical performance (SSCP) for implantable devices and for class III devices, other than custom-made or investigational devices. The SSCP shall be validated by a notified body (NB) and made available to the public via the European database on medical devices (Eudamed) 1. The SSCP is intended to provide public access to an updated summary of clinical data 2 and other information about the safety and clinical performance of the medical device. The SSCP will be an important source of information for intended users – both healthcare professionals and if relevant for patients. It is one of several means intended to fulfil the objectives of the Medical Device Regulation (MDR) to enhance transparency and provide adequate access to information 3. The SSCP is not intended to:  give general advice on the diagnosis or treatment of particular medical conditions, nor  replace the instructions for use (IFU) as the main document that will be provided to ensure the safe use of a particular device, nor  replace the mandatory information on implant cards 4 or in any other mandatory documents. The main purpose of this document is to provide guidance on the presentation, content and validation of the SSCP. The word “shall” is used when there is a corresponding “shall” in the MDR, otherwise “should” or “recommended” etc. is used indicating the interpretation of the MDR. Abbreviations CIV ID clinical investigation identification number, generated by Eudamed for clinical investigations under the Medical Device Directives (2) (3) CMR carcinogenic, mutagenic or toxic to reproduction CS ‘common specifications’ as defined in the MDR 5 EU European Union Eudamed European database on medical devices FSCA field safety corrective action 6 FSN field safety notice7 1 MDR, Article 32 (1) 2 MDR, Article 32 (2)(f) , Article 61 (11) and Article 83 (3)(d) 3 MDR, Recital (43) 4 MDR, Article 18 5 MDR, Article 2 (71) 6 MDR, Article 2 (68) Medical Device Medical Device Coordination Group Document MDCG 2019-9 4(24) IFU instructions for use MDR Medical Device Regulation (1) NB notified body 8 PMCF post-market clinical follow-up9 PMS post-market surveillance10 PSUR periodic safety update report11 SRN single registration number for an economic operator12 SSCP summary of safety and clinical performance TD technical documentation 13 UDI-DI Unique Device Identification - device identifier14 URL Uniform Resource Locator (internet address) General requirements and re commendations for the SSCP The information in the SSCP should be sourced entirely from the technical documentation (TD) of the device 15. Examples of such documents are design verification/validation reports, the risk management report/file, the clinical evaluation report, and post-market surveillance (P MS) and post-market clinical follow-up (PMCF) plans and reports. The IFU includes information extracted from the same sources as the SSCP, but may itself be used as a source for the SSCP if appropriate. The SSCP shall be kept updated in Eudamed 16. When the PMCF evaluation report17 and the periodic safety update report (PSUR)18 are updated at least annually19, the SSCP shall be reviewed and updated20 if needed to ensure that any clinical and/or safety information in the SSCP remains correct and complete. When updating the SSCP, all sections of the document shall be updated if needed so that they are in alignment with the most current version of the relevant parts of the TD of the device. This guide outlines the minimum content of the SSCP. The manufacturer may add further information from the TD of the device to enhance the comprehension of the mandatory information providing:  it does not affect the readability of the SSCP and  it excludes any element of a promotional nature. 7 MDR, Article 2(69) 8 MDR, Article 2 (42) 9 MDR, Annex XIV Part B 10 MDR, Article 2 (60) 11 MDR, Article 86 Periodic safety update report 12 MDR, Article 31(2) 13 MDR, as specified in Annexes II and III. 14 MDR, Article 2 (15) and Article 27 15 MDR, Annex II and III 16 MDR, Article 29 (4) and Annex VI Part A 2.14 17 MDR, Article 61 (11) 18 MDR, Article 86 (1) 19 MDR Article 86 (1); PSUR for class IIa devices shall be updated when necessary and at least every two years 20 MDR, Article 61 (11) and Article 83 (3)(d) Medical Device Medical Device Coordination Group Document MDCG 2019-9 5(24) The SSCP shall be objective and adequately summarise both favourable and unfavourable data21. For further guidance on the contents of the SSCP, please refer to sections 1-8 of this document and to the template in the Appendix. The format and structure of this template is recommended. It addresses all of the SSCP content requirements of the MDR 22, but the order has been revised to enhance its presentation. The IFU shall contain all that is needed to directly find the SSCP in Eudamed. The following applies to the IFU 23.  It shall state that the SSCP is available in the European database on medical devices (Eudamed), where it is linked to the Basic UDI-DI.  It should provide the URL to the Eudamed public website: https://ec.europa.eu/tools/eudamed  It should state the value of the Basic UDI-DI. Alternatively, another metadata can be stated provided it can be used to unambiguously search and find the intended SSCP in Eudamed. Translations to other EU languages No single language will be understood by all intended users and patients in the EU – see the European Survey on Language Competences initiated by the European Commission (4). In order to meet the requirement in the MDR that the SSCP shall be written in a way that is clear to the intended user and, if relevant, to the patient 24, the SSCP should be translated into the languages accepted in the Member States where the device is envisaged to be sold. This is by analogy with the requirement for an IFU 25. Note that Member States may have different language requirements for an IFU depending on whether the information is intended for health care professionals or for patients. The SSCP part intended for patients should be provided in all the languages required for IFUs intended for patients in the Member States concerned. If the selection of European languages for the SSCP does not include English, then an English translation of the document should also be provided. English is the most common language used in medical scientific publications and is understood by many healthcare professionals in the EU. Always providing an English-language version of the SSCP further enhances access to information 26 about devices available on the EU market. There should be one SSCP document for each language. Each SSCP document should state in which language the SSCP was validated by the NB. The manufacturer should ensure, through their quality management system, that the translations are correct. 21 MDR, Annex XIV, Part A Clinical evaluation, (2) 22 MDR, Article 32 (2) 23 MDR, Article 32 (1) and Annex I, 23.4 (d) 24 MDR, Article 32 (1) and Recital (43) 25 MDR, Annex II (2), Article 10 (11) 26 MDR, Recital (43) Medical Device Medical Device Coordination Group Document MDCG 2019-9 6(24) Relevant SSCP information for patients The MDR indicates that patients are also intended recipients of the information in the SSCP, “if relevant” 27. Devices for which information will be especially relevant for patients include:  implantable devices for which patients will be given implant cards28, and  class III devices that are intended to be used directly by patients. For these devices, a part of the SSCP specifically intended for patients should be provided. Note: Devices listed in MDR Annex XVI, and eligible for a SSCP, should always be considered as relevant for patient information. For devices other than the two groups listed above, including any devices listed in Annex XVI and eligible for a SSCP, the manufacturer may consider whether it is relevant to provide specific information intended for patients. This can be based on the manufacturer’s analysis of the device in question. Readability The SSCP should always have one part for intended users/healthcare professionals, and when it is relevant (see above) a second part for patients. Both should be clear and provide information at an appropriate depth to reflect the healthcare professionals’ and the patients’ different levels of knowledge 29. For further guidance, see references (5) and (6) in this guide. It should not be assumed that the patient has any formal education in a medical discipline or any prior knowledge of medical terminology or clinical research. It is recommended that the readability of the part of the SSCP intended for patients is assessed for example by a test given to lay persons. The manufacturer may use a method it finds adequate for the readability test to confirm that the SSCP is written in a way that is clear to the patient 30. Medical terminology, relevant for the medical device and the clinical context, should be used consistently throughout the part of the SSCP that is intended for healthcare professionals. Stylistic recommendations The SSCP should be presented in an organised and unambiguous manner. Usually, abbreviations and acronyms should not be used; if they are, then in the text, the abbreviation or acronym should follow the full phrase it is intended to replace. It may then be used thereafter throughout the document. 27 MDR, Article 32 (1) 28 MDR, Article 18 29 MDR, Article 32 (1) and Recital (43) 30 MDR, Article 32(1), Article 2 (38) Medical Device Medical Device Coordination Group Document MDCG 2019-9 7(24) Medical terms should be explained in simple language in the parts intended for patients. Consistency should be assured by giving the lay term with a description first, and then the medical term immediately afterwards (in brackets). On a case-by-case basis the lay or medical term (but preferably the lay term) may then be used throughout the part intended for patients. It is recommended to keep the information for patients/lay persons and for intended users/healthcare professionals in two separate parts of the SSCP, separated by a “page break”. This enhances their readability and facilitates printing of each part separately. See the template in the Appendix of this document. The SSCP should be written in a font type and size which allow easy reading. Since the SSCP is intended for the public, it needs to be in a format that everyone can read (and that is not editable) without the need for a license. Therefore the SSCP file uploaded in Eudamed should be in PDF format. When downloaded, the PDF file should be printable and searchable with t he search function in the program used to view the file, for example the Adobe Reader. Validation and uploading of the SSCP Validation of the initial SSCP by the NB When the NB has assessed that all the required elements 31 are included in the draft SSCP, accurately presented and in alignment with the most current version of relevant documents in the TD, the SSCP has been validated by the NB. In the circumstance that the conformity assessment is performed according to Annex X and XI in the MDR and there are two NBs involved, it is the NB which assesses the TD according to Annex X that shall validate the SSCP. The validation of the SSCP by the NB covers only one of the language(s) accepted by the NB and agreed with the manufacturer. The manufacturer should state in the revision history in each SSCP document in which language the SSCP was validated by the NB. The timing of the SSCP validation may depend on the class of device and the conformity assessment routes:  For class III devices and class IIb im plantable devices, except sutures and staples etc. 32, the validation is performed when a draft SSCP as a part of the application documents is submitted to the NB involved in the conformity assessment 33, prior to issuing the certificate.  For class IIa implantable and some IIb implantable devices such as sutures and staples etc34, a draft SSCP as a part of the application documents shall be submitted to the NB involved in the conformity assessment. The draft 31 MDR, Article 32 (2), Article 61 (11), and Article 83 (3) (d) 32 MDR, Article 52 (4) 2nd paragraph 33 MDR, Article 32 (1) 34 MDR, Article 52 (4) 2nd paragraph Medical Device Medical Device Coordination Group Document MDCG 2019-9 8(24) SSCP shall be validated by the NB35. In the circumstance if more than one device is covered by the relevant certificate, at least one draft SSCP shall be validated against relevant documents in the TD during the initial conformity assessment, prior to issuing the certificate. Draft SSCPs that are not validated at the initial conformity assessment, shall be validated against relevant documents in the TD at least once during the period of validity of the certificate. Validation of updates of the SSCP between certifica tion activities The manufacturer has an obligation to keep the SSCP updated; for further details see the section “General requirements and recommendations for the SSCP” in this guide. Furthermore the manufacturer shall prepare a periodic safety update report (PSUR) that includes data gathered as a result of the post-market surveillance plan, description of any preventive and corrective actions taken, conclusions of the benefit-risk determination, and the main findings of the PMCF 36. If the PSUR contains information rendering any information in the SSCP incorrect or incomplete, the SSCP shall be updated 37 to be in line with the information in the most recent PSUR. The manufacturer shall submit a PSUR to the NB at least annually, or for class IIa implantable devices 38 at least every two years39. If the SSCP has been updated with new/changed information, except for strictly editorial modifications, the manufacturer should submit the updated SSCP to the NB when submitting the required PSUR.  If the SSCP has been previously validated, the NB should validate the updated SSCP against the submitted and evaluated PSUR. Both the NB and the manufacturer should make an effort to keep the validation time short in order to meet the MDR requirement of an update of the SSCP at least annually if indicated 40.  If the SSCP has not previously been validated41, the NB may defer the validation until a validation against the relevant documents in the TD is planned during the period of validity of the certificate. In addition, as part of its surveillance activities, the NB shall verify that the manufacturer has appropriately updated the SSCP. The NB should take into consideration its assessment of the PMS plan and PSUR, the PMCF plan and its evaluation report, and/or other relevant information. 35 MDR, Article 32 (1) 36 MDR, Article 86 (1) 37 MDR, Article 29 (4) and Annex VI Part A 2.14, and Article 61 (11) and Article 83 (3)(d) 38 In this context applicable for implantable devices intend ed to be placed in the teeth, MDR Annex VIII, 5.4. Rule 8) 39 MDR, Article 86 (1) 40 MDR, Article 61 (11) 41 May only be applicable for class IIa implantable devices and some IIb implantable devices such as sutures, staples etc. as listed in MDR, Article 52 (4) 2nd paragraph Medical Device Medical Device Coordination Group Document MDCG 2019-9 9(24) Validation of SSCP at certificate renewal With each certificate renewal application, the manufacturer should:  For class III devices and class IIb impl antable devices, other than sutures and staples etc. 42, submit a draft SSCP which has been updated within the previous 12 months, regardless of whether there are new data or conclusions.  For class IIa implantable and IIb implantable devices, such as sutures and staples etc.43, confirm that the SSCP in Eudamed is in alignment with the current version of the TD, or provide an updated SSCP where required. At certificate renewal, the same principles should apply for the validation of the SSCP documents as at the initial certification. Uploading of the SSCP in Eudamed The SSCP shall be uploaded in Eudamed by the NB 44, which is the only actor that can manage the SSCPs in Eudamed. Timelines for uploading of the SSCP documents in Eudamed:  The NB shall upload the SSCP validated in conjunction with an initial conformity assessment at the same time that it uploads the issued certificate.  For class IIa implantable and IIb implantable devices, such as sutures and staples etc. 45, the NB shall upload the SSCPs of all the devices covered by the issued certificate at the same time that it uploads the issued certificate, even if some of the SSCPs have not been validated yet, and are to be validated during the period of validity of the certificate. The manufacturer should state in a revision history in the SSCP document whether that revision was validated by the NB. It is important and should be transparent to the public 46 whether the SSCP document has been validated yet by the NB. See the example of a revision history in section 9 and in the template in the Appendix of this guide.  The NB shall upload a SSCP whenever it has been validated against relevant documents in the TD, and thus replacing the SSCP uploaded at the initial certification with the currently validated revision.  The manufacturer is responsible for the translations of the SSCP into other languages 47, once the “master” SSCP has been uploaded by the NB. If the “master” SSCP is in a language other than English, then an English translation should be provided by the manufacturer within 90 days of the upload of the “master” SSCP. The NB should upload the English translation within 15 days of receiving this from the manufacturer.  The manufacturer decides when it translates the initial “master” SSCP into other languages in the Member States depending on when/if they plan to place the product on that market. 42 MDR, Article 52 (4) 2nd paragraph 43 MDR, Article 52 (4) 2nd paragraph 44 MDR, Article 32 (1) 45 MDR, Article 52 (4) 2nd paragraph 46 MDR, Recital (43) 47 See page 4 in this guide, Translations to other EU languages; The manufacturer should ensure, through their quality management system, that the translations are correct. Medical Device Medical Device Coordination Group Document MDCG 2019-9 10(24) The NB does not validate the translated SSCP documents. It should upload them in Eudamed within 15 days of receiving them. The manufacturer shall verify that the SSCP, and any translations needed for any single Member State, have been uploaded in Eudamed before placing a device on that market 48.  When receiving an updated SSCP document in conjunction with the PSUR, the NB should upload the updated SSCP document within 15 days after it is validated, or within 15 days after deeming the validation to be deferred 49 until a validation against the relevant documents in the TD is planned during the period of validity of the certificate.  At certificate renewal, the NB shall upload any updated SSCPs of all the devices covered by the reissued certificate at the same time that it uploads the reissued certificate. The NB should ensure the revision history indicates whether or not these have been validated by the NB.  The manufacturer should provide updated translations to the NB within 90 days of the upload of the updated “master” SSCP. The NB should upload these translations within 15 days of receiving them from the manufacturer. Guidance for each of the required sections of the SSCP document 1. The identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN The first section of the SSCP shall ident ify the device and the manufacturer, and should also contain some general information related to the device: 1.1. Device trade name(s) (this include all trade names the device may have on the market in different Member States) 1.2. Manufacturer’s name and address 1.3. Manufacturer’s SRN (single registration number) 1.4. Basic UDI-DI 1.5. Medical device nomenclature 50 description / text 1.6. Class of device51 1.7. Year when the first certificate (CE) was issued covering the device 1.8. Authorised representative if applicable; name and the SRN 1.9. NB’s name (the NB that will va lidate the SSCP) and the NB’s single identification number 52 48 MDR, Article 29 (4) and Section 2 of Part A of Annex VI (2.14) 49 May only be applicable for class IIa implantable devices and some IIb implantable devices as listed in MDR, Article 52 (4) 2nd paragraph 50 MDR, Article 26 51 MDR, Annex VIII 52 MDR, Article 43 (1) Medical Device Medical Device Coordination Group Document MDCG 2019-9 11(24) 2. The intended purpose of the device and any indications, contraindications and target populations 2.1. The device's intended purpose(s) shall be described. 2.2. The indications shall be described. This includes the stages and/or severities of the pathologies, the specific medical conditions, and the specific anatomical locations or confirmation that no anatomical locations are contraindicated, as applicable. The target population(s) shall be specified, for example if the device is intended for adults and/or children and/or infants/neonates. 2.3. Any contraindications or restrictions for use or limitations of the device shall be included. The information can be sourced from the IFU, or from the clinical evaluation report. 3. A description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intende d to be used in comb ination with the device 3.1. A description of the device shall be presented, including its operating principles and mode(s) of action. Design characteristics should be included, for example key functional elements and any materials or substances in contact with the patient’s tissues. Include information on whether the device is for single use, and its method of sterilisation. For absorbable implants the stability retention profile, including time to loss of stability and the absorption time, should be provided. A picture or drawing can be added accompanied by text. Information about the constituents should be provided, as required for the IFU 53, if the device incorporates  a medicinal substance (including a human blood or plasma derivative), or  tissue(s) or cells of human or animal origin, or their derivatives, or  substances or combinations of subs tances that are absorbed by or locally dispersed in the human body, or  materials incorporated into the device that contain or consist of CMR (carcinogenic, mutagenic or toxic to reproduction) substances or endocrine-disrupting substances, or  materials that could result in sensitisation or an allergic reaction by the patient or user. In Eudamed, the SSCP is associated to one unique Basic UDI-DI. All UDI-DIs/devices associated to this Basic UDI-DI will be seen as having the same 53 MDR, Annex I (23.2) (e) and (r), and (23.4) (s) Medical Device Medical Device Coordination Group Document MDCG 2019-9 12(24) SSCP (a UDI-DI/device must always be associated with one and only one Basic UDI-DI). If the device is a system of several components/devices, each device in the system should have a Basic UDI-DI but also one Basic UDI-DI for the system. It is the Basic UDI-DI for the system that is intended to be provided in section 1.4 in the template, and that will be associated with the SSCP in Eudamed. The device system, and any Basic UDI-DIs of included devices, should be described in section 3.1. The device description in the SSCP shall therefore include all the device(s)/device system associated with the same Basic UDI-DI. The description of the device(s)/device system should be comprehensive and can be presented in different ways to include, if such exist, any configurations / combinations / different sizes / specification of any soft-ware versions that can be related to safety and/or performance and their release dates / etc. The description should also include any model number or similar designation used to identify the device(s)/device system. 3.2. A reference to previous generation(s) or variants shall be provided, if such exist. This applies both to changes/variants of the device itself (same Basic UDI-DI) and to previous generation(s) or variants associated with other Basic UDI-DIs, if available. A description of the differences shall be provided, highlighting the reasons for the change; for example changes to the intended clinical benefits, changes to reduce iden tified clinical risks, or changes for manufacturing reasons etc. 3.3. If there are any accessories 54 that are not themselves devices, but are intended by the manufacturer to be used in combination with the device, they shall be described or listed. The list of accessories should include all those that are essential for the safe and correct use of the device. 3.4. If there are any other devices and products intended to be used in combination with the device, they shall be described or listed. However, generic surgical equipment and/or other generic devices do not need to be listed. In the part of the SSCP that is intended for patients, section 3 may be limited to the device(s) in question (Basic UDI-DI) including relevant and necessary accessories from a patient’s perspective; see suggested headings for section 3 in the template in the Appendix. 4. Information on any residual risks and any undesirable effects, warnings and precautions 54 MDR, Article 2 (2) Medical Device Medical Device Coordination Group Document MDCG 2019-9 13(24) 4.1. Residual risks and undesirable effects This section of the SSCP guide and template includes residual risks 55, other than those contraindications, limitations, warnings and precautions that are included in sections 2.3 and 4.2. Description of residual risks and undesirable effects Risk is defined in the MDR 56 as the combination of the probability of occurrence of harm and the severity of that harm. Harm is defined in the standard ISO 14971:2012 57 as physical injury or damage to the health of people, or damage to property or the environment. Thus the term ‘risk’ includes both clinical and non-clinical harms. The term ‘residual risk’ is defined in the standard ISO 14971:2012 58 as “risk remaining after risk control measures have been taken”. There is a requirement in the MDR that the IFU shall contain information on any residual risks and any undesirable side-effects 59, i.e. no sort of residual risk or undesirable side-effect related to the device is excluded from disclosure. The SSCP should contain information on at least the same residual risks and undesirable side-e ffects as included in the IFU. For the purpose of the SSCP, an undesirable effect 60 can be understood as any undesirable side-effect related to the device and that is experienced by the patient and/or can be diagnosed and/or measured in the patient. For the clarity of the SSCP, undesirable side-effects can be annotated also in other terms as appropriate, to present any undesirable side-effects related to the device in question. There may be device-specific terminology for describing side-effects and risks in device -specific ISO standards or scientific literature that is important to use to allow comparison of clinical data. For example, some events indicated in the MDR by the terms ‘adverse events’ 61, ‘undesirable side-effects’ or ‘incidents’62, may all be annotated as ‘adverse events’ in the scientific literature. Any further discussion on risks can be included in the SSCP if needed for clarity or comprehension. Quantitative data The definition of risk 63 includes the probability of occurrence of harm. Therefore the information in the SSCP on risks shall also include 55 MDR, Annex I, (23.1) (g) 56 MDR, Article 2 (23) 57 EN ISO 14971:2012 Medical devices – Application of risk management to medical devices, section 2.2 58 EN ISO 14971:2012 Medical devices – Application of risk management to medical devices, section 2.15 59 MDR, Annex I , 23.4 (g) 60 MDR, Article 32 (2) (h) 61 MDR, Article 2 (57) 62 MDR, Article 2 (64) Medical Device Medical Device Coordination Group Document MDCG 2019-9 14(24) quantifications. This information can be sourced from the clinical evaluation report where an updated examination of qualitative and quantitative aspects of clinical safety is available, with clear reference to the determination of residual risks and side-effects 64. It should also be clarified in the SSCP whether quantitative data on side-effects or residual risks rela te to clinical data that were obtained proactively, for example from a structured prospective follow-up study of the device itself, or if the expected frequencies 65 come from a systematic review of the scientific literature. It should be disclosed in the SSCP if data from spontaneously reported incidents or serious incidents 66 are used as one of the sources for estimating quantitative data on side-effects or residual risks, in which case significant under-reporting needs to be considered. A relation to time should also be included when presenting the quantitative data, for example during five or ten years of use from implantation, or adverse events per 100 patient-years for implantable devices with constant hazards, etc. The quantitative data and the relation to time should always be presented together. To use tabulated lists for the presentation of side-effects and residual risks with quantitative data and a relation to time, may enhance the readability. In the part of the SSCP that is intended for patients, residual risks and side-effects should be explained and quantified in a way that patients and lay persons can understand. A statement should be included about how potential risks have been controlled or managed, and also a statement on what to do if the patient believes that he/she is experiencing side-effects related to the device or its use. See the example in the template in the Appendix. 4.2. All warnings and precautions pertaining to the device should be presented. However warnings and precautions solely related to for example installation/preparation of a device or relating to special procedural steps can be discussed on a general level in the SSCP if a link (URL) to the IFU on the manufacturer’s website is provided. Always include any warnings, precautions or measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions. If any particular clinical follow-up is necessary and mentioned in the IFU, that information should also be included in the SSCP. 63 MDR, Article 2 (23) 64 MDR, Annex XIV, Part A Clinical evaluation, (1) 65 MDR, Article 88 (1) 66 MDR, Article 2 (64) and (65) Medical Device Medical Device Coordination Group Document MDCG 2019-9 15(24) 4.3. Other relevant aspects of safety s hould be described. If the device has been subject to any field safety corrective action (FSCA including FSN), the date of the FSCA and a summary of the associated circumstances and any actions undertaken should also be included. 5. The summary of clinical evaluation as referred to in Annex XIV, and relevant information on post-market clinical follow-up This part of section 5 relates to content intended for the user/healthcare professional. This section is intended to summarise, in a comprehensive manner, the clinical evaluation results and the clinical data 67 forming the clinical evidence68 for the confirmation of conformity with relevant general safety and performance requirements 69, the evaluation of undesirable si de-effects and the acceptability of the benefit-risk ratio70. It shall be an objective and balanced summary of the clinical evaluation 71 results of all the available clinical data related to the device in question, whether favourable, unfavourable, and/or inconclusive. See suggested headings for this section in the Appendix of this document. 5.1. The SSCP should include a statement if conformity of the device was assessed and endorsed by the NB on the basis of equivalence. If equivalence was used, t hen the device(s) for whic h equivalenc e has been demonstrated should be identified by name and Basic UDI-DI if available, together with the name(s) of its/their manufacturer(s). The SSCP should also include a statement whether the equivalent device’s SSCP is available in Eudamed. If not available in Eudamed, the SSCP should include a summary of the clinical data pertaining to the equivalent device, written in accordance with the recommendations of this section 5, with a clear note that it relates to the equivalent device. It should be evident from the summary what the clinical evidence for the equivalent device was based on: whether it was clinical investigations of that device itself, or if any other data were used and then the sources of that data. Also include a summary of how long-term safety and performance of the equivalent device has been confirmed. 5.2. All clinical investigations of the device in question, conducted before the CE- marking, should be summarised. It is recommended to keep the format clear 67 MDR, Article 61 (11) and Article 2 (48) 68 MDR, Article 2 (51) 69 MDR, Annex I 70 MDR, Article 61 (1) and Annex XIV, Part A (1) 71 MDR, Annex XIV, Part A (2) Medical Device Medical Device Coordination Group Document MDCG 2019-9 16(24) by grouping the information for each study. The summary of each investigation should include the following non-exclusive list:  Identity of the investigation/study: If performed under the Medical Device Directives or the MDR, then give the CIV ID or single identification number. Add reference details if the clinical investigation report is available in Eudamed 72. For other studies, the title of the study and a clear reference to a clinical trials database or publication where detailed data on the study can be found (7) 73 should be included. In the circumstance that the investigation/study was conducted outside EU, identify the country/-ies where it was performed.  Identity of the device including any model number/version  Intended use of the device in the investigation  Objectives of the study  Study design: randomised controlled trial, other pivotal trial, short-term feasibility study, other; and the duration of the follow-up  Primary and secondary endpoint(s)  Inclusion/exclusion criteria for subject selection  Number of enrolled subjects, including if applicable in different treatment arms  Study population: main baseline characteristics of each study group, including gender and age of enrolled subjects  Summary of study methods  Summary of results: any clinical benefits 74; any undesirable side-effects or adverse events, and their frequency in relation to time; any results on long-term benefits or risks, for exampl e implant survival rates at 5 or 10 years and/or cumulative experience in patient-years. A statement of percentage completeness of follow-up should be provided. Add a note if the study is still ongoing for long-term follow up.  Any limitations of the study, such as high loss to follow-up, or potential confounding factors that may question the results.  Any device deficiency and any device replacements related to safety and/or performance during the study. 5.3. Summary of other clinical data and the main findings pertaining to the device itself should be included if available. This can be sourced 75 for example from:  A systematic literature review yielding articles in which the device in question was used. References to these articles should be provided. A bibliography can be added at the end of the SSCP document if there are many references.  Clinically relevant information based on clinical data obtained from the implementation of the manufacturer’s PMCF and PMS plans, such as: 72 MDR, Article 77 (7) 73 WMA Declaration of Helsinki, sections 35, 36, MDR Recital (64) 74 MDR, Article 2 (53) 75 MDR, Article 2 (48) Medical Device Medical Device Coordination Group Document MDCG 2019-9 17(24) - Conducted PMCF investigation(s)76; include information on each study as outlined in section 5.2 in this guide. - New or changed likelihood of an undesirable side-effect(s), or significant increase in the frequency or severity of incidents, or any identified trends77, or any other main findings from the PMCF evaluation report or PSUR78.  Analysis of clinical data from medical device registries. Any known limitations such as incomplete follow-up should be disclosed. 5.4. An overall summary of the clinical performance79 and safety should be provided, and that is supported by clinical evidence80, based on clinical data and the clinical evaluation results pertaining to the device in question. It is recommended that the overall summary should include the following:  The clinical performance normally leads to clinical benefits for the patient. Give a description of the documented clinical benefits 81 for patients with relevant and specified clinical outcome measures, and the success rate for achieving the outcome measures. This should be described for all clinical claims the manufacturer presents in the IFU, and in any information, marketing, or promotional material that it distributes. For a non-absorbable implant, there should also be information about the expected lifetime of the device including data on implant survival rates.  Benefit-risk assessment for the various indications including the acceptability of the benefit-risk ratio 82. This includes a summary of the evaluation of undesirable side-effects. In the case of a device without an intended medical purpose 83, the requirement to demonstrate clinical benefit shall be understood as a requirement to demonstrate the performance of the device. The summary of the clinical evaluation shall be based on relevant data concerning safety and performance 84. 5.5. The SSCP shall have a section on planned or ongoing PMCF85 that should include the following (non-exclusive list):  Summary of the latest approved PMCF plan for the device. Include any planned or ongoing studies (brief description), and if there are any unanswered questions relating to the use of the device and how they will be investigated. 76 MDR, Article 74 (1) 77 MDR, Article 88 (1) and Annex XIV Part B (6.1) (b) 78 MDR, Article 61 (11), Article 83 (3) (d) 79 MDR, Article 2 (52) 80 MDR, Article 61 (1) and Article 2 (51) 81 MDR, Article 2 (53) 82 MDR, Article 61 (1) and Annex I Sections 1 and 8 83 MDR, Annex XVI 84 MDR, Article 61 (9) 85 MDR, Annex XIV Part B Medical Device Medical Device Coordination Group Document MDCG 2019-9 18(24)  If any emerging risks, complicati ons or unexpected device failures have been detected, and how these will be followed up. The information on clinical evaluation and PMCF intended for patients, in section 5 The part of the SSCP intended for patients should be provided with a brief summary which enables the patient to understand the basis upon which clinical safety and perform ance has been de monstrated. The su mmary shoul d include the following (non-exclusive list):  Clinical background of the device A description of the relative novelty of the device: if the product has a proven clinical track record of safety and performance, or if there are one or more novel design features.  The clinical evidence for the CE marking A description whether clinical evidence is based on data concerning an equivalent device, on data collected during a clinical investigation of the device itself, or on a combination of the two. A short lay-summary of the clinical investigations performed on the device itself should be given, if such exist. If there are clinical investigation reports on the device itself available in Eudamed, this should be stated and identification numbers should be given 86 (CIV ID or single identification number). The summary should not make misleading claims regarding the strength of clinical evidence, either by direct reporting or omission.  Safety - A description of the benefit-risk a ssessments related to safety and performance for each indication claimed by the manufacturer, including information to address benefit-risk issues of interest to specific patient populations, if applicable. - A description of how the manufacturer continuously collects information on safety and performance and in particular if any clinical studies (PMCF) are ongoing or planned. A description of the purpose of any such studies, for example to corroborate safety and performance claims based on equivalence data, or to demonstrate long-term safety. 6. Possible diagnostic or therapeutic alternatives This part of the SSCP document should contain a review of how the device relates, in terms of benefit-risk, to diagnostic or therapeutic alternatives and the specific conditions under which the device and its alternatives can be considered 87. 86 MDR, Article 77 (7) 87 MDR, Recital 49 Medical Device Medical Device Coordination Group Document MDCG 2019-9 19(24) If reference is made to the “state of the art”, that statement should be supported for example by referring to relevant recognised guidance documents generated by specialty medical societies or educational bodies. In the part of the SSCP intended for patients the text should include a recommendation to discuss any possible diagnostic or therapeutic alternatives with a healthcare professional who can take into consideration the individual patient’s situation. See the proposed text in the template in the Appendix. 7. Suggested profile and training for users The experience, education and/or training of the intended user(s) shall be described 88. This includes any specific mandatory training before using the device, and any update training for continued safe use of the device. If the device is intended to be handled directly by the patient, section 7 should be included in the SSCP part intended for patients and any required training should be described. 8. Reference to any harmonised standards and CS applied A list with all applied common specifications (CS), international standards harmonised under the Medical Device Directives (2)(3) and/or the MDR, and relevant adopted monographs of the European Pharmacopoeia 89 shall be provided. The year/revision of the applied CS, standard or monograph, should be listed together with information whether it was applied in full or in part. The year/revision of an applied harmonised standard or CS may change in the technical documentation for the device. However, an update of the SSCP concerning this change can wait until the next revision of the SSCP is issued. This list in section 8 does not need to be included in the part of the SSCP that is intended for patients. 9. Revision history The SSCP document should include a revision history. The purpose is to include the following information:  The SSCP revision number  Date when the revision was issued 88 By analogy with the IFU, see MDR, Annex I, 23.1 (a) 89 MDR, Article 8 (2) Medical Device Medical Device Coordination Group Document MDCG 2019-9 20(24)  Description of the main changes  In which language the SSCP was validated by the NB  In case of a SSCP on class IIa implantable or some90 IIb implantable devices; whether the SSCP revision has been validated yet or not by the NB See an example of a table for a Revision history in the Appendix of this guide. References 1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2017:117:TOC 2. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:01993L0042-20071011 3. Council Directive of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (90/385/EEC) http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:01990L0385-20071011 4. The European Survey on Language Competences: measuring foreign language student proficiency. Patrícia Costa and Patrícia Albergaria-Almeida / Procedia - Social and Behavioral Sciences 191 (2015) 2369 – 2373 https://www.sciencedirect.com/science/article/pii/S187704281502515X 5. Summaries of Clinical Trials Results for Laypersons https://ec.europa.eu/health/sites/health/files/files/eudralex/vol- 10/2017_01_26_summaries_of_ct_results_for_laypersons.pdf 6. Common European Framework of Reference for Languages: Learning, teaching, assessment (CEFR) https://www.coe.int/en/web/common-european-framework-reference- languages/home 7. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles- for-medical-research-involving-human-subjects/ 90 MDR, Article 52 (4) 2nd paragraph Medical Device Medical Device Coordination Group Document MDCG 2019-9 21(24) Appendix: Template for the SSCP Texts in italic in the template are general information texts proposed to be included in the SSCP document. Note that there shall always be SSCP information dedicated to users/healthcare professionals for all implantable devices and for all class III devices, other than custom-made or investigational devices. When relevant, a second part dedicated to patients/lay persons should be added. See further recommendations on relevant SSCP information for patients in this guide. Summary of safety and clinical performance This Summary of Safety and Clinical Perform ance (SSCP) is intend ed to provide public access to an updated summary of the main aspects of the safety and clinical performance of the device. The SSCP is not intended to replace the Instructions For Use as the main document to ensure the safe use of the device, nor is it intended to provide diagnostic or therapeutic suggestions to intended users or patients. The following information is intended for users/healthcare professionals. If the SSCP includes a part intended for patients, the following can be added: Following this information there is a summary intended for patients . 1. Device identification and general information 1.1. Device trade name(s) 1.2. Manufacturer’s name and address 1.3. Manufacturer’s single registration number (SRN) 1.4. Basic UDI-DI 1.5. Medical device nomenclature description / text 1.6. Class of device 1.7. Year when the first certificate (CE) was issued covering the device 1.8. Authorised representative if applicable; name and the SRN 1.9. NB’s name (the NB that will validate the SSCP) and the NB’s single identification number 2. Intended use of the device 2.1. Intended purpose 2.2. Indication(s) and target population(s) 2.3. Contraindications and/or limitations Medical Device Medical Device Coordination Group Document MDCG 2019-9 22(24) 3. Device description 3.1. Description of the device 3.2. A reference to previous generation(s) or variants if such exist, and a description of the differences 3.3. Description of any accessories which are intended to be used in combination with the device 3.4. Description of any other devices and products which are intended to be used in combination with the device 4. Risks and warnings 4.1. Residual risks and undesirable effects 4.2. Warnings and precautions 4.3. Other relevant aspects of safety, including a summary of any field safety corrective action (FSCA including FSN) if applicable 5. Summary of clinical evaluation and post-market clinical follow-up (PMCF) 5.1. Summary of clinical data related to equivalent device, if applicable 5.2. Summary of clinical data from conducted investigations of the device before the CE-marking, if applicable 5.3. Summary of clinical data from other sources, if applicable 5.4. An overall summary of the clinical performance and safety 5.5. Ongoing or planned post-market clinical follow-up 6. Possible diagnostic or therapeutic alternatives 7. Suggested profile and training for users 8. Reference to any harmonised standards and CS applied 9. Revision history SSCP revision number Date issued Change description Revision validated by the Notified Body Yes Validation language: No (only applicable for class IIa or some IIb implantable devices (MDR, Article 52 (4) 2 nd paragraph) for which the SSCP is not yet validated by the NB) Yes Validation language: No If the SSCP concerns a device for which it is relevant to provide information to patients in lay man’s language, the following text can be included and then followed by a “page break”: Medical Device Medical Device Coordination Group Document MDCG 2019-9 23(24) A summary of the safety and clinical performance of the device, intended for patients, is given below. Summary of safety and clinical performance Document revision: Date issued: This Summary of Safety and Clinical Perform ance (SSCP) is intend ed to provide public access to an updated summary of the main aspects of the safety and clinical performance of the device. The information presented below is intended for patients or lay persons. A more extensive summary of its safety and clinical performance prepared for healthcare professionals is found in the first part of this document. The SSCP is not intended to give general advice on the treatment of a medical condition. Please contact your healthcare professional in case you have questions about your medical condition or about the us e of the device in your situation. This SSCP is not intended to replace an Implant card or the Instructions For Use to provide information on the safe use of the device. 1. Device identification and general information o Device trade name o Manufacturer; name and address o Basic UDI-DI o Year when the device was first CE-marked 2. Intended use of the device o Intended purpose o Indications and intended patient groups o Contraindications 3. Device description o Device description and material/substances in contact with patient tissues o Information about medicinal substances in the device, if any o Description of how the device is achieving its intended mode of action o Description of accessories, if any 4. Risks and warnings Contact your healthcare professional if you believe that you are experiencing side- effects related to the device or its use or if you are concerned about risks. This document is not intended to replace a consultation with your healthcare professional if needed. o How potential risks have been controlled or managed o Remaining risks and undesirable effects o Warnings and precautions o Summary of any field safety corrective action, (FSCA including FSN) if applicable Medical Device Medical Device Coordination Group Document MDCG 2019-9 24(24) 5. Summary of clinical evaluation and post-market clinical follow-up o Clinical background of the device o The clinical evidence for the CE-marking o Safety 6. Possible diagnostic or therapeutic alternatives When considering alternative treatments, it is recommended to contact your healthcare professional who can take into account your individual situation. o General description of therapeutic alternatives 7. Suggested training for users

emdn_eudamed_nomenclature_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 1 The European Medical Device Nomenclature (EMDN) The European Medical Device Nomenclature (EMDN) will be the nomenclature of use by manufacturers when registering their medical devices in the EUDAMED database. Founded on pre-established criteria and requirements1 and based on orientations provided by the Medical Device Coordination Group (MDCG) , the European Commission decided in favour of the use of the ‘Classificazione Nazionale Dispositivi medici (CND)’2 as the basis for the EMDN . Currently, a n extrao rdinary revision of the CND is ongoing so that to release the first version of the EMDN, which will be i ntegrated in EUDAMED for use by operators. The EMDN will be fully available and accessible to any operators and will be copyright free. To the extent possible, t he Commission will map the EMDN to the G lobal Medical Device Nomenclature (GMDN) . This task has been undertaken with th e hopes of possibly facilitating EMDN code search by operators current ly using GMDN . The correspondence between the nomenclatures is intended to be visible to operators and incorporated in the future database in the form of a searching tool. Therefore, and in cooperation with GMDN, t he mapping exercise is currently ongoing . The level of quality and reliability of this mapping is dependent on the commitment of all relevant parties to work together in ma pping and validating the result s. A sub -group of the MDCG on nomenclature which includes experts from National Competent Authorities and stakeholders has been established to oversee regulatory activities linked to nomenclature . The sub -group will aim to define the rules and processes related to the creation, update , maintenance and use of the European Medical Device Nomenclature. Additionally, t he Commission is currently collaborating with the World Health Organisation (WHO ) in the context of their work and activities on a future international medic al device nomenclature. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements 2 CND is currently used in Italy, Portugal and Greece.

FAQ_MDR_180117_V1.0-1.pdf.txt

Page 1 of 13 CAMD Transition Sub Group FAQ – MDR Transitional provisions Disclaimer : The information presented in this document is for the purpose of general information only and is not intended to represent legal advice to any individual or entity. It reflects the outcome of discussions within the Transition Sub Group (TSG) of the CAMD (established in May 2017) to establish recommendations on the interpretation of transition -related provisions. It is not intended to be a guidance document . We recommend that you should obtain your own legal advice before taking any action based on information given here. The content of this FAQ table will be updated cont inuously. While we strive to provide the following information in as timely and accurate a manner as possible , this document does not make any claims or guarantees about the accuracy, completeness or sufficiency of its contents. Participants of the Transit ion Sub Group, authors and reviewers of this document expressly disclaim liability for any errors and omissions in the contents. Page 2 of 13 Glossary: • AIMDD/MDD compliant device = device that is compliant with Directive 90/385/EEC/ Directive 93/42/EEC • AIMDD/MDD certificates = certificates in accordance with Directive 90/385/EEC/ Directive 93/42/EEC • DoA = date of application of the MDR • MDR = Medical Device Regulation (EU) 2017/745 • MDR compliant de vice = device that is compliant with the MDR • MDCG = Medical Device Coordination Group • MFR = manufacturer • PRRC = person responsible for regulatory compliance • NB = notified body • “old” NB = NB that has issued an AIMDD/MDD certificate • The Directives = Directives 90/385/EEC, 93/42/EEC Document History Version Publication Note V1.0 17/01/18 Original publication Conten ts: I - Issue: Transition in general ................................ ................................ ................................ ................................ ................................ .............................. 3 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) ................................ ................................ ............. 4 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) ................................ ................. 7 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR ................................ ................................ ................................ ................................ .. 11 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) .... 12 Page 3 of 13 I - Issue: Transition in general 1 Question: When does the Medical Devices Regulation (EU) 2017/745 (= MDR) apply? Answer: The MDR shall apply from 26 May 2020 (= date of application (DOA)) , see Art. 123 para 2 MDR . There are however exceptions to that general rule. Some provisions apply earlier (e.g. regarding notified bodies or the Medical Device Coordination Group), some later (e.g. regarding UDI labelling). For the exceptions, see Art. 123 para 3 MDR (earlier application: a -c, i; p ostponed application: d –h). 2 Question: When do the Directives 90/385/EEC , and 93/42/EEC [= the Directives] cease to apply ? Answer: In general the Directives 90/385/EEC and 93/42/EEC are repealed with effect from 26 May 2020 (= DoA), see Art. 122 MDR . However there are some exceptions , e.g. • in order to deal with devices that are compliant with the Directives or • to serve as a “back up” in case EUDAMED is not fully functional at DoA (see Art. 122 MDR). 3 Question: What is the applicable legislation until 26 May 2020 (= DoA )? Answer: Laws and regulations adopted by Member States in accordance with the Directives (= Directives regime). There are however exceptions (see for example Art. 123 para 3 a – c, i MDR and Art. 120 para 5 and 6 MDR ). Page 4 of 13 II - Issue: Placing on the market of MDR compliant devices until 26 May 2020 (Art. 120 para 5 -7 MDR) 4 Question: Is it possible to place a device, which is compliant with the MDR (= MDR compliant device ), on the market prior to 26 May 2020 (= DoA) ? Answer: Yes, see Art. 120 para 5 MDR. Manufacturer s (= MFR ) are – until 26 May 2020 (= DoA) normally required to place devices on the market that comply with the Directives (= AIMDD/MDD compliant devices) , however Art. 120 para 5 MDR offers the option to place MDR compliant devices on the market before DoA. 5 Question: Is it possible for all types of devices (for all different risk classes I – III) compliant with the MDR (= MDR compliant device) to be placed on the market prior to 26 May 2020 (according to Art. 120 para 5 MDR )? Answer: Yes, all types of devices - regardless of their risk class – may be placed on the market according to Art. 120 para 5 MDR. This includes for example custom made devices (Art. 2 para 3 MDR ) and system s and procedure packs (Art. 2 para 10 and para 11 MDR). However , devices being subject to the “clinical evaluation consultation procedure” according to Art. 54 MDR (= certain class III and class IIb devices) may not be placed on the market in ac cordance with Article 120 para 5 MDR before the Medical Device Coordination Group ( MDCG ) and the expert panels have been established (see Art. 120 para 7 MDR) . Depending on the risk class of the device, conformity assessment may requir e the involvement of a NB designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). In this c ase, such devices cannot complete a conformity assessment, and therefore may not be placed on the market, before NBs have been designated and notified under the MDR. Page 5 of 13 6 Question: As a MFR , which obligations of the MDR do I need to fulfil in order to place a MDR compliant device on the market before the DoA according to Art. 120 para 5 MDR? Answer: As many obligations as are possible , while taking into account that • EUDAMED is not fully functional and • the MDR is not fully applicable at that point in time . Generally speaking, that is to say that: • first, the device as such needs to be MDR compliant (see Annex I) and • second, the MFR has to comply with the MDR. In particular, the MFR shall undertake an assessment of the conformity of that device in accordance with the applicable conformity assessment procedures set out in Art. 52 MDR . This may, depending on the risk class of the devic e, necessitate the involvement of a notified body designated and notified in accordance with the MDR (see Art. 120 para 6 MDR). The following requirements of the MDR need to be fulfilled by t he MFR (non -exhaustive list) : • clinical evaluation • risk management • QMS • Post-market surveillance • Technical documentation and other reports • Liability for defective devices Page 6 of 13 However, exceptions /adaptations are possible /necessary , particularly due to the fact that EUDAMED may not be fully functional before the DoA . For example : • in the absence of a fully functional EUDAMED some requirements of the Directives shall – where necessary - apply in place of the relevant provisions of the Regulation (e.g. registration of d evices and economic operators). • A person responsi ble for regulatory compliance (PRRC, Art. 15 MDR) needs to be available but not necessarily registered until EUDAMED is available . . • The assignment of an UDI (Art. 27 para 3 MDR) is not possible as long as there are - no issuing entities designated by the Commission according to Art. 27 para 2 MDR or - as long as the legal fiction according to Art. 120 para 12 does not apply (it shall apply from 26 May 2019 , see Art. 123 para 3 i MDR ). It is of no significant use as long as there is no UDI database . • An implant card and the information according to Art. 18 MDR need to be provided, however without the UDI related content (as the requirement to place the UDI carrier on the devices will be stepwise introduced after the DoA). 7 Question: Are MDR compliant devices placed on the market according to Art . 120 para 5 MDR subject to the so called “sell off” provision in Art. 120 para 4 MDR (see below)? Answer No, the possibility of their being made available/put into service is not time-limited. Page 7 of 13 III - Issue: Placing on the market of devices in conformity with the Directives after 26 May 2020 (Art. 120 para 2 -3 MDR) 8 Question: Do certificates issued by notified bodies in accordance with the Directives (= AIMDD/MDD certificates ) prior to 25 May 2020 remain valid after the DoA? Answer: Yes, as specified in Art. 120 para 2 MDR. In general , they remain valid until the end of the period indicated on the certificate. Certain AIMDD/MDD certificates (Annex 4/IV, refer to Art. 120 para 2 first sentence MDR) become void at the latest on 27 May 2022, others (refer to Art. 120 para 2 second sentence MDR) on 27 May 2024 at the latest. In other words, after 27 May 2024 there will be no more valid AIMDD/MDD certificates. 9 Question: What kind of certificates remain valid according to Art. 120 para 2 MDR? Answer: All certificates which are commonly issued by Notified Bodies with reference to the Council Directives MDD and AIMDD. That is [see for example NBOG BPG 2010 -3, similar NB-MED/2.5. 1Rec 4]:  EC Design -Examination Certificate (Annex II section 4 MDD, Annex 2, section 4 AIMD)  Certificate of Conformity (Annex IV MDD, Annex 4 AIMD)  EC Type Examination Certificate (Annex III MDD; Annex 3 AIMD)  EC Certificate Full Quality Assurance System (Annex II excluding section 4 MDD; Annex 2 section 2 AIMD)  EC Certificate Production Qualit y Assurance (Annex V MDD, Annex 5 AIMD) Page 8 of 13  EC Certificate Product Quality Assurance System (Annex VI MDD) 10 Question: May a “ declaration of conformity ” be considered as a “certificate” according Art.120 para 2 MDR? Answer: No, since it is not a certificate issued by a NB. 11 Question: Is it possible for a MFR to have valid MDR and valid AIMDD/MDD certificates in parallel until the 27 May 2024 expiry date? Answer: Yes. 12 Question: May devices, that are compliant with the Directives (= MDD/AIMDD compliant devices ), be placed on the market/put into service after 26 May 2020 (= DoA) ? Answer: Yes, under certain conditions (see answer on question 1 7) as specified in Art. 120 para 3 MDR. In general , after 26 M ay 2020 , devices need to comply with the MDR in order to be placed on the market/put into service (see Art. 5 MDR) . However , for a limited time (depending on the validity of the MDD/AIMDD certificates) there is the option to continue to place devices on the market that are compliant with the Directives. Making use of this option may postpone the immediate need for a new certificate under the MDR. 13 Question: May MFR s of class I devices , that are compliant with the Directives , make use of the derogation in Art. 120 para 3 MDR (= be placed on the market after the DoA)? Answer: No, they must comply with the MDR , unless the device concerned is a class I device with measurement function or in sterile condition covered by a valid MDD certificate . Page 9 of 13 14 Question: May devices that are excluded from the scope of the MDR (e.g. via Art. 1 para 6 lit h) nonetheless benefit from Art. 120 para 3 MDR ? Answer: No, these devices do not fall under the MDR, thus Art. 120 para 3 MDR is not applicable. 15 Question: May MDD/AIMDD compliant devices , which under the MDR will be subject to an “upgrade” in risk class (“up- classification”) , e.g. formerly class IIa -> then class III , benefit from Art. 120 para 3 MDR ? Answer: Yes, under the conditions specified in Art. 120 para 3 MDR (e.g. valid AIMDD/MDD certificate ). Devices which are in a different respectively higher risk class in MDR than under the Directives are not as such excluded from the scope of Art. 120 para 3 MDR . 16 Question: If, according to Art. 120 para 3 MDR, a MFR intend s to place a MDD/ AIMDD compliant device on the market after the DoA, that , under the MDR , will be subject to an “upgrade” in risk class (“up-classification”) , what is the relevant risk class with regard to the applicable MDR requirements listed in Article 120 para 3 MDR (e.g. PSUR)? Answer: The risk class under MDD/AIMDD . 17 Question: What are the requirements for the placing on the market/putting into service of MDD/AIMDD compliant devices according to Art. 120 para 3 MDR after DoA? Answer: See Art. 120 para 3 MDR. In short: 1. A valid AIMDD/MDD certificate according to Art. 120 para 2 MDR [All certificates necessary for the placing on the market of the device in question need to be valid , e.g. a class III device needs to have a valid QMS as well as product specific certificate .] 2. Continuous compliance of the device with the Directives Page 10 of 13 3. No signif icant changes in the design and intended purpose [If there is a significant change in either the design or the intended purpose , Art. 120 para 3 MDR cannot be claimed . Qualification of a change as “significant ” according to Art. 120 para 3 MDR shall be determined on a case by case basis. However, - limitations of the intended purpose - design changes related to corrective actions assessed and accepted by the Competent Authority are not considered “ significant ” in the sense of Art. 120 para 3 MDR. . 4. Appl ication of MDR requirements in place of the corresponding requirements of the Directives with regard to: a. Registration of economic operators and of devices (see Art. 31 MDR and Art. 29 MDR) b. Post market surveillance (PMS) (see Art. 83 -86, 92 MDR including Annex III but without the PMS having to be an integral part of the QMS) c. Market surveillance (see Art. 93 – 100 MDR, but device s tandards to be met = Directives ) d. Vigilance (see Art - 87-92 MDR) However exceptions are possible in the case that EUDAMED is no t fully functional in time (then see Art. 123 para 3 d and e MDR). Moreover, the “old” NB which issued the AIMDD/MDD certificate shall continue to be responsible for the appropriate surveillance of all the applicable requirements relating to the devices it has certified. This should be agreed on between the “old” NB and the MFR on a contractual basis . Page 11 of 13 IV - Issue: The so called “sell off” provision of Art. 120 para 4 MDR 18 Question: What is the so called “sell off” provision (Art. 120 para 4 MDR) about? Answer: It is intended to limit the time during which AIMDD/MDD compliant devices, that have already been placed on the market (either before the DoA or by virtue of Art. 120 para 3 after the DoA) , may be made available e.g. by a distributor . After May 27, 2025 these devices may not be made available/put into service (= deadline) . If such devices are still within the supply chain by this date - i.e. have not reached the final user as being ready for use (e.g. the hospital) - they are not “marketable” any more. This provision is thus primarily dealing with the “making available” of AIMD/MDD compliant devices once they have been placed on the market , e.g. within the supply chain . It does not apply to the “placing on the market” of these devices by the MFR . Please also note, that this provision is not intended to apply to second hand sales (see recital 3). This means , once a device has been made available to the final use r (e.g. the hospital) as being ready for use, the further making available of this device is not subject to/covered by the MDR. 19 Question: Does Art. 120 para 4 MDR enable MFRs to place MDD/AIMDD compliant devices on the market until May 27, 2025? Answer: No. Art. 120 para 4 MDR is not applicable to the “placing on the marke t” of MDD/AIMDD compliant devices (see question 18). The only way to place MDD/AIMDD compliant devices on the market after DoA is Art. 120 para 3 MDR (see question s 12-17). Given th at MDD/AIMDD certificate s will no longer be valid after May 27 2024 , this option ceases to exist from that date onwards . Page 12 of 13 V – Issue: EUDAMED and its relevance for the application of certain provisions of the MDR (Art. 123 para 3 d and e, Art. 120 para 8, Art. 122 MDR) 20 Question: Do all devices have to be registered according to Art. 29 para 4 MDR by the DoA? Answer: No. Even if EUDAMED is fully functional at the DoA there will be a n 18-month “interim phase ” (= EUDAMED fully functional but Art. 29 para 4 MDR not yet applicable) during which the different devices to be placed on the market may be registered “step by step” in EUDAMED accordin g to Art. 29 para 4 MDR instead of nationally according to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR) . However , at the end of this “interim phase ” it must be ensured that all devices of a MFR’s portfolio have been registered in EUDAMED. If EUDAMED is not fully functional until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). 21 Question: Must NBs have entered all the certificate related information of all devices according to Art. 56 para 5 MDR into EUDAMED by the DoA ? Answer: No. Even if EUDAMED is fully functional at the DoA there will be an 18-month “interim phase” (= EUDAMED fully functional but Art. 56 para 5 MDR not yet applicable) during which the relevant information according to Art. 56 para 5 MDR may be registered in EUDAMED “step by step = certificate by certificate” instead of nationally acco rding to the Directives (see Art. 123 para 3 e and Art. 120 para 8 MDR). However , at the end of this “interim phase” it must be ensured that all the relevant data regarding all certificates have been registered in EUDAMED. If EUDAMED is not fully functio nal until a date after the DoA, the 18 -month “interim phase” will be postponed accordingly (beginning at the later of the dates referred to in point d) of Art. 123 para 3 MDR). Page 13 of 13 22 Question: What happens if EUDAMED is not fully functional at the DoA? How does this affect the application of obligations and requirements of the MDR that relate to EUDAMED ? Answer: The relevant provisions to refer to are mainly Art. 123 para 3 d and e . Art. 123 para 3 d MDR: The different Articles listed in Art. 123 para 3 d (= dealing with e.g. the registration of devices and economic operators, clinical investigations, notified bodies, vigilance, post -market surveillance, market surveillance) are not fully postponed with regard to their applicati on but generally remain applicable from the DoA. However , their application is postponed as far as the obligations and requirements within these Articles relate to EUDAMED (which is not fully functional yet). To that extent they shall apply from the date c orresponding to 6 months after the date of notice of full functionality . Meanwhile ( until EUDAMED is fully functional ) the corresponding provisions of the Directives regarding exchange of information continue to apply . The principle is that the derogation applies to the electronic exchange of information/upload to EUDAMED. If the derogation is applicable this does not necessarily mean that the information itself does not need to be prepared/exchanged. This exchange of in formation e.g. reports will have to be done by other means in lieu of exchange via EUDAMED (Directives regime ). The underlying idea behind this paragraph was to ensure compliance with the new obligations and requirements via the “old” systems as far as pos sible. The actual practical implication of this concept with regard to the different Articles listed in Art. 123 para 3 d MDR needs a closer look and further guidance , which is in progress. Art. 123 para 3 e MDR : For the application of Art. 29 para 4 MDR and Art. 56 para 5 MDR in the case that EUDAMED is not fully functional in time, see question 20 and 2 1.

ivd_mfr_stepbystep.pdf.txt

MEDICAL DEVICES CHANGE OF LEGISLATION Internal market, Industry, Entrepreneurship and SMEs1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the IVDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (IVDR Classes A–D) and confirm conformity assess - ment routes for existing and future products. Check the requirement for involving the Notified Bodies Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 56) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market performance follow-up plan (PMPF, Annex XIII Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for IVDs under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know!Implementation Model for In-Vitro Diagnostic Medical Devices Regulation Step by Step Guide Ref. Ares(2018)3873813 - 20/07/20182Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs related to the new risk classification system and the need of involving a Notified Body and costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the IVDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, re - source requirements and a steering group, and ensure overall responsibility for IVDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transi - tional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through IVDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (performance evaluation, technical documentation, relations with other economic operators, Unique Device Identifica - tion, labelling, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for IVDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the IVDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the IVDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89124-3 DOI: 10.2873/41862 ET-04-18-659-EN-N

scheer_o_015.pdf.txt

Final Version Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices Scientific Committee on Health, Environmental and Emerging Risks SCHEER GUIDELINES on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties The SCHEER adopted this document at plenary meeting on 18 June 2019 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 2 ABSTRACT The SCHEER was requested to provide Guidelines on the benefit -risk assessment (BRA) of the presence, in the medical devices specified in the regulation , of phthalates , which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction (CMR) or endocrine -disrupt ing (ED), according to the criteria outlined in the legal obligation section from the mandate. Phthalates are widely used in industry as plastici sers of polymers, in a variety of applications such as coated fabrics and roofing membranes, as well as in me dical devices, adhesives, paints, inks and enteric -coated tablets. Di -(2-(ethylhexyl) phthalate (DEHP) is the most widely used phthalate in medical devices. Dimethyl phthalate (DMP) and diethyl phthalate (DEP) are not used as plasticis ers but e.g. as addit ives in cosmetics, medical devices, and household products. The interaction of phthalates with the polymers they are embedded in is weak, so they may be released from the plastic product into the environment and into the human body if the product is in con tact with it. The Medical Device Regula tion, Regulation (EU) 2017/745 allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w. when a proper justification can be provided (Annex I, Chapter II Section 10.4). Fo r such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the risk associated with such alternatives should be weighed against the risk of the u se of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1 . However, the risk by itself is not the only parameter to consider: also the impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device shall be evaluated. These Guidelines describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices and/or or parts or materials used therein at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alternatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. The approach of these Guidelines may also be used for a BRA of other CMR/ED substances present in medical devices. During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices, SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data needed for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices. Pending on new scientific evidence, it is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Keywords: Guidelines, benefit -risk assessment , CMR/ED phthalates, medical devices, SCHEER . Guidelines to be cited as: SCHEER (Scientific Committee on Health, Environmental and Emerging Risks), Guidelines on the benefit -risk assessment of the presence of phthalates in certain medical devices covering phthalates which are ca rcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties, final version adopted at SCHEER plenary on 18 June 2019. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 3 ACKNOWLEDGMENTS Members of the Working Group are acknowledged for their valuable contribution to this opinion. The members of the Working Group are: SCHEER members: Teresa Borges Rodica Mariana Ion Wim H. de Jong (Chair and Rapporteur) Demosthenes Panagiotakos Emanuela Testai Theo Vermeire SCCS members: Ulrike Bernauer Christophe Rousselle External experts: Stéphane Bégué (Etablissement Français du Sang, EFS, Paris, France) Hilde B. M. Kopperud (Nordic Institute of Dental Materials, Oslo, Norway) Maria Rosaria Milana (Istituto Superiore di Sanità, Dip. Ambiente e Salute, Roma, Italy) Tanja Schmidt (Ansbach University of Applied Science, Ansbach, Germany) Experts from EU Agencies : Francesco Pignatti (European Medicines Agency ) Evgenia Stoyanova (European Chemicals Agency ) Katarina Volk (European Food & Safety Authority ) All Declarations of Working Group members are available at the following webpage: http://ec.europa.eu/health/scientific_committees/experts/declarations/scheer_wg_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 4About the Scientific Committees (2016 -2021) Two independent non -food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commissio n's attention to the new or emerging problems which may pose an actual or potential threat . They are: the Scientific Committee on Consumer Safety (SCCS) and the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER). The Scientific Comm ittees review and evaluate relevant scientific data and assess potential risks. Each Committee has top independent scientists from all over the world who are committed to work in the public interest. In addition, the Commission relies upon the work of other Union bodies, such as the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCHEER This Committee, on request of Commission services, provides Opinions on questions concerning health, environmental and emerging risks. The Committees addresses questions on: -health and environmental risks related to pollutants in the environmental media and other biological and physical factors in relation to air quality, water, waste and soils. -complex or multidisciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health, for example antimicrobial resistance, n anotechnologies, medical devices and physical hazards such as noise and electromagnetic fields. SCHEER members Roberto Bertollini, Teresa Borges, Wim de Jong, Pim de Voogt, Raquel Duarte -Davidson, Peter Hoet, Rodica Mariana Ion, Renate Kraetke, Demosthen es Panagiotakos, Ana Proykova, Theo Samaras, Marian Scott , Remy Slama, Emanuela Testai, Theo Vermeire, Marco Vighi, Sergey Zacharov Contact European Commission DG Health and Food Safety Directorate C: Public Health, Country Knowledge, Crisis management Unit C2 – Country Knowledge and Scientific Committees Office: HTC 03/073 L -2920 Luxembourg SANTE- C2-SCHEER@ec.europa.eu ISBN 978-92-76-15387-0© European Union, 2020 ISSN 2467-4559 doi: 10.2875/784367 EW-CA-20-001-EN-N The Opinions of the Scientific Committees present the views of the independent scientists who are members of the committees. They do not necessarily reflect the views of the European Commission. The Opinions are published by the European Commission in their original language only. http://ec.europa.eu/health/scientific_committees/policy/index_en.htm Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 5 TABLE OF CONTENTS ACKNOWLEDGMENTS ................................ ................................ ................................ ........... 3 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine -disrupting phthalates used in medical devices ................................ ................................ .............................. 6 1. Introduction ................................ ................................ ................................ .............. 7 2. Framework for Benefit -Risk Assessment ................................ ................................ ..... 10 3. Assessment of the presence of phthalates in a medical device ................................ ....... 15 4. Assessment of possible alternative substances, materials, designs or medical treatments . 18 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates ................................ ................................ ........ 23 6. Justification for the use of CMR/ED phthalate ................................ .............................. 25 7. Benefit assessment ................................ ................................ ................................ .. 27 7.1 Material benefit ................................ ................................ ................................ ....... 28 7.2 Clinical benefits ................................ ................................ ................................ ....... 28 8. Methodologies for Benefit –Risk Assessment ................................ ............................... 29 9. Uncertainty analysis ................................ ................................ ................................ . 30 10. Conclusions ................................ ................................ ................................ ............. 34 11. Consideration of the responses received during the public consultation process ............... 35 B. REFERENCES ................................ ................................ ................................ ........... 36 C. ANNEXES ................................ ................................ ................................ ................ 40 Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates ........... 40 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances ......... 44 Annex 3: Definitions/descriptions – References - Glossary ................................ ....................... 45 Annex 4: CMR and/or ED substances ................................ ................................ .................... 51 Annex 5: Legislation on CMR and/or ED phthalates ................................ ................................ . 53 Annex 6: Use of phthalates in medical devices ................................ ................................ ....... 57 Annex 7: Approaches for Benefit -Risk Assessment ................................ ................................ .. 60 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 6 A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine - disrupting phthalates used in medical devices Scope The Regulation (EU) 2017/745 on m edical devices (MDR), Annex I “General Safety and Performance Requirements”, Chapter II “Requirements regarding design and manufacture”, Section 10.4 deals with the presence of substances that may be released from a medical device. Annex I Chapter II Section 10.4.1 state s that substances that are carcinogenic, mutagenic, or reprotoxic (CMR) of category 1A and 1B, or substances having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans, shall only be present in device s, or parts thereof or those materials used therein , above 0.1% weight by weight (w/w) when justified according to a set of criteria listed under Section 10.4.2. These Guidelines1 describe the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices at percentages above 0.1% by weight (w/w). They also describe the evaluation of possible alt ernatives for these phthalates used in medical devices , including alternative materials, designs or medical treatments . They are intended to be used by the relevant stakeholders e.g. manufacturers, notified bodies and regulatory bodies. These Guidelines apply to those medical devices and components thereof indicated in Annex I section 10.4.1.of the MDR . They do not provide information for the BRA of the use of a medical device itself . However, the BRA as described can be integrated within the risk management system for individual medical devices. For the BRA of medical devices in general, stakeholders are referred to section A7.2. of MEDDEV 2.7/1, revision 4. Additional information may be found elsewhere, for example in the following documents FDA 2 016, 2018, EN ISO 14971, ISO/TR 24971. It should be noted that the acceptability of any risk is evaluated in relation to the benefit of the use of the medical device. When the word “patient” is used in these Guidelines, this also covers professional users and other persons (e.g. donors in case of blood donation) exposed to the medical device as well. Annex 1 to these Guidelines describes the mandate, Annex 2 describes Annex I Chapter II Section 10.4. of the MDR regarding the use of substances that could be released from the medical device and pose a risk to patients, and Annex 3 describes the definitions used in these Guidelines. 1 It should be noted that, in accordance with Regulation (EC) 2017/745, Annex I, Chapter II Section 10.4.3. and 10.4.4., updates of these Guidelines might be available in the future. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 7 1. Introduction Placing medical devices on the market, making them available on the market and putting them into service are all activities governed by Regulation (EU) 2017/745 that replaces Directive s 90/385/EEC and 93/42/EEC . Medical devices are defined in the MDR as presented in the text box below: For the purposes of this Regulation, the following definitions apply (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes : — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anat omy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended a ction by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conce ption; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. As a general requirement , the medical device shall perform acc ording to its intended purpose and be safe for professional users and patients , or where applicable other persons (e.g. donor s) on which the device is used. The conformity of medical devices shall be evaluated against the requirements of the Regulation (EU) 2017/745. They shall be presumed to be in conformity with this Regulation if they are in conformity with EU - harmonised standa rds or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union. Although not mandatory, these standards provide a route to comply with the MDR. For medical devices the horizontal standards EN ISO 14971 and EN ISO 10993 -1 are especially relevant. EN ISO 14971 describes the application of a risk management process for medical devices, whereas EN ISO 10993 -1 deals with the biological evaluation and t esting of medical devices within a risk management process. According to EN ISO 10993 -1, evaluation of the biological safety of a medical device should be a strategy Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 8 planned on a case -by-case basis to identify the hazards and estimate the risks of known hazards. In Annex A of EN ISO 10993 -1, a series of endpoints is indicated from which a selection can be made for the biological evaluation of a medical device. The selection is based on the nature of the device's contact with the body (device category: surfa ce device, external communicating device, or implant device; type of contact: skin, mucosal membrane, compromised surface, blood, tissues, organs; duration of the contact: limited ≤24 h, prolonged >24 h to 30 days, permanent >30 days). A systematic literat ure review is part of the biological evaluation of a medical device in order to avoid unnecessary testing (EN ISO 10993 -1). This systemic literature review should also be performed for a CMR/ED phthalate or potential relevant alternatives identified for a given in a medical device. In addition to EN ISO 10993 -1, a series of EN ISO 10993 standards has been published describing various assays and approaches for the evaluation of the endpoints identified in EN ISO 10993 -1 for the biological evaluation of medic al devices. Assays described in the various standards include cytotoxicity, sensitisation, irritation, systemic toxicity, implantation, haemocompatibility, genotoxicity, and carcinogenicity endpoints. Additionally immunotoxicity and organ -specific toxiciti es need to be considered, if appropriate. In addition, reproductive and developmental toxicity should be addressed for novel materials, materials containing substances with a known reproductive or developmental toxicity, medical devices with relevant targe t populations (e.g. pregnant women), and/or medical devices where there is the potential for local presence of device materials in the reproductive organs (EN ISO 10993 -1:2018). For the risk assessment EN ISO 10993 -17 describes determination of allowable l imits for leachable substances, whereas EN ISO 10993 -18 describes methods for chemical characterization of materials used in medical devices. In addition to the horizontal standards, vertical i.e. device specific standards and standards for clinical investigation are available ( e.g. EN ISO 14155). Furthermore, the EU also provides guidance in MEDDEV documents (e.g. MEDDEV 2.7/1 rev.4 for clinical evaluation of medical devices). The MDR states that substances that are classified as carcinogenic, muta genic, or toxic to reproduction (CMR) of category 1A or 1B, or substances identified at EU level as having endocrine -disrupting (ED) properties for which there is scientific evidence of probable serious effects on humans (CMR/ED substances, in this text) , shall only be present in a device s or parts thereof or those materials used therein above 0.1% weight by weight (w/w) when justified. Annex 4 provides further information on the classification of CMR and on identification of ED substances. The justificatio n for the use of CMR/ED substances in a medical device above 0.1% w/w, shall be based on an analysis of potential patient and user exposure, availability of possible alternatives, an argumentation why possible alternatives are appropriate or inappropriate, and on the most recent Guidelines of this Scientific Committee. Phthalates are a group of substances widely used in medical devices. When used as plastici sers they may comprise a substantial part of the medical device. A typical concentration of Bis(2 -ethylhexyl) phthalate (DEHP; CAS 117 -81-7) in plastici sed polyvinyl chloride (PVC) can be 30% based on weight (ECB 2008, SCENIHR 201 5). For many years the reproductive toxicity and the possible endocrine disrupting activity of certain phthalates has been a source for debate. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 9 Phthalates currently classified as reproductive toxicants category 1B under the Classification, Labelling and Pa ckaging (CLP) regulation (EC 1272/2008) and identified as substances of very high concern (SVHC) under Article 57 (c) of REACH Regulation (EC) 1907/2006 are listed in Annex 5 of this document . This list may be updated, so it is recommended to consult the An nex VI of the CLP Regulation. In addition, the Commission Implementing Decision (EU) 2017/1210 and Commission Implementing Decision (EU) 2018/636 identified some phthalates as substances of very high concern (SVHC) according to Article 57(f) of REACH Regu lation (EC) 1907/2006, due to their endocrine disrupting properties with probabl e serious effects to humans, namely Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) , Diisobutyl phthalate (DIBP) , and Dicyclohexylphthalate (DCHP) . Bis(2- ethylhexyl) phthalate (DEHP), was also identified in 2014 as a substance of very high concern in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) because it is a substance with endocrine disrupting prop erties for which there is scientific evidence of probable serious effects to the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) of Article 57 REACH. https://echa.europa.eu/documents/10162/21837b30 -0318-8b45-92db-9e8c39f89dee SCENIHR adopted an Opinion on the safety of medical devices containing DEHP - plasticised PVC in 2008, and a revision of this Opinion in 201 5 (SCENIHR 2008, 201 5). The main source for DEHP exposure of the general population was determined to be food. In addition, the use of medical devices can increase the exposure considerably in the course of specific medical treatments, for e xample during massive blood transfusions, haemodialysis, and in neonatal intensive care units (NICU) for prematurely born neonates (SCENIHR 201 5). Although quite a number of alternative substances were available for DEHP, for some of them serious data gaps were observed regarding hazard identification and exposure estimation (Bui et al., 2016, SCENIHR 201 5). The Danish EPA assessed different alternatives and concluded that to various degrees some substances can be considered to be relevant alternatives to DEHP in terms of human health hazards, especially regarding the endpoints reproductive and developmental toxicity (Nielsen et al. 2014). However, for a number of possible alternatives the data set was limited. Some alternatives showed a low migration rate and some of them are already used as substitutes in medical devices for traditional DEHP -applications. For example, four additional plasticisers for PVC (BTHC, DEHT, DINCH, and TOTM) used in medical devices have recently been included in th e updated chapters of the European Pharmacopoeia (Council of Europe, EDQM 2018). Phthalates classified as CMR of category 1A or 1B according to the procedure described in Annex 4 are listed in Annex VI of the CLP regulation (CLP -Regulation (EC) No 1272/200 8, OJ L353). According to article 57 (f) of REACH (Regulation (EC) 1907/2006) or the Biocides Regulation ( Regulation (EC) 528/2012) phthalates can be identified as having ED-properties when there is scientific evidence of probable serious effects to human health . These Guidelines provide a framework of how to perform a BRA for the presence of such CMR and/or ED phthalates in medical devices or parts or materials used therein at percentages above 0.1% weight by weight (w/w) , and shall be used by all relevant stakeholders, e.g. manufacturers and notified bodies, and regulatory bodies for the justification of the presence of CMR/ED phthalates . The evaluation according to the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 10 Guidelines should be performed by a multidisciplinary team including amongst others e.g. a material scientist, medical device specialist, toxicologist and clinician. A justification for the use of a CMR/ED phthalate can also be based on an already availabl e justification relating to a medical device for which equivalence with the device in question can be demonstrated according to the MDR Annex XIV Section 3. The existing justification can be used as a reference, and the data used for this justification sho uld be available . The approach of these Guidelines can also be u sed for a BRA of other CMR/ED substances present in medical devices. Other descriptions for BRA may be “benefit -risk analysis” or “benefit -risk determination” as defined in the MDR. As Annex I Section 10.4.3 indicates a benefit -risk assessment this terminology is used in these Guidelines. 2. Framework for Benefit -Risk A ssessment The MDR allows the use of CMR 1A/1B and/or ED substances in medical devices above a concentration of 0.1% w/w when a proper justification can be provided ( MDR Annex I, Chapter II Section 10.4). For such a justification several steps need to be considered including the availability of alternative substances, materials, designs, and medical treatments. In addition, the r isk associated with such alternatives shall be weighed against the risk of the use of CMR 1A/1B and/or ED identified phthalates covered under MDR Annex I Chapter II Section 10.4.1. However, the risk is not the only parameter to consider . The impact of the possible alternatives on the functionality, performance and the overall benefit -risk ratio of the medical device should also be evaluated. The justification for the presence of CMR 1A or 1B and/or ED phthalates for which there is scientific evidence of probable serious effects on humans should be based on a number of considerations as described below and in Figure 1 . In order to perform the BRA as indicated above , it is important to describe the terminology to compare the risk s of the presence of the phthalates to be evaluated (see text box below). Annex 3 provides a selection of definitions as present in the MDR and/or the OECD Substitution and Alternatives Assessment Toolbox. (http://www.oecdsaatoolbox.org/ ) For the purpose of these Guidelines the following definition for "alternatives" is used: “alternatives are defined as substances, materials, designs and medical treatments that can be used to replace the use of CMR and/or ED substances in medical devices” The alternative therefore is not limited to a possible substitute substance or material but could also be another device design (e.g. coating/production process/ techniques /lower concentration of substances) or medical treatment (e.g. procedure, device) or a combination of technical and substance alternatives that can substitute or eliminate the use of the CMR/ED phthalate (modified from the ECHA REACH guidance on the preparation of an application for authori sation). The functionality and performance of the alternative should be comparable to the extent that there would be no clinical ly relevant difference foreseen in the performance of the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 11 device or in the outcome of the alternative medical procedure. Conside rations of functionality and performance shall be based on proper scientific justification. In order to justify the use of a CMR 1A or 1B and/or ED phthalate, the manufacturer shall clearly demonstrate that the identified alternative(s) are not appropriate to maintain the functionality, performance and benefit -risk ratios of the medical device. A number of aspects need to be considered for the justification of the presence of a phthalate classified as CMR category 1A or 1B and/or identified as ED above content > 0.1% w/w in a medical device , or parts thereof or those materials used therein, as intended to be used. In summary, these aspects can be considered by a stepwise approach given below and presented in Figure 1. Further details and examples on the steps used in the Guidelines are given in the following chapters. Assessment of the CMR/ED phthalate (CMR/ED scenario) Step 1: Description and characterisation of the composition of the medical device (or parts or materials thereof) . Identif ication of the presence and concentration of CMR/ED phthalate (s) in weight by weight percentage (% w/w) . Step 2: Description of the use and function of the CMR/ED phthalate used in medical device. 2a. Description of functionality/performance provided by the presence of the CMR/ED phthalate. 2b. Description of the benefit (material and/or clinical) of the presence of CMR/ED phthalate in the medical device. Step 3: Assessment of the risks of the CMR/ED phthalate. 3a. Determin ation of the patient exposure based on realistic worst -case2 use scenario in the intended use . 3b. Identif ication of biocompatibility, general toxicological and specific CMR/ED hazards associated with the phthalate. 3c. Determin ation of the maxim um tolerable/ acceptable exposure for the patient, based on pre -clinical and clinical information (if available). 3d. Determination of the risks for various intended use scenarios and patient groups. Assessment of possible alternative (s) (non CMR/ED phthalate scenario) Step 4: Inventory of possible alternative (s). 4a. Substances. 4b. Materials. 2 Realistic worst case is the situation where the exposure is estimated us ing a range of factors (i.e. duration, amount, exposure controls), where applicable, the ones that would be expected to lead to maximum amount of exposure (e.g. exposure might be assessed under realistic simulated -use scenarios by EN ISO 10993 -12 and EN IS O 10993 -18 or a non-volatile residue test (USP <661>)). The realistic worst case does not include deliberate misuse. (EU Biocides Regulation 528/2012). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 12 4c. Designs and/or medical treatments3. Step 5: Identification of the potential relevant candidates for assessment as alternatives to CMR/ED phthalates and justification for the selection and exclusion of possible alternatives. This also includes assessment of the availability of the potential alternative (s). Step 6: Description of identified potential relevant alternative(s). 6a. Description of functionality and performance of the potential alternative(s). 6b. Description of the benefit (material and/or clinical) of the use o f the potential alternative(s). Step 7: Assessment of the risk of identified potential relevant alternative (s). 7a. Determination of patient exposure o f the alternative based on a realistic worst -case use scenario in the intended use. 7b. Identification, where available, of biocompatibility, toxicological and CMR/ED hazards associated with the alternative. 7c. Determination of maximum tolerable/acceptabl e exposure of the alternative for patient (if available). 7d. Determination of risk of potential alternatives for various use scenarios and patient groups. Assessment of potential relevant alternative (s) versus CMR/ED phthalate Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Step 9: Comparison of hazard (s) of original CMR/ED phthalate as used in the medical device with hazard (s) of identified potential relevant alternative (s). Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. In addition to patients, the same approach shall be used for the justification of the presence of CMR/ED phthalate in medical devices to evaluate the risk for professional users and for other persons (e.g. donors) exposed to the CMR/ED phthalates. When alternative designs or medical treat ments were identified as potential alternatives in step 5, adequately adopted endpoints for risks and benefits shall be chosen. It should be noted that scientific developments may be available after the initial assessment regarding the use of alternatives for CMR/ED phthalates . Therefore, a 3 It should be noted that for alternative designs and/or medical treatments, appropriate endpoints for r isks and benefits shall be selected. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 13 revision of the BRA of the presence of the CMR and/or ED phthalate may be necessary. Revisions of the above indicated BRA shall occur as indicated in the relevant sections of MDR for the general risk assessment of the me dical device. Figure 1 illustrates the BRA and is based on Eliason and Morose (2011), EMA (2014), FDA (2016) and a critical selection from the OECD Substitution and Alternatives Assessment Toolbox ( http://www.oecdsaatoolbox.org ). It presents the stepwise approach described above including a general description of factors to consider when performing a BRA. Figure 1 presents a use scenario in which the CMR/ED is used in a medical device versus a non -use scenario in which a proper potential alternative is evaluated. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 14 Figure 1 . BRA for evaluation of presence of CMR/ED phthalates and their potential alternatives in medical devices (relevant sections between brackets) . Step 3 (3) Use scenario Assessment of the risks of phthalate 3a. Exposure assessment patient 3b. Biocompatibility, hazard assessment 3c. Maximum tolerable /acceptable dose 3d. Risk characterisation Step 4 (4) Inventory of possible alternatives 4a. Substitute substances 4b. Substitute materials 4c. Alternative designs/treatmentsDefine aim and scope Step 1 (3) Description and characterisation of composition of medical device, IdentifIcation of presence and amount of CMR/ED phthalate Step 2 Description of phthalate 2a. Use, functionality and performance of phthalate (3) 2b. Benefit (7)Step 5 (4) Identification of potential candidates for alternatives and justification for the selection and exclusion Step 6 Description of identified potential relevant alternatives 6a. Functionality, performance (4) 6b. Material and clinical benefit of the use (7) Step 7 (4) Assessment of the risks of Identified potential relevant alternative(s) 7a. Exposure assessment patient or user 7b. Biocompatibility, hazard assessment 7c. Maximum tolerable /acceptable dose 7d. Risk characterisation Step 8 (5) ComparIson of functionality, performance of use and non- use scenario Overall summary report Justification for continued use of CMR/ED phthalate (6)Step 9 (5) Comparison of hazard(s) of use and non-use scenario Step 10 (5,7, 8) Comparison of benefit and risk of use and non-use scenario Uncertainty analysis (9)Non-CMR/ED phthalate scenarioCMR/ED phthalate scenario Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 15 3. Assessment of the presence of phthalates in a medical device4 It is already necessary to provide most of the information as indicated for the use of CMR/ED phthalates in order to prove compliance with the general safety and performance requirements for the phthalate containing medical device. When more than one CMR/ED phthalate is used simultaneously in the medical device, a justification shall be provided for each of the phthalates and their combination. Some risk assessment data regarding the combinat ion of phthalates are available, as EFSA has recently proposed a Group TDI for some of them, having a similar Mode of Action (MOA) in vivo (EFSA 2019, see Annex 5). Information on assessment of combined exposures to phthalates can be found for example at the report by the National Research Council Committee on the Health Risk of Phthalates (2008) and the ECHA website on the restriction of f our phthalates ( https://echa.europa.eu/registry -of-restriction -intentions/ - /dislist/details/0b0236e180d73895 ) and EFSA guidance on cumulative expos ure (EFSA, 2019 https://doi.org/10.2903/j.efsa.2019.5634 ) Step 1: Description and characterisation of the composition of the medical device. Provide a description of the medical device and its composition including identification and the concentration of each CMR/ED phthalate in the device , and the type of chemical /physical binding of the phthalate in the formulation/device, when there is an impact on leakage. Use available chemical information for identifying target phthalates (e.g. CAS Nº; EINECS Nº; IUPAC name). The chemical composition of a medical device can be evaluated by using e.g. EN ISO 10993 -18 (FDIS published in 2019) . Step 2: Use and function of CMR/ED phthalates in the medical dev ice. Characterise the function and use of the CMR/ED phthalates in the medical device and the properties it imparts to the device. Provide a description of the intended use, functionality and performance of the medical device containing the CMR/ED phthala te and how the use of the phthalate is critical for its functionality and performance . For example, for PVC consider, with regard to the performance of the medical device, maintenance, flexibility, durability and for the phthalate viscosity and PVC compatibility. Provide a description of the patients targeted (e.g. with respect to sex, age, probable vulnerable groups5). Provide a description of use types of the medical device for which it is intended (e.g. single vs repeated exposure ). Other aspects that can be relevant include the critical properties (e.g., flexibility), the conditions of use, critical quality criteria, process/treatment and performance constraints (e.g., sterilization, device/drug interactions), regulatory or clinical or other requi rements that the CMR/ED phthalates and the phthalate -containing device need to deliver. Key criteria for the function, 4 The analysis presented in section 3 (steps 1 -3) describes the current use scenario of the CMR/ED phthalate, i.e., the scenario that would continue in the future if no additional action (other than, e.g., a planned regulatory action entering into force) is taken to limit, substitute or eliminate the presence of the CMR/ED phthalate in the medical device. The current scenario can also be referred to as baseline, business as usual or continued use scenario. 5 Vulnerabl e Groups (in these Guidelines): vulnerable groups of the population such as children and individuals with increased susceptibility due to pre -existing disease, medication, compromised immunity, pregnancy or breastfeeding, women and men in reproductive age. These vulnerable groups also include infants, elderly people or people with poor health conditions. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 16 performance and overall use should be outlined and applied as the basis for an identification and screening of possible alternatives and a more detailed assessment of potential alternatives. Justification for the selection of these criteria should be provided. Benefits of the device with CMR/ED phthalates should also be considered e.g. treatment of specific patients groups due to tuning of flexibility of the medical device . Present an inventory of the benefits of the CMR/ED phthalates in the medical device for the patients (separately for vulnerable groups). More detailed information on the benefit assessment is presented in section 7. Step 3: Assessment of the risks of the CMR/ED phthalate. Perform a risk assessment of the CMR/ED phthalate present in the medical device. The risk assessment should contain a description of the potential phthalate exposure of various patient groups for which the medical device is intended (e.g. single vs repeated exposure ). This should separately include vulnerable groups. EN ISO 10993 -1 provides information on use type in terms of exposure potential (e.g. limited ( ≤24h), prolonged (>24h to 30d) and permanen t (>30d)) that slightly differs from the duration of use as defined in the MDR (Annex VIII, 1, transient <60 minutes, short term 60 minutes to 30 days, long term >30 days). Exposure estimation Provide information , preferably based on data from direct measurement or, when not available, an estimation based on worst -case scenario or from scientific literature , on the release of the CMR/ED phthalate from the medical device when used in various clinical modalities. For data generation , analytical contact conditions for the evaluation of leaching of substances from medical device s, should consider fo r example temperature, contact duration and frequency, polarity of contact liquids, flow rates, contact surface, and volume of contact liquids (EN ISO 10993 -1, EN ISO 10993 -12, EN ISO 10993 -18, USP 661). The contact conditions should be set to represent realistic worst -case conditions taking into account the intended use of the medical device. Estimate exposure to the phtha late(s) considering data on the release of the substance from the device. Consider repeated use scenarios (e.g. dialysis, apheresis donation, chronic treatment) and different population groups. The combined exposure to different CMR/ED phthalates also needs to be considered when present in a medical device. More details on the use of phthalates in medical devices are presented in Annex 6. Risk management measures in place and their effectiveness should be described and taken into account in the assessme nt (EN ISO 14971, EN ISO 10993 -1). In addition, data from biomonitoring programs may become available that could also provide information on exposure levels of phthalates in the general population and more specifically during medical treatment. Hazard id entification Describe hazards associated with the CMR/ED phthalate by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity. EN ISO 10993 -1 provides information on hazard endpoints to be considered depending on the exposure and use category of a medical device, whereas allowable limits can be determined according to EN ISO 10993 -17. Possible hazardous effects of combined exposure should Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 17 also be assessed. Identify an adequate point of departure (PoD) for risk ass essment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no-observed - adverse -effect -level (NOAEL ) or lowest -observ ed-adverse -effect -levels (LOAEL ), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non -threshold effects (e.g. in the case of genotoxic carcinogens or for certain substances acting via an ED -mediated MoA), such a dose descriptor could be a T256 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the analysis could refer to these derived figures without referring to detailed assessment how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). However, as some of these data may have been derived in the past, relevant up -to-date scientific evidence (based upon a systematic li terature review) and up -to-date risk assessment methodology for all relevant toxicological endpoints needs to be considered . If such DNEL/DMELs are not used in the assessment, a justification should be presented (e.g. new information /studies). Some of thes e other legislations are defined under Annex 4. In addition, information can also be obtained in the SCENIHR 201 5 Opinion on DEHP. The ED property of the phthalate can be described according to the recently published EFSA/ECHA guidance document . https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2018.5311 This includes impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental effects, and other effects associated with the CMR/ED phthalates. Describe risk (risk characterisation) The risk can be described by comparing exposure levels that are considered safe with the expected exposure (worst -case scenario) to obtain a risk characterisation ratio (RCR). Starting points (points of departure, PoD) for exposure levels that are considered safe could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) for threshold substances. For non -threshold substances, a T25 value or the benchmark dose associated with a 10% response (BMD10) could be used. From these PoDs, acceptable expo sure values can be derived such as “Der ived No -Effect Level ” (DNEL), “Derived Minimum Effect Level” (DMEL) or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE). As such data are often obtained in rat studies, th e use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited p eriod of time. EN ISO 10993 -17:2002 7 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, acceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors . Specifically for ED effects additional assessment factors might be considered as proposed recently (Hass et al., 2019). 6 Animal dose -descriptor; chronic dose rate that will give 25% of the animal's tumours at a specific tissue site after correction for spontaneous incidenc e (Dybing et al., 1997) 7 EN ISO 10993 -17:2002 is currently under revision. It is discussed to replace in the updated version TE by TI. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 18 The risks can also be described by calculation of the Margin of Safety (MoS), which is the ratio between the lowest PoD and the expected exposure (worst case scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18). Perform this evaluation for e very group (patients/donors) for which the device is intended to be used. Determine and describe in which situation the risk can be acceptable for the use of the CMR/ED phthalate in the medical device. The benefit -risk assessment for the use of the CMR/ED phthalate can be performed using for example MEDDEV 2.7/1rev4 and EN ISO 14971 (see also Section 8). The MDR considers a risk acceptable when outweighed by the benefit of using the device in patients (Chapter I of MDR , Chapter VI Article 62 ). In addition to potential CMR/ED effects, discuss any other potential hazards associated with the composition of the device (e.g. by using the EN ISO 10993 series of standards). Evaluate if such effects are associated with the use of the CMR/ED phthalates i n the device. Note: It should be noted that for some genotoxic carcinogens a no effect level is assumed not to exist. Similarly, a scientific debate is ongoing about whether this also applies to ED activity. The assessment of the risk should be accompan ied by an estimation of the impact of uncertainties in the described outcomes (see section 9). 4. Assessment of possible alternative substances, materials, designs or medical treatments8 In general a similar risk assessment as presented in step 3 above has to be performed for the alternative (substance s, material s, designs or medical treatment ). An inventory should be prepared in order to be able to evaluate possible alternative s. An alternative could be another substance/material or device design modifi cation or it could be a clinical procedure (e.g. a process, technique, treatment or modification) or a combination of technical and substance alternatives. Step 4: Inventory of possible alternatives Prepare a list of possible alternatives ( such as substances, materials, designs or medical treatments)9. A description of the alternative scenario (CMR/ED phthalate "non -use scenario”) needs to be presented including identification of alternative substances , materials, designs or medical treatment , e.g. by includ ing consideration of all available information, such as alternative medical devices available on the market, information about independent research, published peer-reviewed studies, systematic literature reviews, risk assessment reports or scient ific opinions from relevant scientific committees and the results of in - 8 The analysis presented in section 4 constitutes the non -use scenario or the scenario that would transpire if the CMR/ED phthalates would no longer be used in the medical device. 9 Information source for alternatives might be the European Pharmacopoeia. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 19 house research and development. The identif ication of possible alternatives should be properly documented. Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates The MDR indicates that an analysis of all possible alternatives shall be performed. However, when many alternatives are available it would not be feasible to do an extensive evaluation of all alternatives. It is therefo re recommended to select a number of potential relevant alternatives based on screening against key criteria for function, performance, toxicity, and overall use in the medical device in question (see below). In addition, analysis of availability and technical feasibility might affect choices for alternatives as well. A preliminary analysis of possible alternative substances, materials or designs or medical treatments should be performed . This preliminary analysis should include a description of their possible use as alternative substance , material , designs or medical treatment s. Justification on how and why alternatives are rejected for further assessment by defining inclusion and exclusion criteria should be provided. Information/data on functionalit y (e.g. level of flexibility in tubes) as well as performance and/or chemical safety assessment (e.g. hazard profile) may be used for rejection of the less likely alternatives (see below ) and no further risk assessment for the alternative is required. The rejection of the less likely alternatives requires justification and documentation. The chemical safety assessment should be done after assessment of the functionality and performance. In addition to the comparison in terms of functionality, technical per formance and risks to patients and users, which are critical elements for the benefit -risk assessment, Annex I Section 10.4.2 of the MDR states that the justification for the presence of CMR/ED substances should also be based on an analysis of the availabi lity of possible alternatives. Availability has several aspects, including for example the availability of necessary quantity (volumes) of the alternative on the market within a required timeframe and the ability to gain access to alternatives that may be proprietary (e.g., via licensing). If potential alternatives can be identified, a shortlist of the potential alternatives can be established for further detailed assessment with regard to technical feasibility, health benefits, comparison of risks, exist ing legal requirements, availability (e.g. sufficient availability or accessible to the manufacturer), and technical performance. In the event that no alternative is identified, i nformation should be presented on the actions undertaken to identify alternat ives. A compilation of resources and elements in support of chemical substitution and an assessment of alternatives can be found on the OECD webpage : http://www.oecdsaatoolbox.org/ Step 6: Description of identified potential relevant alternative(s) and conclusion on their technical feasibility CMR/ED phthalates are present in medical devices for a specific purpose depending on the intended use of the medical device. For example, phthalates offer the possibility for fine tuning the flexibility (e.g. optimal flexibility without kinking) of a PVC -based medical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 20 device. In addition, DEHP has a stabilising effect on red blood cells in blood bags (SCENIHR 201 5). Technical feasibility of an alternative is based on the alternative fulfilling the function of the CMR/ED phthalate. Therefore, the assessment of the functional properties in relation to the intended use of the medical device is essential. Besides functionality, performance under intended use conditi ons should also be considered. Argumentation shall be provided for justifying why possible substances and/or material substitutes, if available, or design or medical treatment changes, if feasible, are inappropriate in relation to main taining the functionality and/or performance of the medical device. For example, it might be the case that replacement is possible for one specific functional use whereas for another functionality the use of the CMR/ED phthalate remains necessary . Also oth er aspects related to performance of the alternatives need to be considered like material processing conditions (Crespo et al., 2007), material quality after sterilisation (Burgos and Jiménez 2009), and possible interaction with drugs in therapeutic infusi on systems (Treleano et al. , 2009, Salloum et al. , 2015, Tortolano et al., 2018). The benefit(s) should also be considered. An inventory of the benefit(s) of the potential alternative substances, materials, designs or medical treatments for patient populations (separately for vulnerable patient groups) should be presented (see section 7 ). The evaluation of the identified potential relevant alternatives can be done in a tiered way to avoid full assessments for each candidate alternative. For example, based on the outcome of the functionality evaluation, the choice of the potential relev ant candidates might be reconsidered and some might be discarded before performing the risk assessment (see Step 7). The ECHA guidance on the preparation of an application for authorisation and ECHA formats for Analysis of Alternatives provide more detailed information on how to conduct an initial screening of possible alternatives and to assess the technical feasibility of potential alternatives. Submitted applications for authorisations contain a number of examples (https://echa.europa.eu/applying -for-authorisation/preparing -applications -for- authorisation ) of technical feasibility assessment for uses of substances of very high concern. Step 7: Assessment of the risk of identified potential relevant alternatives The risk assessment of alternatives is comparative in nature. Its aim is to assist in the conclusion in section 5 whether the transition to the alternatives would lead to lower benefit and/or risk to human health for patients when compared to the current u se of the CMR/ED phthalates in the medical device. Th e methodology of the assessment in this step is similar to that in step 3 as performed for the phthalate to be evaluated with reference to the alternative. If potential relevant alternative s were identified under Steps 1 -6, a risk assessment of these potential relevant alternative substance/material or designs or medical treatments should be performed. The risk assessment should contain a description of the potential substance/material (alternative medical procedure) exposure of various person groups (e.g. including patients, donors, professional users) for which the medical device is intended to be used (considering single or repeated use). This should include separately Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 21 vulnerable groups . For each subgroup a different level of risk may be accepted based on the potential benefit of the medical device for that particular group . Risk management measures (EN ISO 14971, EN ISO 10993 -1) and their effectiveness to reduce exposure should be described and t aken into account in the assessment. Exposure estimation Estimate the potential release of the alternative substance(s) when used in various treatment modalities. Consider also the rate of leaching to estimate the potential exposure to the alternative substance. Multiple use scenarios (including various types of possible contact) should be considered for the exposure estimation of the alternative substance (e.g. frequent use of dialyzer) and different population groups. Hazard identification Identify hazards based on literature, supplier documentation and other information (such as risk assessments performed by regulatory bodies). Describe hazards associated with the alternative substance/material by considering all relevant toxicological endpoints for acute as well as for repeated dose toxicity including human data. Identify an adequate point of departure (PoD) for risk assessment. In case of a threshold Mode of Action, such a PoD could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest - observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response (Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non - threshold effects (e.g. in the case of genotoxic carcinogens or for substances acting via an ED -mediated MoA), such a dose descriptor could be a T25 value or the benchmark dose associated with a 10% response (BMD10) (ECHA, 2012). Hazards should preferably be evaluated by a relevant exposure route for the intended use of the assessed medical device. For the hazard identification special attention should be on the determination of any potential CMR and/or ED property of the alternative substance used . For further information purposes, a procedure is described in ECHA Guidance on the application of the CLP criteria https://echa.europa.eu/documents/10162/23036412/clp_en.pdf/58b5dc6d -ac2a-4910- 9702-e9e1f5051cc5 or by searching Annex VI of CLP regulation. ED propert ies of the alternative substance/material can be described according to the recently published EFSA/ECHA guidance document . https://echa.europa.eu/documents/10162/23036412/bpr_guidance_identif_ed_en.pdf/1a 4d2811 -3faa-fe61-1de2-3cbce8fd4d95 These effects include impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), developmental eff ects, and other potential toxic effects associated with phthalates with ED properties and reprotoxic effects category 1A/B. It needs also to be considered that the potential alternative (substances, materials, designs or medical treatments) could also have other hazards than those of the CMR/ED activity. These other hazards and their possible associated risks should be discussed for example by using the EN ISO 14971 and the EN ISO 10993 series. See also Table 1. Descri ption of risk (risk characteri sation) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 22 The risk can be described by comparing exposure levels that are considered safe with the expected exposure (realistic worst case use scenario). Exposure levels that are considered safe could be “Derived No Effect-Levels” (DNEL s) for threshold substances, “Derived Minim um Effect Levels” (DMEL s) for non -threshold substances or intakes over lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE ). As such data are often obtained in rat studies, the use of the TDI seems more appropriate in view of the critical effect window for androgenic reproductive toxicity in rats has been reported to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only for a limited period of time. EN ISO 10993 -17:2002 calculates for medical devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body mass and the utilization factor. When necessary, a cceptable exposure levels can be derived by dividing the point of departure for risk assessment by appropriate assessment or uncertainty factors. For medical devices allowable limits of their chemical constituents can be determined by EN ISO 10993 -17. The risks can also be described by calculation of the Margin of Exposure (MoE) or the Margin of Safety (MoS) due to the substances present in a medical device , which is the ratio between the lowest PoD and the expected exposure (e.g. realistic worst case use scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18 ). Perform this evaluation for every patient group for which the device is intended to be used. Where a reference DNEL and /or a reference DMEL have already been derived in the context of other EU legislations, the assessment could refer to these derived figures without referring to a detailed assessment of how these data have been derived (e.g. under REACH legislation, Food Contact Material legislation). Data on the relevant exposure route of the medical device application (e.g. intravenously) are preferred (see also Table 1A, EN ISO 10993 -1). The risk can be described by the so -called risk characterisation ratio (RCR), being a ratio between the exposure and the DNEL /DMEL . If such DNEL/DMELs are not used in the assessment, a justification should be stated (e.g. new information /studies). Determine and describe acceptability of the risk for the use of the potential alternative s. Risks may be acceptable when they are outweighed by the benefits for the patient. Consider any known adverse events associated with the operation of the device using the phthalate, and whether the potential alternatives might affect these adverse event s. These considerations can be based upon a systematic literature review (see MEDDEV 2.7/1rev4) . This exercise has to be performed for each potential relevant alternative substance and/or materials . A large number of phthalates exist and some may be potential relevant alternatives for the CMR/ED phthalate used in the medical device. However, a number of these phthalates are also classified as CMR and/or designated ED (see above and Table 1 Annex 5 ). Such phthalates might be identified as alternatives when the CMR/ED risk is reduced compared to the phthalate intended to be used. In addition, different substances , have also been proposed as alternative plastici sers. In 201 5 SCENIHR published an updated Opinion of potential alternative plastici sers for DEHP (SCENIHR Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 23 2015). Although many alternatives were potentially available, it was also observed that for many of them the information on potential risks and the necessary risk assessment was rather limited precluding their use as alternative s. For DEHP an extensive amount of literature is available, allowing a very careful evaluation of the risk associated to its use . In the event that the risk assessment of a potential relevant alternative cannot be performed due to lack of information, document ation should be presented on the actions undertaken to obtain information to characterise the risk, including the outcome (for example, QSAR /read across could be performed). Note shall be taken that alternative designs or medical treatments might lead to adaptation of endpoints for the benefit -risk assessme nt when compared to the toxicological endpoints of CMR/ED phthalates. The assessment of the risk should be accompanied by an estimation of the uncertainties in the described outcomes which might be qua ntitative (e.g. confidence interval, standard deviation) or qualitative (see section 9). Conclude the analysis of the potential relevant alternative(s) with a summary describing the possible scenario(s) ( see Fig ure 1). 5. Assessment of potential relevant alternative substances, materials, designs or medical treatments versus CMR/ED phthalates Based on the information obtained above a decision can be made on the appropriateness of potential relevant alternative s (substance, material , design or medical treatment ). In this evaluation several factors need to be included such as weighing of technical feasibility, benefits and risks . And, if possible, quantification of benefits and risks. These steps entail a comparison of the CMR/ED phthalate “use-scenario” (summarised in step 3) with the “Non-use scenario ” (summarised in step 4) as shown in Figure 1. Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternative (s). Compare the functionality and performance of CMR/ED phthalate in the medical device and the potential relevant alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 8 for each candidate identified as the potential relevant alternative in section 4. If several potential relevant alternatives have a similar functionality and hazard profile, exposure conditions and possibilities for Risk Management Measures (RMM) res ulting in risk reduction should be considered (see below). Risk management is described in EN ISO 14971. In this comparison also additional issues not directly related to the functionality and performance of the alternative itself, like technical possibili ties, sterilisation effects and Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 24 interactions with infusion liquids, are important for the application of the alternative and the comparison with the CMR/ED phthalates, and thus should be considered. Step 9: Comparison of risk(s) of CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives. Compare the risk of both CMR/ED phthalate and alternative substance/material (or designs or medical treatments by choosing adequate endpoints). Perform step 9 for each potential relevant alternative. There may be difficulties in comparing the risks of a substance e.g. a phthalate, and the risks of a technical alternative such as medical design or medical treatment. For example, there may be risks as sociated with alternative technologies but these may not be of the same nature of the risk of the phthalate. However, the potential relevant alternative must represent a reduction in the overall risks to human health (Step 10) . Therefore, a comparison of risks must be conducted and the applicant will need to consider how these different risks might be compared in terms of risks to human health. Note that an alternative medical design or medical treatment may also result in expo sure to other risks previously not present in the treatment modality. Possible risks of these substances will also need to be considered in the assessment. The comparison with technological alternatives such as a medical design or medical treatment can nor mally not be fully quantitative (i.e. with directly comparable numeric values), as the hazards and associated risks will not be expressed in similar terms, but will in most cases be qualitative or semi -quantitative. Nevertheless, a clear and transparent de scription can give a good basis to conclude whether overall risks are reduced or not (Step 10) . Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Present summary/overvi ew of comparison of benefit and risk of CMR/ED phthalate used in the medical device with the potential relevant alternatives, including uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters presented. The summary should contain various aspects of functionality, performance, risk and benefit of the use of the original CMR/ED phthalate used in the medical devic e and the potential relevant alternative (s). In section 6 below the justification of the use of a CMR/ED phthalate is described based on the summary table comparing an alternative with the CMR/ED phthalate. Perform step 10 for every potential relevant alternative. Each of the assessments performed in steps 1 to 1 0 is associated with uncertainties. Certain uncertainties can be described by the use of measures like the standard deviation or confidence interval. For other uncertainties , a description may be necessary to explain the extent of the uncertainty and its impact on the final outcome . Benefit and risks should be described and weighted against each other in the use of the potential alternative substance /material in the medical device (or designs or medical treatments by choosing adequate endpoints) similar to the procedure for the CMR/ED phthalate (see step 2). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 25 6. Justification for the u se of CMR/ED phthalate Based on the comparison of functionality, performance, availability, risk and benefit, an argumentation can be built as to why a possible substance and/or material alternative, if available, or changes in designs or medical treatment, if feasible, are inap propriate in relation to maintaining the functionality, performance and the benefit -risk ratio or profile (quantitative/semi -quantitative or qualitative) of the medical device containing a CMR/ED phthalate. Explain the importance of any difference in ter ms of benefits and risks between the CMR/ED phthalate to be used in the medical device and potential relevant alternatives using value judg ements and explain how the use of the CMR/ED phthalate can be justified over the alternatives by describing the accep tability of trade -offs in the achievement of some criteria against others. Any advantage in benefits needs to be weighed against possible disadvantages in terms of functionality and risks. Both differences in benefits and risks need to be considered jointly. In building the argumentation for the use of a CMR/ED phthalate, note can be taken of the Memorandum on weight of evidence and uncertainties of SCHEER (SCHEER 2018). This Memorandum describes a methodology that classifies the strength of evidenc e in the human health risk assessment based on integration of different lines of evidence into strong, moderate, weak, uncertain and inconclusive (no suitable evidence available). Any weight of evidence evaluation needs to show the overall confidence in t he assessment. The argumentation should specifically take into account the intended use of such devices. This should include consideration and discussion of possible high risk groups such as children or pregnant or breastfeeding women, and other patient groups considered particularly vulnerable to such substances and/or materials. In addition, where applicable and available, any future update of these Guidelines shall be considered. A Table with the most relevant information and values should be used to p resent an overview of the performed assessment comparing the CMR/ED phthalate with potential alternative(s). A non-exhaustive example of such Table is presented below. The Table should be extended depending on the number of criteria evaluated and the numbe r of potential alternatives identified. Table 1: Example for a comparison of CMR/ED phthalate with potential relevant alternative(s). Assessment criteria Description (examples) Reference phthalate Alternative I Alternative II etc. Identification of substances/material etc Name and CAS number Chemical information CAS 117-81-7 Functionality/performance Used as plasticiser e.g. DEHP Clinical benefit/performance Treatment possibility e.g. Flexibility of tubing / red blood Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 26 cells storage Material benefit Concentration (% w/w) Leaching from medical device for relevant conditions e.g. media, temperature, etc (mg per hour/day) Exposure estimation (realistic worst case use scenario ) for relevant route of exposure Hazard identification Local and systemic acute and repeat -dose toxicity, ED - properties, organ toxicity, CMR properties, biocompatibili ty, and others Identification of a point of departure for risk assessment ( LOAEL, NOAEL, BMD, T25, BMD10) Identification of dose levels associated with minimal or negligible risk (e.g. DNEL, DMEL, TDI , TE, TI) Risk characterisation (MoE, MoS, RCR) Confidence estimation (see Table 2) Technical feasibility Other This Table shall be completed for every component of the medical device that contains CMR/ED phthalate(s ) above the 0.1% w/w level. For some medical devices used as a system (e.g. blood bag system) the whole system might be evaluated. Note that in case of alternative designs or medical treatments adequate endpoints for the comparison shall be chosen. These endpoints may represent risks that may be of a different nature than that of the risk of the phthalate. When the outcome of the comp arison shows that the alternative fulfils a comparable or better intended functionality as well as performance and shows a reduced risk, the use of a CMR/ED phthalate is not possible. The risk assessment should also indicate whether there would be a reduce d hazard concerning CMR and/or ED properties, and/or reduced exposure overall resulting in reduced risk. In this evaluation, other toxicities (e.g. for any Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 27 other organ or system ) of the potential relevant alternatives shall also be considered. So, the full toxicological profile of the potential relevant alternatives shall be taken into account. A balanced weighing of the benefit versus the risk has to be performed . For example it is possible to use a combination of a CMR/ED phthalate and PVC/material with h igh intrinsic toxicological hazards, thus accepting a risk from a toxicological perspective, in case the clinical benefit is very high . In contrast, a minor loss in medical functionality might be acceptable if there is a large reduction or even absence of risk. Each comparison of a potential alternative for the use of a phthalate should be based on the combination of functionality , risk and benefits for patients. In this final evaluation , the assessment of uncertainties associated with the alternatives (e.g. on the nature of the risks; assumptions made) should also be considered (see Table 2 below section 9). Therefore, where possible, quantitative results should be collected and compared (e.g. NOAEL, estimated exposure in mg/kg) and their uncertainties should be reported. Also a qualitative description of the uncertainties may be useful (see Table 2 below sec tion 9). Their impact on the conclusions should also be discussed. Although not the main subject of these Guidelines, it should be realised that availability and accessibility on the market might be a limitation for the introduction of an alternative subst ance/material. Some chemicals proposed as alternatives are widely available (e.g. BTHC, DEHT, DINCH, and TOTM) however, this may not be the case for other alternatives identified . The lack of the availability of a potential alternative for a medical device might result in the conclusion that replacement is not feasible and that the use of a phthalate with CMR and/or ED property continues in order to keep the device available for pat ients. So, besides technical feasibility in terms of functionality and risk reduction (risk assessment of the phthalate versus the alternative), also availability and accessibility on the market needs to be considered. The BRA of the CMR/ED phthalate shoul d be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated. A plan to perform an update of the relevant part of the technical file of the device needs to be submitted during the certification process (post -market surveillance plan referred to in Article 84, the requirements are set out in Section 1.1 of Annex III MDR) and this should also cover upd ates needed on the justification for the presence of CMR/ED phthalates . 7. Benefit assessment These Guidelines do not provide information for the benefit -risk assessment of the use of a medical device itself but are limited to the methodology on how to perform a BRA for the justification of the presence of CMR 1A or 1B and/or ED phthalates in a medical device above 0.1% (w/w). The evaluation of the overall benefit -risk assessment of a medical device is presented in other documents (e.g. MEDDEV 2.7/1 rev4, EN ISO 14971). The benefits of the CMR/ED phthalate use in a medical device need to be compared to the benefits of the potential relevant alternatives, with the focus of the analysis being on Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 28 the net or incremental benefits of use of the CMR/ED phthalate in comparison to the alternatives. These benefits may include material or clinical benefits. Uncertainties about the estimates or reliability of the data, assumptions, etc. for the parameters need to b e presented. 7.1 Material benefit A medical device does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but may be assisted in its function by such means. For the use of phthalates in medical devices, additional functionalit ies need to be considered. One of the functionalit ies is the fine -tuning of the flexibility of PVC when used as plasticiser s e.g. in intubation devices. For blood bag materials other requirements are , for example, resistance to heat and chemicals, especially during sterili sation, and permeability of gases to assure that pH and oxygen levels remain stable . In addition, DEHP has an additional property namely the stabilising effect on red blood cells (RBCs) (SCENIHR 2015). A number of alternatives were evaluated as alternative for DEHP in blood bags (Simmchen et al., 2012, SCHENIR 2015). Platelets are extremely sensitive to changes in the pH of the medium in which they are suspended, so sufficient gas permeability to O2 and CO 2 has to be assured in the containers devoted to their storage (Simmchen et al. , 2012). For this reason, DEHP has been almost fully replaced with BTHC, DINCH, and/or Trioctyltrimellitate (TOTM or Tri( 2 - ethyl hexyl)trimellitate (TEHTM) ) (Simmchen et al. 2012, Prowse et al. 2014). A better gas exchange has been found in bags plasticised with these chemicals . Also other materials, like polyolefins, are currently used for platelet storage bags (Prowse et al. 2014). This potentially will allow the stor age of platelet concentrates for up to 7 days, if measures to prevent bacterial contamination can be safely implemented. It should be noted that the benefit of phthalates in terms of material functionality and performance may differ from device to device. An alternative may be available for one application while this may not be available for another in view of added or specific demands on the functionality of the p hthalate . 7.2 Clinical benefits Clinical benefit of medical devices is defined in the MDR as follows: ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnos is, or a positive impact on patient management or public health; (Regulation (EU)2017/745: Article 2 Definitions: (53)): This “clinical benefit” has to be substantiated by the manufacturers in the “clinical evaluation” of the medical device, which includes a number of considerations. These include a discussion and overall conclusions covering safety and performance results, assessment of risks and clinic al benefits, discussion of clinical relevance in accordance Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 29 with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device and limitations of the investigation. A ”clinical benefit ” could include any meaningful, measurable, patient -relevant outcome as presented below. SCHEER identified the following examples that may be relevant for the use of phthalates (list not exclusive):  Improved survival rates  Improved length of hospital stay  Improved time of intervention  Improved time of placing ( among others in tubes and catheters)  Improved product quality/ clinical performance ( among others in tubes and catheters) in terms of: o Improved leakage rates o Improved breakage rates o Improved knotting rates o Improved blockage rates o Improved bending performance rates o Improved release rates of toxic substances o Improved release rates of (nano -)particles  Improved displacement rates  Improved possibilities for sterili sation  Reduction of diameters in relation to performance  Possibility to produce “multiple -purpose” devices, (e.g. inclusion of additional sensors), and therefore reduction of over -all patient -stress and patient -impact  Improved observability (safety) in terms of translucence, printability, radiopaque lines included, identifiab ility, traceability, etc. ( among others in tubes and catheters)  Fewer adverse events , e.g. r educed mucosal or endothelial irritation or injury rates ( among others in tubes and catheters)  Fewer serious adve rse events and serious incidents The benefit of the use of the CMR/ED phthalate should always be judged with respect to the “intended use” of the medical device and the exposed patient -group to the medical device and weighed in its clinical impact (“clinically relevant difference”). These aspects should be judged by clinical experts. Quantitative information on the benefits should be provided where possible or at a minimum qualitative description of their magnitude. Information on the probability of the benefit to occur and/or the duration of the benefit should also be included. 8. Methodologies for Benefit –Risk A ssessment In general, a Benefit - Risk A ssessment (BRA) aims to evaluate the desired effects of therapeutic mean s, medicine s or device s, against their undesired effects, i.e., risks for human health. An appropriate BRA can contribute to a more objective analysis and help conformity verification bodies and authorities towards a more objective and transparent decision -making process. Weighi ng the benefits and risks can be a complex task. It may involve the evaluation of a large amount of data that should be as accurate as possible , Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 30 without methodological weaknesses and biases. There is always some uncertainty around the actual benefits and r isks, because they can only be determined by looking at the information that is available at a given point in time which may contain various sources of uncertainty. For the BRA of medical devices in general, guidance is available in section A7.2. of MEDDEV 2.7/1, revision 4 “Clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC” . EN ISO 14971 (FDIS published in 2019) and the accompanying ISO/TR 24971 provide information on the risk benefit analys is to be performed within a risk management process. Additional information may be found elsewhere, for example in the documents of the FDA 2016, 2018,. It should be noted that the acceptability of any risk is weighted against the benefit of the use of the medical device. Several methodologies for BRA have been proposed (Guo et al, 2010 , Mt-Isa et al. 2014), of which most methodologies are so far , mainly used for pharmaceutical products. However, it should be underlined that f or medical devices the quantitative determination of a benefit -risk ratio may be rather difficult to be made and expressed in a figure. In such cases a qualitative approach of weighing the benefit based on expert judgement might be used. One methodology, namely the multi criteria decision analysis (MCDA), can be generally applied to various areas of BRA. Therefore, this methodology might also be suitable for performing the BRA of medical devices (see Annex 7). The MCDA methodology has its origins in decisi on theory aiming to evaluate multiple conflicting criteria in decision making. These criteria can include the benefits and risks of the use of a medical device on human health. The final BRA of both the used CMR/ED phthalate and potential relevant alterna tives should contain all aspects as indicated in the framework above. A quantitative or semi - quantitative description of the risks (e.g. MoS, RCR) and of the benefits of a medical device containing a CMR/ED phthalate or alternative should be the basis for a BRA. However, a lthough quantitative approaches for a BRA are preferable, a qualitative description of the value judgements about the balance of benefits and risks might also be an acceptable approach when justified (see step 10). 9. Uncertainty analysis Uncertainty plays an important role in medical decision making. It is widely accepted that, despite the methodological and technological improvements that were achieved in the past decades, there is never absolute certainty regarding the safety, effective ness, or performance of a medical treatment or use of a device. Therefore, the degree of certainty and thus uncertainty of the benefits and risks of a medical device is a factor that should always be considered when making BRA. There are various sources of uncertainty in bio -medical studies; a major source of uncertainty is the biological differences among individuals. Another source of uncertainty is the intra - and inter - variability of the laboratories, with respect to equipmen t, reagents, and methods used. It is also accepted that diagnostic tools which evaluate benefit and risk share several limitations , giving false negative and false positive results in a variety of cases. Observer variation occurs quite often and should alw ays be taken Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 31 into account. Other factors that may influence the degree of uncertainty include: the type of clinical information available (e.g., clinical investigation data, observational studies, evidence derived from registries or use experience), the re presentativeness of the information (e.g., sample size, relevance of the sample to the referent population exposed to the device), as well as the statistical inferences derived from the information. A number of techniques for uncertainty analysis are descr ibed in t he Guidance for Socio - Economic Analysis of ECHA (ECHA 2011). The aim is to determine whether uncertainties in the estimation of impacts could affect the overall conclusions. More accurately , the techniques shown can be used to either reduce the va riability of estimates, or to help test whether uncertainties affect the conclusions drawn. The only way to actually reduce uncertainty is through better data, better understanding and knowledge of the uncertainties and through further analysis. However, i n most cases residual uncertainties will remain. Recently EFSA published a guidance on uncertainty analysis (EFSA 2018 a) and a description of the principles and methods behind the guidance for uncertainty analysis (EFSA 2018 b). The EFSA Guidance recogni ses that the form and extent of uncertainty analysis, and how the conclusions should be reported, vary widely depending on the nature and context of each analysis and the degree of uncertainty that is present. Therefore it is important to identify appropriat e options for each BRA. The EFSA documents provide a flexible framework for uncertainty analysis within which different methods may be selected, according to the needs of each BRA. It seems likely that also for medical devices a similar flexibility is need ed in view of the broad range of medical devices used. EFSA describes a number of main elements of uncertainty that need to be considered in the uncertainty analysis: EFSA: Main elements of uncertainty analysis  Identifying uncertainties affecting the assessment. This is necessary in every assessment and should be done in a structured way to minimise the chance of overlooking relevant uncertainties. In assessments that follow standardised procedures, it is only necessary to identify nonstandard uncertai nties.  Prioritising uncertainties within the assessment plays an important role in planning the uncertainty analysis, enabling the assessor to focus detailed analysis on the most important uncertainties and address others collectively when evaluating overa ll uncertainty. Often prioritisation will be done by expert judgement during the planning process, but in more complex assessments it may be done explicitly using influence analysis or sensitivity analysis.  Dividing the uncertainty analysis into parts. In some assessments, it may be sufficient to characterise overall uncertainty for the whole assessment directly, by expert judgement. In other cases, it may be preferable to evaluate uncertainty for some or all parts of the assessment separately and then comb ine them, either by calculation or expert judgement.  Ensuring the questions or quantities of interest are well -defined. Each question or quantity of interest must be well -defined so that the true answer or value could be determined, at least in principle. This is necessary to make the question or quantity a proper subject for scientific assessment, and to make it possible to express uncertainty about the true answer or value clearly and unambiguously. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 32 Some assessments follow standardised procedures, within which the questions and/or quantities of interest should be predefined. In other assessments, the assessors will need to identify and define the questions and/or quantities of interest case by case.  Characterising uncertainty for parts of the uncertainty analysis. This is needed for assessments where assessors choose to divide the uncertainty analysis into parts but may only be done for some of the parts, with the other parts being considered when characterising overall uncertainty.  Combining uncertainty f rom different parts of the uncertainty analysis. This is needed for assessments where the assessors quantify uncertainty separately for two or more parts of the uncertainty analysis.  Characterising overall uncertainty. Expressing quantitatively the overall impact of as many as possible of the identified uncertainties, and describing qualitatively any that remain unquantified. This is necessary in all assessments except those standardised assessments where only standard uncertainties are identified (e.g. inter-and intra -species uncertainty factors).  Prioritising uncertainties for future investigation. This is implicit or explicit in any assessment where recommendations are made for future data collection or research, and may be informed by influence or sensit ivity analysis.  Reporting uncertainty analysis. Required for all assessments, but extremely brief in standardised assessments where only standard uncertainties are identified. A number of methods that can be used in the uncertainty analysis include:  Sensitivity analysis  Scenario analysis  Expert judgement  Monte Carlo Simulations Some of these techniques can be used in combination (e.g. scenario analysis together with expert judgement to establish ranges for key variables) but also together with less commonly used techniques such as risk -risk analysis, Delphi techniques and portfolio analysis, which can be used to help reduce the variability of estimates but are not discussed in these Guidelines. After performing the uncertainty analysis , the observed overall confidence associated with a BRA can be expressed as a probability score. This score gives the risk assessor an indication what the uncertainty is in the BRA. In situations where sufficient data are available, a quantitative categori sation of probability levels is preferred. If this is not possible, the manufacturer should give a qualitative description. A good qualitative description is preferable to an inaccurate quantitative description ( EN ISO 14971). EFSA (EFSA, 2018 b) and SCHEER (2018) use a rather detailed probability scale of 9 and 7 probab ility levels, respectively. EFSA stresses that this scale may be used as an aid to support the development of judgements and that other ranges or qualitative descriptions can be used as well. EFSA (2018 b) also argues that presenting the numerical probabilities alongside verbal expressions of probability, e.g. ‘Likely (> 66% probability)’, increases the consistency of interpretation. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 33 A detailed scale does not seem to be applicable for the uncertainties that can be obtained during a BRA evaluation of medical devices. For medical devices, a probability scale as indicated in Table 2 may b e used EN ISO showing a 5-level scale recommended by ISO for semi -quantitative assessments ( EN ISO 14971, Table D4 ). Table 2 further show s the verbal terms and subjective probability ranges that are based on a simplification of the EFSA/SCHEER scales. Table 2: Probability scale for (semi -)quantitative description of the overall confidence ISO probabil ity term Subjective probability range Probability term Frequent Probable Occasional Remote Improbable > 90% 66-90% 33-66% 10-33% <10% very l ikely likely as likely as not unlikely very unlikely Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 34 10. Conclusions These G uidelines are intended to be used for a BRA of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine -disrupting (ED) properties . The Guidelines can be used for the justification of the use of CMR/ED phthalates in a medical device according to the Regulation (EU) 2017/745 on medical devices. They also provide a framework on how to assess and compare possible alternative substances, materials , designs or medic al treatments to the use of CMR/ED phthalates in medical devices. Major aspects include the functionality of phthalates, the performance of the medical device using the phthalate or the potential relevant alternative for the phthalate, as well as the risk assessment of the phthalate or the alternative s. In the end , the benefit (s) shall be weighed against the possible risk s of the use of the CMR/ED phthalate and of the alternative substance, materials , desig ns or medical treatments . This overall analysis will determine whether it is justified or not to use a CMR/ED phthalat e in a medical device. In view of the concern of the CMR/ED properties of phthalates, further research to possibilities to replace these p hthalates in medical devices is highly encouraged by the SCHEER . During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in medical devices , SCHEER noticed that a number of BRA methodologies are theoretically available. However , there is a considerable lack of data for the BRA for potential relevant alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers to generate data of high quality on such alternatives for CMR/ED phthalates in medical devices . As the BRA of the presence of phthalates may have an impact on the conclusions of the "overall" benefit -risk determination of the medical device, a periodic update of the BRA of the medical device may be needed. The BRA of the presence of the CMR/ ED phtha late should be updated when new scientific information becomes available on alternatives for the use of phthalates, when new Guidelines are released, or as the "overall" benefit -risk determination of the medical device is updated . A plan to perform an update of the general BRA for the medical device should be included in the dossier before marketing the device, and this should also include a plan regarding the necessary updates on the evaluation of alternatives for CMR/ED phthalate s. Pending on new scientific evidence, i t is recommended to evaluate the use and usefulness of these Guidelines after an application period of three years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 35 11. Consideration of the responses received during the public consultation process A public consultation on these Guidelines was opened on the website of the non -food scientific committees from 18 March to 29 April 2019 . Information about the public consultation was broadly communicated to national authorities, international organisation s and other stakeholders. A to tal of 197 submissions from 19 contributors (providing 378 comments and additional references ) provided input to different chapters and subchapters of the document. The vast majority of comments came from industry and were requesting clarifications . Each submission was carefully considered by the SCHEER and the scientific opinion has been revised to take account of relevant comments. The literature has been accordingly updated with relevant publications. The SCHEE R expresses their thanks to all contributors for their comments and for the literature references provided during the public consultation. The text of the comments received and the response provided by the SCHEER is available at: https://ec.europa.eu/health/scientific_committees/consultations/public_consultations/sch eer_consultation_08_en Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 36 B. REFERENCES  Bui TT, Giovanoulis G, Cousins AP, Magnér J, Cousins IT, de Wit CA. Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ. 2016 Jan 15;541:451 -467. do i: 10.1016/j.scitotenv.2015.09.036 .  Burgos N, Jiménez A.Degradation of poly(vinyl chloride) plasticized with non - phthalate plasticizers under sterilization conditions. Polymer Degradation and Stability 94 (2009) 1473 –1478.  Crespo JR, Balart R, Sanchez L, López J. 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EFSA Journal 2018;16(1):5123, 39 pp. (https://doi.org/10.2903/j.efsa.2018.5123 .)  EFSA Scientific Committee, Benford D, Halldorsson T, Jeger MJ, Knutsen HK,More S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V, Solecki R, Turck D, Younes M, Craig P, Hart A, Von Goetz N, Koutsoumanis K, Mortensen A, Ossend orp B, Germini A, Martino L, Merten C, Mosbach -Schulz O, Smith A and Hardy A, 2018. Scientific Opinion on the principles and methods Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 37 behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. 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Benefit -Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics. Guidance for Industry and Food and Drug Administration Staff. September 25, 2018. Washington , USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM404773.pdf  FDA. US Food and Drug Administration. Factors to Consider Regarding Benefit - Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions. Guidance for Industry and Food and Drug Administration Staff. December 27, 2016. Washington, USA. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G uidanceDocuments/UCM506679.pdf  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report of the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 38  Hass U, Christiansen S, Andersson A -M, Holbech H, Bjerregaard P. Report on interpretation of knowledge on endocr ine disrupting substances (EDs) – what is the risk? Danish Centre on Endocrine Disruptors, Denmark . (http://www.cend.dk/files/ED_Risk_report -final-2019.pdf)  Katsikantami I, Sifakis S, Tzatzarakis MN, Vakonaki E, Kalantzi OI, Tsatsakis AM, Rizos AK. A global assessment of phthalates burden and related links to health effects. Environ Int. 2016;97:212 -236. doi: 10.1016/j.envint.2016.09.013  Mariana M, Feiteiro J, Verde I, Cairrao E. The effects of phthalates in the cardiovascular and reproductive systems: A review. 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Impact of the nature and concentration of plasticizers on the ability of PVC to sorb drug. International Journal of Pharmaceutics 496, 664 –675, 2015.  SCHEER 2018 Memorandum on weight of evidence and uncertainties. Revision 2018. https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/s cheer_o_014.pdf  SCENIHR Opinion on The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). 2015 https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_047. pdf  Simmchen J , Ventura R , Segura J . Progress in the removal of di -[2-ethylhexyl] - phthalate as plasticizer in blood bags. Transfus Med Rev. 2012; 26(1):27 -37. doi: 10.1016/j.tmrv.2011.06.001. Epub 2011 Aug 5.  Tortolano L, Matmati H, Bourhis M,Manerlax K, Lemare F, Saunier J,Yagoubi N. DinCH and ESBO actual migration from PVC infusion tubings used in an oncopediatric unit. J. Appl. Polym. Sci. 135, 46649, 2018. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 39  Treleano A,Wolz G,Brandsch R, Welle F. Investigation into the sorption of nitroglycerin and diazepam intoPVC tubes and alternative tube materials during application . Intl JPharmac 369, 30 –37, 2009.  Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008 ; 118(4):1479 -90. doi: 10.1172/JCI34241. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 40 C. ANNEXES Annex 1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates 1. Background What are phthalates? Phthalates are the esters of 1,2 -benzenedicarboxylic acid (o -phthalic acid) and their chemical structure consists of one benzene ring and two ester functional groups linked with two consecutive carbons on the ring10. The hydrocarbon chains of the ester groups are either straight or branching; they give each substance its name and they are responsible for the different properties amo ng phthalates. Phthalate esters (PEs) may be categori sed into three distinct groups according to the length of their carbon chain. High molecular weight (HMW) phthalates include those with 7 –13 carbon atoms in their carbon chain and low molecular weight (L MW) those with 3 –6 carbon atoms in their backbone. DEHP is classified as a LMW phthalate. A third group includes dimethyl phthalate (DMP) and diethyl phthalate (DEP)11. What are they used for? Phthalates are widely used in industry as plastici sers of polym ers such as polyvinyl chloride (PVC). HMW phthalates are used in a variety of applications such as coated fabrics and roofing membranes. LMW phthalates are used in medical devices, adhesives, paints, inks and enteric -coated tablets. DEHP is the most widel y used phthalate in medical devices. DMP and DEP are not used as plastici sers but e.g. as additives in cosmetics, medical devices, and household products. Potential CMR or endocrine -disrupting properties The interaction of phthalates with the polymers the y are embedded in is weak, so they may migrate from the plastic product into the environment and into the human body if the product is in contact with it. Correlation between exposure to a range of phthalates and adverse health effects has been documented in animals and humans (see for example tables in Mariana et al. 2016 and Katsikantami et al. 2016). A number of phthalates are suspected of and/or have been classified or identified as having CMR or endocrine -disrupting properties. 10 A global assessment of phthalates burden and related links to health effects. Katsikantami et al., Environ Int. 2016 Dec;97:212 -236. https://www.ncbi.nlm.nih.gov/pubmed/?term=katsikantami 11 Footnote added by SCHEER. It should be noted that there are hundreds of phthalates of which only a limited number is used as plasticiser in polymers. Phthalates can be categorised according to the length of the carbon chain and one of these categorisations is mentioned in the mandate of DG GROW. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 41 Previous work of Commission Scientific Committees on phthalates Previous opinions on the most commonly used phthalate DEHP [di -(2-(ethylhexyl) phthalate] in medical devices were issued by EU Scientific Committees in 2002 (SCMPMD), 2008 and 2015 (SCENIHR). The 2008 Opinion concluded that "So far, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans", but noted that "newborn and pre -term born male infants are of special concern" . In the 2015 Opinion, SCENIHR additi onally identified that "patients subject to haemodialysis procedure may be at risk of DEHP induced effects" . The Committee noted that "Food is the primary source of exposure to DEHP for the general population." In both opinions, the Committee emphasised th at "the benefit of the medical devices must also be considered" and in the 2008 Opinion the Committee states that "each alternative to DEHP, however, must also be evaluated with regard to their functionality in respect to medical devices. The risk and bene fits of using alternative plasti cizers should be evaluated case by case." In the 2015 opinion, the Committee states that “The potential for replacement of DEHP in these products should be considered against their efficiency in the treatment, as well as the toxicological profile and leaching properties of the alternative materials.” The legal obligation Article 5 paragraph 2 of the Regulation 2017/745 on medical devices stipulates: "A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose." Accordingly, Section 10.4 of Annex I, which deals with substances in medical devices, states that "Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device." Particular substances of concern are those which (a) are carcinogenic, mutagenic or toxic to reproduction (CMR), of category 1A or 1B,12 or (b) have endocrine -disrupting properties (ED)13. The Regulation states that: "Devices, or those parts thereof or those materials used therein that:  are invasive and come into direct contact with the human body,  (re)administer medicines, body liquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body" 12 in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 13 identified as such in accordance with the relevant provisions of Regulation (EC) No 1907/2006 or respectively of Regulation (EU) No 528/2012 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 42 shall only contain any such substance ab ove the concentration of 0.1% weight by weight where justified pursuant to Section 10.4.2. The justification shall be based on several elements, including the latest relevant scientific committee guidelines on benefit -risk assessment of the presence of suc h substance in devices. According to Section 10.4.3, the Commission shall provide a mandate to the relevant scientific committee to prepare such guidelines for phthalates which are subject to these provisions. These guidelines are explicitly requested by t he Regulation to be available at the latest on the date of application of the Regulation, and are to be updated whenever appropriate on the basis of the latest scientific evidence, or at least every five years. 2. Terms of reference The Scientific Committee is requested to provide guidelines on the benefit -risk assessment of the presence, in the medical devices specified below, of phthalates which have one or more of the following properties: carcinogenic, mutagenic, toxic to reproduction or endocrine -disrup ting, according to the criteria outlined in the previous section. The devices covered, or those parts thereof of those materials used therein, are those which:  are invasive and come into direct contact with the human body,  (re)administer medicines, body l iquids or other substances, including gases, to/from the body, or  transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body. The guidelines shall include guidance on how, for an individual device, to:  analyse and estimate potential patient or user exposure to the substance,  analyse possible alternative substances, materials, designs, or medical treatments,  to justify why possible substance and/or material substitutes, if available, or design change s, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratios of the product, including taking into account if the intended use of such devices includes treatment of children or treatment of pregnan t or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials. In addition, the Scientific Committee is requested to :  identify any relevant knowledge gap , and  to give consideration to what extent of new evidence would be deemed appropriate to justify an update of these guidelines before the maximum period of five years. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 43 In order to ensure the appropriateness of this guidance the Scientific Committee should inter alia :  involve at the appropriate level the notified bodies active in the field of medical devices, or other relevant stakeholders such as Competent Authorities, professional and patient associations, industry associations, while maintaining scientific independence ,  involve to the necessary extent the relevant EU Agencies and Scientific Committees. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 44 Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances The requirement for justification of the presence of CMR 1A or 1B and/or ED hazardous substances is described in Annex I 10.4.2 as presented in the text box below. 10.4. Substances 10.4.1. Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as fa r as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine -disrupting properties for which there is scientific ev idence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been ad opted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established the rein. 10.4.2. Justification regarding the presence of CMR and/or endocrine -disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the subs tance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer -reviewed studies, scientific opinions from relevant scientific committees and an analysis of the avail ability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit -risk ratio s of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances an d/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3 and 10.4.4. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 45 Annex 3: Definitions/descriptions – References - Glossary Definitions ( Regulation (EU) 2017/745 ) Benefit -risk determination: means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer. Performance: means the ability of a device to achieve its intended purpose as stated by the manufacturer. Clinical performance: means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteri stics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer. Clinical benefit: means the positive impact of a de vice on the health of an individual, expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health. Risk: means the combination of the probability of occurrence of harm and the severity of that harm. Adverse event: means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or othe r persons, in the context of a clinical investigation, whether or not related to the investigational device. Serious adverse event: means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subjec t, that resulted in any of the following: (i) life -threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitali sation or prolongation of patient hospitali sation, (iv) medical or surgical intervention to p revent life -threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) fetal distress, fetal death or a congenital physical or mental impairment or birth defect. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 46 Incident: means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use -error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesir able side -effect. Serious incident: means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a pati ent's, user's or other person's state of health, (c) a serious public health threat. Serious public health threat : means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time. Device deficiency: means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer. Regulation (EU) 2017/745 Annex XIV Clinical evaluation and post -market clinical follow -up. Part A “Clinical evaluation” Section 3 describes the characteristics that shall be considered for demonstration of equivalence . “A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. T he following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: Technical : the device is of similar design; is used under similar conditions of use; has similar specifications and pr operties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and cr itical performance requirements; Biological : the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including de gradation products and leachables; Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 47 Clinical : the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has simila r relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in or der to justify their claims of equivalence. ” Definitions on assessment of alternatives (OECD Toolbox Glossary) Note: The term "chemical" is used synonymously with "substance" Alternativ es assessment : A process for identifying and comparing potential chem ical and non -chemical alternatives that can be used as substitutes to replace chemicals or technologies of high concern1 Chemical substitution : The process of replacing a chemical of concern with a safer chemical, material or product, or technology/process that eliminates the need to use that chemical Cost/benefits and availability : The negative (cost) and positive (benefit) implications, direct and indirect, resulting from some actio n. This includes both financial and non - financial information. Availability refers to the production of an alternative and its market accessibility3 Functional use approach : This approach starts with identifying the function that is desired. The concept is applied in two ways: first and foremost, to characteri se the purpose a chemical or mixture serves, or the properties it imparts in a product or process (functional use), and second, to eva luate the function of the product and how its use may influence the assessment of alternatives4, 5 Material substitution : The process of replacing a material containing a chemical of concern with a safer chemical, material, product or technology/process that eliminates the need to use that chemical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 48 Mixture : A composition of at least two chemicals in which they do not react6 Technical feasibility : The determination as to whether the performance or functional requirements of a chemical, material or product could be fulfilled or replaced by eliminating or using an alternative chemical, material, product, process or technology, while considering any need for process adaptations and changes3 Process modification : Changes in manufacturing processes to eliminate, reduce or substitute chemicals of concern. Such changes may include synthesis pathways, waste reduction, and manufacturing procedures where chemicals are used. Product performance : The ability of a product to meet identified performance requirements. The boundaries of performance characteristics are defined by the user3 Product substitution : The process of replacing a product containing a chemical of concern with a chemical, material or product or technology/process that eliminates, reduces or substitutes the need to use that chemical. 1 Adapted from Alternatives Assessment Guide, version 1.0 . 2013. Interstate Chemicals Clearinghouse. 2 REACH. Title I, Chapter 2, Article 3. 3 Current Landscape of Alternatives Assessment Practice: A Meta -Review. Organisation for Economic Cooperation and Development. 2013. 4 U.S. EPA. 2006. National Pollution Prevention and Toxics Advisory Committee (NPPTAC) Recommendation to the EPA Administrat or and Deputy Administrator on Incorporating the Functional Use Approach into OPPT Activities. 5 Lavoie, E. T., et al. 2010. "Chemical Alternatives Assessment: Enabling Substitution to Safer Chemicals." Environmental Science & Technology 44(24): 9244 -9249. 6 Adapted from U.N. Global Harmonized System of Classification and Labelling of Chemicals . 2003. 7 ECHA, 2008. Guidance on Socio -Economic Analysis - Restrictions. 8 Adverse event means pre -clinical and clinical occurrences of an effect whereas incident indicates a clinical effect occurring during post -market surveillance. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 49 Reference s  ECHA (2011) Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  EFSA (2019) Draft update of the risk assessment of di -butylphthalate 1 (DBP), butyl-benzyl -phthalate (BBP), bis(2 -2 ethylhexyl)phthalate (DEHP), di - isononylphthalate (DINP) 3 and di -isodecylphthalate (DIDP) for use in food contact 4 materials http://www.efsa.europa.eu/en/consultations/call/190221 .  Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk - benefit methodologies for assessing drug safety and efficacy -report o f the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657 -66. Glossary BBP Benzylbutylphthalate BMD Bench Mark Dose BRA Benefit -Risk Analysis BTHC Butyryl -tri-n-hexylcitrate CAS Chemical Abstracts Service CEN European Committee for Standardization CLP Classification Labelling and Packaging regulation (EC No 1272/2008) CMR Carcinogenic, Mutagenic, toxic to Reproduction (Reprotoxic) DBP DiButylphthalate, DCHP Dicyclohexylphthalate DEHP Diethylhexylphthalate DIBP Diisobutylphthalate DIDP Di isodecyl phthalate) DINCH 1,2- cyclohexan edicarboxylic acid, di isononyl ester) DINP Di isononyl phthalate) DIPP Diisopentylphthalate DMEP Bis(2-methoxyethyl)phthalate DNHP Dihexylphthalate DHNUP 1,2-Benzenedicarboxylic acid, di -C7-11-branched and linear alkyl esters DPP Dipentyl phthalate DMEL Derived Minimum Effect Level DNEL Derived No Effect Level EC European Commission ECB European Chemicals Bureau (now ECHA) ECHA European Chemicals Ag ency (formerly ECB) Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 50 ED Endocrine Disruptor EEC European Economic Community EMA European Medicines Agency EFSA European Food Safety Authority EN-ISO CEN and ISO combined published document FDA Food and Drug Administration (USA) FDIS Final Draft International Standard ISO International Organization for Standardization LOAEL Lowest Observed Adverse Effect Level MCDA Multi Criteria Decision Analysis MDD Medical Device Directive (Council Directive 93/42/EEC) MDR Medical Device Regulation (EU 20 17/745) MoA Mode of Action MoE Margin of Exposure MoS Margin of Safety NICU Neonatal Intensive Care Unit NOAEL No Observed Adverse Effect Level OECD Organization for Economic Cooperation and Development PoD Point of departure PVC Polyvinyl chloride RBC Red Blood Cell RCR Risk Characterisation Ratio REACH Registration, Evaluation, Authorisation and restriction of CHemicals. SCHEER Scientific Committee on Health, Environmental and Emerging Risks SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks T25 25 % increase of the tumour rate over controls TDI Tolerable Daily Intake TE Tolerable Exposure (EN ISO 10993 -17:2002 in mg/day) TEHTM Tri( 2 -ethyl hexyl)trimellitate also TOTM Trioctyltrimellitate TI Tolerable Intake TOTM Trioctyltrimellitate also TEHTM Tri( 2 -ethyl hexyl)trimellitate TWI Tolerable Weekly Intake Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 51 Annex 4: CMR and/or ED substances CMR substances are substances identified and classified as carcinogenic, mutagenic or toxic for reproduction of different categories based on the intrinsic toxic properties of a substance for which categories 1A and 1B apply to these Guidelines. In Europe, classification for these endpoints is harmonised through harmonised classification and labelling (CLH). Details can be found at https://echa.europa.eu/regulations/clp/understanding -clp. For a specific substance to be classified as CMR 1A, 1B or 2 a dossier needs to be prepared and if the Commission finds that the proposed classification is appropriate, it submits a draft decision concerning the inclusion of that substance in Part 3 of Annex VI to the CL P Regulation (Regulation (EC) 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures).  Category 1A means that the substance is a known human carcinogen, mutagen or reproductive toxicant based on human evidence.  Category 1B means that the substance is a presumed human carcinogen, mutagen or reproductive toxicant based on animal studies.  Category 2 means that a substance is considered as suspected carcinogen, mutagen or reproductive toxicant based on limited evidence from ani mal studies or humans (not part of these Guidelines) . Documents on the classification are publicly available , and a tutorial to search entries is given here: http://www.chemsafetypro.com/Topics/EU/Annex_VI_to_CLP:_List_of_Harmonised_Class ification_and_Labelling_for_Certain_Hazardous_Substances.html Guidance for the identification of endocrine disrupto rs (ED) in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009 has been published on 7th June 2018 by ECHA and EFSA (doi: 10.2903/j.efsa.2018.5311; EFSA Journal 2018;16(6):5311) which can be accessed via: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2018.5311 This EFSA/ECHA Guidance describes when a substance shall be considered as having endocrine disrupting properties. “A substance shall be considered as having endocrine disrupting properties if it meets all of the following criteria: a) it shows an adverse effect in [an intact organism or its progeny]/[non -target organisms], which is a change in the morphology, physiology , growth, development, reproduction or life span of an organism, system or (sub)population6 that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other in fluences; b) it has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system; c) the adverse effect is a consequence of the endocrine mode of action. It should be highlighted that the ‘endocrine mode of action ’ as stated in point (b) should be interpreted as ‘endocrine activity ’ while the term ‘endocrine mode of Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 52 action’ in point (c) covers the link between the adverse effect and the endocrine activity identified in points a) and b), respectively. Keeping this in mind point (b) abo ve should be understood as (differences from above in italics ): it shows endocrine activity, i.e. it has the potential to alter the function(s) of the endocrine system; Consequently point (c) above should be understood as (differences from above in italics ): the substance has an endocrine disrupting mode of action, i.e. there is a biologically plausible link between the adverse effect and the endocrine activity. ” EDs identified with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 concern ing the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), will finally enter the REACH candidate list of substances of very high concern for potential inclusion in REACH Annex XIV. The information can be found in the respecti ve decision document accessible via : https://echa.europa.eu/candidate -list-table. For substances having endocrine -disrupting properties as indicated above, there is currently no information concer ning whether it is foreseen to publish them in central lists or annexed to a Regulation. EDs identified by the delegated act pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products, can be accessed through the Biocidal Products Committee opinions on active substance approval which can be accessed via ECHA’s website (https://echa.europa.eu/regulations/biocidal -products -regulation/approval -of-active - substances/bpc -opinions -on-active -substance -approval ). Substances undergoing an ED assessment under the REACH or Biocidal Products regulations that have been brought for discussion to ECHA’s ED Expert Group are included in ECHA’s endocrine disruptor (ED) assessment list: https://echa.europa.eu/ed - assessment . For each substance, the table shows the assessing or evaluating Member State (submitter), the outcome and the suggested follow -up for the assessment, and the date of the latest update to the list entry. Recently the Commission Implementing Decision (EU) 2017/1210 was published that identified some phthalates (Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl phthalate (DBP) and Diisobutyl phthalate (DIBP)) as substances of very high concern due to their endocrine disrupting properties with probable serious effects to humans (European Commission 2017). https://publications.europa.eu/en/publication -detail/ -/publication/357b3d45 -620f-11e7- 9dbe-01aa75ed71a1/language -en/format -PDF For completeness, even if not relevant for the purpose of this guidelines, Bis(2 - ethylhexyl) phthalate (DEHP) was also identified in 2014 as a substance of very high concern due to its endocrine disrupting properties with probable serious effects to the environment. In addition, Commission Implementing Decision (EU) 2018/636 identified Dicyclohexylphthalate (DCHP) as subs tance of very high concern (SVHC) according to Article 57(f) of REACH Regulation (EC) 1907/2006, due to its endocrine disrupting Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 53 properties with probable serious effects to humans. https://eur -lex.europa.eu/legal - content/EN/TXT/PDF/?uri=CELEX:32018D0636&fr om=EN Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 54 Annex 5: Legislation on CMR and/or ED phthalates Due to their reprotoxic properties and additionally since 2014 for DEHP due to their endocrine disrupting properties for the environment and since 2017 for DEHP, BBP, DBP, and DIBP due to their endocrine disrupting properties for human health , a considerable number of phthalates have been identified as substances of very high concern (SVHC) and therefore included in the candidate list for the inclusion in Annex XIV of the REACH regulation (Annex XIV of REACH EC 1907/2006 , see https://echa.europa.eu/de/candidate -list-table for the most recent update of the candidate list). Eight phthalates are also listed on the Authorisation list (Annex XIV of REACH), namely DEHP, BBP, DIBP, DBP, DIPP (diisopentylphthalate), Bis(2 -methoxyethyl) phthalate, dipentyl phthalate, and N -pentyl -isopentylphthalate. Since February 2015 DEHP, BBP, DIBP, and DBP cannot be used within the European Union withou t authorisation. The same provision would apply to the remaining four phthalates on Annex XIV from July 2020. To date, applications for authorisation have been submitted for DEHP and DBP only. However, imported articles do not come under the authorisation requirement. For the purpose of evaluating applications for authorisation, the ECHA Committee for Risk Assessment (RAC) has developed reference DNELs for several substances, including DEHP, BBP, DBP, and DIPP. (See Evaluating Applications table/Ref erence D NELs on ECHA’s website: https://echa.europa.eu/applying -for-authorisation/evaluating -applications .) Risks to human health arising from the use of an Annex XIV substan ce in medical devices regulated by Directives 90/385/EEC, 93/42/EEC or 98/79/EC are exempted from authorisation requirements under Title VII of the REACH Regulation14. ECHA is currently preparing a recommendation on the inclusion of the ED properties for environment for DEHP in Annex XIV to REACH .15 If DEHP is included on Annex XIV for environmental hazards , applications for authorisations may need to be prepared for uses of the substance in medical devices in the future. REACH Annex XVII (entry 51) also restricts the placing on the market of articles containing DEHP, BBP, DBP, and DIBP in concentration greater than 0.1% weight by weight of the plasticised material, individually or in combination in a range of articles. These articles include toys16 and childcare articles, as well as other primarily consumer and professional use articles whic h lead to dermal or inhalation exposure. (For risk assessment conclusions, including derivation of a DNEL for DIBP, see Compiled RAC & SEAC opinion and background document on ECHA’s website: https://echa.europa.eu/previous -consultations -on-restriction -proposals/ -/substance - rev/13919/term .) 14 These Regulations will be replaced by:  Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC •Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU 15 https://echa.europa.eu/draft -recommendation -for-amendment -of-authorisation -list-entries -previous - consultation 16 The Toy Safety Directive (2009/48/EC) stipulates that chemicals that are susceptible to cause cancer, change genetic information, harm fertility or harm an unborn child (CMR substances) are no longer allowed in accessible parts of toys beyond the concentration limits set in the CLP Regulation ((EC) No 1272/2008). Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 55 REACH Annex XVII (entry 52) restricts the placing on the market and the use of DINP, DIDP, and DNOP, as a substance or in mixture, in concentrations greater than 0.1% weight by weight of the plasticised material in toys and childcare articles which can be placed in the mouth of children. In 2010, the European Commission requested ECHA to review the scientific evidence on the risks posed by articles containing these phthalates with the view to conclude on the need or not for further actions under REACH. The report and RAC risk assessment conclusions (including information on the derivation of DNELs) can be foun d on ECHA’s website: https://echa.europa.eu/consultations -draft-review - report -previous -consultations/ -/substance -rev/1108/term . EFSA recently launched a consultation on its updated 2005 risk assessments of DBP, BBP, DEHP, DINP and DIDP which are authorised for use in plastic FCM, by using the same database as ECHA for its 2017 assessment of certain phthalates. The draft update of the ri sk assessment can be found here: http://www.efsa.europa.eu/en/consultations/call/190221 In addition to the REACH legislation, there is also product -specific legislation which regulates certain phthalates, i.e. the Cosmetic Products’ Regulation (EC/1223/2009) and the Regulation on materials and articles intended to come into contact with food ( Food Contact Materials, Regulation EC 1935/2004 , as general framework regulation and Regulation EU 10/2011 specific for plastic materials and articles destined to be in contact with foodstuffs , recently amended by Regulation 2018/831 ). Both in the MDD (93/42/EEC) and the more recent MDR (2017/745), phthalates are specifically mentioned for their use in medical devices. For a number of phthalates there is legislation available that might contain information relevant for the use of phthalates in medical devices. Of specific relevance for medical devices may be the Regulation EU 10/ 2011, which also incl udes provisions for the use of phthalates in food contact materials and articles with respect to migration limits. This may be a parallel with migration (and thus potential internal exposure) of phthalates as present in polymers used for medical device man ufacturing. In Annex I of the Regulation EU 10/2011 all substances are listed, which are authorised for the use as starting material or additive for plastic layers in plastic materials and articles. Each substance must not exceed its specific migration lim it (SML). The following phthalates and other plastici sers17 are authorised for use as additives: DBP (SML) = 0.3 mg/kg food only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical supp ort agent in polyolefins in concentrations up to 0.05% in the final product BBP, SML = 30 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles; 17 Not exhausti ve examples for other than phthalates Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 56 (b) plasticiser in single -use materials and articles in contact with non -fatty foods, not for contact with infant formulae and follow -on formulae (Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Direc tive 2006/125/EC); (c) technical support agent in concentrations up to 0.1% in the final product. DEHP, SML = 1.5 mg/kg food Only to be used as: (a) plasticiser in repeated use materials and articles in contact with non -fatty foods; (b) technical su pport agent in concentrations up to 0.1% in the final product. DINP SML = 9 mg/kg food (cumulative with DIDP) only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Di rective 2006/125/EC) (c) technical support agent in concentrations up to 0.1% in the final product. DIDP, SML = 9 mg/kg food ( cumulative with DINP) Only to be used as (a) plasticiser in repeated use materials and articles; (b) plasticiser in single -use materials and articles in contact with non -fatty foods , not for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and processed cereal -based foods and baby foods for infants and young children (Directive 2006/125/EC) (c) te chnical support agent in concentrations up to 0.1% in the final product. Furthermore, for certain plasticizers listed in Regulation (EU) 10/2011, including a number of phthalates, applies a group restriction (Group restriction number 32), that is, the sum of these substances must not exceed an SML of 60 mg/kg foodstuff. DEHP, BBP, DBP and DIBP must not be contained in homogenous materials above the concentration of 0.1% w/w from July 2019 on according to the Restriction of Hazardous Substances Directive in electrical and electronic equipment RoHS2 (2011/65/EC). For medical devices and in vitro diagnostic products this restriction takes effect in July 2021. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 57 Table 1 CMR Classification*) and ED designation**) of phthalates (status Jan 2019) Phthalate Abbreviation CAS number CMR Classification* ED identification** bis(2- methoxyethyl)phthalate DMEP 117-82- 8 Repr 1B - bis (2-ethylhexyl)phthalate DEHP 117-81- 7 Repr 1B ED dibutyl phthalate DBP 84-74-2 Repr 1B ED 1,2- benzenedicarboxylic acid, dipentylester, branched and linear 84777 - 06-0 Repr 1B - n-pentyl - isopentylphthalate PIPP No CAS 776297 - 69-9? Repr 1B - di-n-pentyl phthalate DnPP 131-18- 0 Repr 1B - diisopentylphthalate DiPeP 605-50- 5 Repr 1B - benzyl butyl phthalate BBP 85-68-7 Repr 1B - ED diisobutylphthalate DIBP 85-69-5 Repr 1B ED dihexylphthalate DHP 84-75-3 Repr 1B dicyclohexylphthalate DCHP 84-61-7 Repr 1B ED *) as indicated in Annex VI to CLP_ATP10 (in force from 1 December 2018). **) according to the ECHA Candidate List of substances of very high concern for Authorisation published in accordance with Article 59(10) of the REACH Regulation https://echa.europa.eu/candidate -list-table As substances of concern, knowledge on the exposure to phthalates is important and biomonitoring of populations provides important information. For some of the phthalates already human biomonitoring assessment values, namely Biomonitoring equi valents (BE) or human biomonitoring (HBM) values, have been derived – these are concentrations of biomarkers (metabolites) in urine, which reflect an acceptable chronic exposure, since the basic assumption is an equilibrium between external exposure and in ternal burden (Angerer et al. 2011, Apel et al. 2017). In the course of the work done within the HBM4EU project, Human Biomonitoring Guidance Values (HBM -GVs) could be derived for DEHP and DINCH (see HBM4EU Deliverable D5.2, https://www.hbm4eu.eu ). In addition, HBM-GVs for the following SVHC phthal ates are finalised in September 2019 (Deliverable D5.6) and will also be published on the website: BBzP, DiBP, and DnBP. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 58 Annex 6: Use of phthal ates in medical devices Phthalates are abundantly used in polyvinyl chloride (PVC) medical devices such as blood bags, intravenous bags, nutrition pockets, tubing, catheters, respiratory masks or disposable gloves. More than 40% of all plastic -based disposable medical devices are made from PVC. Di -2-ethylhexyl phthalate (DEHP) has been for many years the most commonly used phthalate ester plasticiser in medical devices. A survey among the Danish Medical Device Industry found that 95% of the products contained DEHP [Huntley P, edit or The classified phthalates should be phased out of medical devices. Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark]. Safety concerns have been expressed for several high -risk patients groups, s uch as neonates, infants, pregnant and breast -feeding women exposed to DEHP. The SCENIHR in its Opinion of 201 5 indicated that “a lack of evidence of causation between DEHP -PVC and any disease or adverse effect does not mean that there are no risks”. This lack of evidence applies to all phthalates classified as CMR and/or identified as ED. Therefore the requirement of patient subgroup analysis for the target patient groups as defined in the “Intended Use” of a medical device is now included in the Regulatio n (EU) 2017/745. For the use of DEHP, high risk groups were identified including patients undergoing haemodialysis, extracorporeal membrane oxygenation (ECMO), and prematurely born infants in Neonatal Intensive Care Units (NICU), (SCENIHR 201 5). The actua l exposure of such patient groups relative to the toxicity including CMR/ED property needs to be determined. However, even if the remaining risk is high, the benefit of the treatment should be considered as well. It might be useful to evaluate the patient subgroups separately:  Paediatric Population (see subgroups)  Peripubertal males  Pregnant women  Breast -feeding women  any other patient group considered particularly vulnerable or exposed to high levels of phthalates. For purposes of this Guideline, the following ranges of paediatric subpopulations are proposed to be used as a guide for manufacturers in medical devices (ref. SCCS Notes of Guidance – SCCS/1602/18, section 3 -6.9.1, page 7818) 18 https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs _o_224.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 59 Definition of Paediatric Population Subgroups Paediatri c Subgroup Approximate Age Range Full-term neonate <1 week Newborn 1 week–2 months Early infant 2–6 months Crawlers/toddler 6 months –2 years Preadolescent 2–12 years Adolescent 12–18 years In view of ED activity, a dditional (paediatric ) subpopulations may need to be considered includ ing:  very low birth weight describes newborns less than 1.5 Kg  low birth weight describes newborns less than 2.5 Kg  preadolescent age group typically ranges from 11 to 13 years.  peripubertal males or females It should be realised that the benefit of medical devices including the use of phthalates must also be considered: The survival of prematurely born infants often depends on the availability of the same medical devices that result in a relative ly high phthalate content exposure due to treatment. Whenever possible, material with low release potential should be used (see SCENIHR opinion 201 5). Besides the direct patient benefits of the treatment with a medical device containing phthalates, other functionalities may also need to be considered. For example, DEHP has a stabilising effect on red blood cells (RBCs). RBCs have increased survival rates when stored in DEHP containing blood bags. DEHP is incorporated into the cell walls of RBCs and stabil ises the membrane integrity of the RBCs. This results in a prolonged shelf life and thus patient availability of blood stored in DEHP containing blood bags (SCENIHR 2015). A maximum limit of extractable DEHP of 15 mg/100 mL for flexible PVC containing DEHP is indicated in EN ISO 3826 -1 on containers for the collection of human blood and blood components. The plasticiser industry has been investing and developing alternatives to DEHP in medical devices. Today, other plasticisers such as Di -isononyl cyclohe xanoate (DINCH, CAS 166412 -78-8), Tri -2-ethylhexyl trimellitate (TEHTM, CAS 3319 -31-1), butyryl tri -n- hexyl citrate (BTHC, CAS 102818 -95-1) and Dioctyl Terephthalate (DOTP, CAS ‎6422-86- 2) are being proposed in medical applications such as medical tubing and blood bags. https://www.plasticisers.org/applications/medical -applications/ Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 60 In conclusion, for any BRA on the use of phthalates and the development of alternatives in me dical devices, careful consideration should be used to appropriate patient subgroup analysis regarding medical device use and the resulting potential exposure. Reference Huntley P, Editor . The classified phthalates should be phased out of medical devices. Program Meeting on Alternatives to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, Denmark. https://pvc.dk/wp -content/uploads/2016/02/pvc -alternativer -til-klassificerede -ftalater - program.pdf Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 61 Annex 7: Approaches for Benefit -Risk Assessment Several approaches for BRA have been proposed especially in the context of medicinal products. The Innovative Medicines Initiative PROTECT Project (www.imiprotect.eu), presented a detailed review of approaches used for BRA (Mt -Isa et al. 2014). In this review, a large number of approaches were identified and classified as descriptive (qualitative or semi -qualitative) or quantitative frameworks (relying on quantitative methods of trading risks and benefits following mathematical principles), metrics (measure s for benefits and risks that are usually endpoint specific), estimation techniques (i.e., simulation techniques and meta -analysis) , and utility survey techniques (to elicit stakeholders’ preferences). Concerning quantitative frameworks, according to the European Medicines Agency (EMA) Project Report (EMA/227124/2011), there is no agreement on any one approach to be used in regulatory submission on the benefits and risks of medicines. However, EMA has encouraged the use of quantitative frameworks in regulatory submissions of applications for marketing authorisation of medicinal products. Although there is little experience with quantitative frameworks in the area of medical devices, some of the BRA appro aches used for pharmaceuticals may also be relevant for medical devices and particularly regarding the use of CMR/ED phthalates. In particular, approaches based on multicriteria decision analysis ( MCDA) have attracted much attention during the past years in the field of medical decisions. For an introduction to MCDA see Dodgson et al. (2009). In brief, MCDA is based on decision theory and belongs to the general class of multi - criteria analysis mode ls that accommodate decision making with multiple objectives. The main purpose of MCDA is to bring together evaluations of options on different criteria into one overall evaluation. The starting point for MCDA approaches include s identification of the alte rnatives and the criteria against which the alternatives are appraised. MCDA includes weighting, which ensures that the units of value on all the criteria are comparable so that benefits and risks can be compared by using a common unit of value. In this wa y, the added value of benefits can be compared to the loss of value from the risks. A number of different weighting methods can be used, ranging from precise elicitation of weights, to weights based on qualitative judgements or including uncertainty. A generic framework for conducting an MCDA can be based on the steps of the PROACT - URL framework (Hammond et al. , 1999), as presented below. A detailed description of the different implementations of MCDA techniques is beyond the scope of this guideline. The c hosen techniques and analyses should be presented and justified among others on the basis of internal consistency, logical soundness and transparency. Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 62 STEP Description and relation to framework for Benefit -Risk Assessment described in section A of the Guidelines Problem Describe the medical device, its intended use, and the therapeutic context; frame the decision problem in terms of potential alternatives to CMR/ED phthalate. See Step 1: Description and characterisation of the composition of the medic al device; and Step 2: Use and function of the phthalates in the medical device. Objectives Identify the full set of criteria to evaluate different alternatives. See Step 2: Use and function of the phthalates in the medical device; and Step 3: Assessment of the risks of the CMR/ED phthalate. See 7 Benefit assessment . Alternatives Identify alternatives that are being evaluated against each other. See Step 4: Inventory of possible alternatives; and Step 5: Identification of the candidates for assessment as potential relevant alternatives for phthalates . Consequences Describe how the alternatives perform for each of the criteria, i.e., the magnitudes of all effects in terms of the different benefits and risks. See Step 2: Use and function of the phthalates in the medical device; Step 3: Assessment of the risks of the C MR/ED phthalate; Step 6: Description of identified relevant potential alternative(s); Step 7: Assessment of the risk of identified potential relevant alternatives. For a summary table see Table 1. Example for a comparison of CMR/ED phthalate with potential alternative(s). Trade -offs Assess the balance between benefits and risks using judgements of weights associated with the criteria and the value associated with the benefits and risks of every alternative. MCDA techniques commonly achieve this through num erical analysis. A number of different weighting methods can be used. Conduct sensitivity analyses to explore uncertainties using different scenarios, and assess how different weights affect the overall ordering of the alternatives. See also Step 8: Compar ison of functionality and performance of CMR/ED phthalate as used in the medical device with functionality and performance of identified potential relevant alternatives; Step 9: Comparison of risk(s) of original CMR/ED phthalate as used in the medical device with risk(s) of identified potential relevant alternatives; and Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device with identified potential relevant alternatives. Uncertainty Report the uncertainty associated with the benefits and Risks. Consider how the balance between benefits and risks is affected by uncertainty. A quantitative model will Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices (final version) _________________________________________________________________________________________ __________________________________________________________________________________ 63 explore in sensitivity analyses and scenario analyses (or by explicitly incorporating probability distributions in the model) the effects on the overall benefit -risk balance of all sources of uncertainty. See 1.9 Uncertainty analysis. Risk tolerance Describe any considerations that could or should affect the decision maker’s attitude toward risks (e.g., special population, unmet medical need). Linked -decisions Discuss how the value judgements and data are consistent with similar decisions on medical devices. References  Dodgson J, Spackman M, Pearman A, Phillips LD. Multi -criteria analysis: A manual. London: Department for Communities and Local Government, First published in 2000 by the Department for Environment, Transport and the Regions; 2009.  ECHA 2011 Guidance on the preparation of socio -economic analysis as part of an application for authorisation, European Chemicals Agency 2011 .  Hammond JS, Keeney RL, Raiffa H, Smart Choices: A Practical Guide to making Better Decisions, Boston, MA: Harvard Business School Press; 1999.  Mt-Isa S, Hallgreen C.E., Wang N., Callréus T., Genov G., Hirsch I., Hobbiger S., Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki I., Micaleff A., Ashby D. - Balancing benefit and risk of medicines a systematic review and classification of available methodologies, Pharmacoepidemiology and Drug Safety, May 2014 .

md_transitional-provisions-art-3-and-4_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 rev. 1 Class I Transitional provisions under Article 120 (3 and 4) – (MDR) March 2020 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 MDCG 2020 -2 revision 1 changes MDR postponement dates : from 2020 to 2021 How can a ffected manufacturers of some class I devices1 make efficient use of the transitional provisions in A rticle 120 (3 ) and (4) of Regulation (EU) 2017/745 – Medical Devices Regulation ( MDR )? Background: The corrected MDR2 Article 120 (3) allows under certain condition s, some class I devices pursuant to Directive 93/42/EEC – Medical Devices Directive (MDD) , for which the Declaration of C onformity was drawn up prior to 26 May 2021 and for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body, to be placed on the market3 until 2 6 May 20244. In order to make use of this article , the following conditions must be met: 1. The device continues to comply with Directive 93/42/EEC, 2. A notified body will need to be involved under the MDR (e.g. re -usable surgical instruments or up -classified devices) 3. A valid Declaration of C onformity , according to Annex VII of the MDD , must be drawn up befor e 26 May 2021, 4. No significant changes to the design or intended purpose of the device after 26 May 202 15, 5. The requirements of the MDR relating to post -market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in Directive 93/42/EEC .6 This shall be in place on the 26 May 2021. Scope The scope of this document is to provide guidance related to the information to be provided in the form of a Declaration of Conformity by manufacturers of Class I devices (devices which are non - 1 Class I devices for which the conformity assessment procedure pursuant to the MDR would require the involvement of a notified body. 2 Corrigendum to Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/E EC and 93/42/EEC (OJ L 117, 5.5.2017), of 27.12.2019. 3 Devices which are not placed on the market but put into service may also make use of the transitional provisions . 4 Article 120(4) ‘and may continue to be made available on the market …until 26 May 2025’ . 5 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD . 6 Upcoming guidance on harmonised practices and technical solutions to facilitate exchange of information in absence of EUDAMED . Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 sterile or do not have a measuring function) that are required to have certificates after 26 May 2024 according to the MDR. Content of a val id Declaration of Conformity The manufacturer or his authorised representative established in the European Union is obliged to issue a Declaration of Conformity that the product has undergone a conformity assessment procedure required by the MDD before being placed on the market. With the Declaration of Conformity, the manufacturer declares that the products concerned meet the relevant provisions of the MDD. MDD Annex II, Annex V, Annex VI set out that a Declaration of Conformity must cover one or more medical devices manufactured 7 clearly identified by means of product name, product code or other unambiguous reference for class IIa, IIb and III devices, and also class Im and class Is devices. This is however not necessary for other Class I devices, as it is not required by the MD D (Annex VII) and as there is no certificate from a notified body to which the issued Declaration of Conformity is related. Guidance on the content of the Declaration of C onformity can be found, inter alia, in the “The ‘Blue Guide’ on the implementa tion of EU products rules 2016 (2016/C272/01) ”8 and the standard EN ISO/IEC 17050 -1.9 According to this standard , the declaration may take the form of a document or any other suitable medium , and should contain sufficient information to enable all products covered to be traced back to it. The model declaration in Annex III of Decision No 768/2008/EC and the ‘Blue Guide’ on the implementation of EU products rules 2016 (2016/C272/0 1) describe the content of the Declaration of C onformity to be as follows: 1. A number identifying the product. This number does not need to be unique to each product. It could refer to a product, batch, type or a serial number .10 This is left to the discretion of the manufacturer .11 2. The name and address of the manufacturer or the authorised representative issuing the declaration. 3. A statement that the declaration is issued under the sole responsibility of the manufacturer. 7 MDD Annex II, paragraph 2 ‘This declaration must cover one or more medical devices manufactured, clearly identified by means of product name, product code or other unambiguous reference and must be kept by the manufacturer.’ 8 https://eur -lex.europa.eu/legal -content/GA/TXT/?uri=CELEX:52016XC0726(02) . 9 EN ISO/IEC 17050 -1 : 2004 Conf ormity assessment – Supplier’s D eclaration of Conformity – Part 1: General requirements /EN ISO/IEC 17050 -2 : 200 4 Conformity assessment – Supplier’s Declaration of C onformity – Part 2: Supporting documentation . 10 The ‘number’ may be an alpha -numerical code or could also refer to a software version . 11 In addition, whether this is expressly envisaged or not by the Union harmonisation legislation, manufacturers are free to add a number identifying the Declaration of Conformity itself in line with EN ISO/IEC 17050 -2. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 4. The identification of the product allowing traceability. This is any relevant information suppleme ntary to point 1 describing the product and allowing for its traceability . Where relevant for the identification of the product , it may contain an image, but unless specified as a requirement in the Union harmonisation legislation this is left to the discr etion of the manufacturer. 5. All relevant Union harmonisation legislation complied with; the referenced standards or other technical specifications (such as national technical standards and specifications) in a precise, complete and clearly defined way; this implies that the version and/or date of the relevant standard is specified.12 6. If applicable, t he name and identification number of the notified body ,13 when it has been involved in the conformity assessment procedure ,14 15 and the reference to the relevant certificate. 7. If applicable, a ll supplementary information that may be required (for example category) . 8. The date of issue of the declaration; signature and title or an equivalent marking of the authorised person16 17  This could be any date after the complet ion of the conformity assessment , but must be before 26 May 202 1 if the manufacturer wants to make use of the transitional period in Article 120(3) and (4) of the MDR . Every Declaration of C onformity must be based on proper technical documentation according to Annex VII para graph 3 of the MDD. The technical documentation and the D eclaration of Conformity should be subject to appropriate measures of document and record control. The Declaration of Conformity is to be kept by the manufacturer and shall be at the disposal of the competent authorities for a period ending at least five years after the last product has been manufactured. Necessary amendm ents/updates to the t echnical documentation should be done in a transparent manner. Both t he changes and the dates of when the changes were made should be recorded. On the basis of the Declaration of Conformity and the corresponding technical documentation, the manufacturer should be able to demonstrate that the Declaration of Conformity was lawfully18 issued before 26 May 202 1 and that, subsequently, there are no significant changes in the design or intended 12 According to the MDD , referencing st andards or technical specifications complied with is voluntary . 13 For class I devices in scope of this guidance document, the involvement of a notified body is not required. 14 Not all Union harmonisation legislation requires the intervention of a notified body (e.g. the Low Voltage Directive and the Toys D irective . 15 The name and address of the person who keeps the technical documentation may also be required by some pieces of Union harmonisation legislation since according to those, not only the manufactu rer shall keep the technical documentation. 16 This could be the m anaging director of the company or another representative of the company to whom this responsibility has been delegated. 17 It is not necessary for the signatory to be domiciled in the Europea n Union. A manufacturer established outside the Union is entitled to carry out all the conformity assessment procedures at his premises and, to sign the Declaration of Conformity . 18 Lawfully according to the Directive and to any relevant national provisions which apply. Medical Device Medical Device Coordination Group Document MDCG 2020 -2 rev.1 purpose19 in the meaning of Article 120(3) MDR. Taking into account Article 123(3) and 123 (3)(d), and a s EUDAMED will not be fully functional in May 202 1, it is required that the manufacturer keep the Declaration of Conformity together with the technical documentation available to the Competent Authorities . This would also include details o f all device registrations and economic operator registrations completed pursuant to national provisions implementing the requirements of Articles 14 (1) and (2) of Directive 93/42/EEC. 19 Guidance on significant changes under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD .

09 MDCG 2020-9 Regulatory Requirements for Ventilators and Reated Accessories.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-9 MDCG 2020-9 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 REGULATORY REQUIREMENTS FOR VENTILATORS AND RELATED ACCESSORIES Options for supporting production and/or placing on the market of ventilators in the context of COVID-19 pandemic 1. INTRODUCTION AND SCOPE The World Health Organization (WHO) declared the COVID-19 outbreak a pandemic on March the 12th 2020. Patients infected by SARS-CoV-2 virus and developing the COVID-19 disease with acute and severe respiratory symptoms have to be treated with mechanical ventilators to assure possibilities of survival. This guidance document focuses on ventilators and related accessories that are currently regulated under the Council Directive 93/42/EEC (MDD)1. According to the MDD, devices may be placed on the market and/or put into service only if they comply with the requirements laid down in this Directive when duly supplied and properly installed, maintained and used in accordance with their intended purpose2. The devices must meet the essential requirements set out in Annex I of the MDD, which apply to them, taking account of the intended purpose of the devices concerned. In addition, devices may be placed and circulate on the European single market if they have been subject to a conformity assessment in accordance with the provisions of Article 11 of the MDD. Under the current COVID-19 context, the demand for ventilators and related accessories has rapidly increased. Therefore, this document intends to outline the different regulatory options for placing these devices on the EU market indicating their feasibility to allow short-term supply. 2. TYPES OF MEDICAL DEVICES AND THEIR PARTS /COMPONENTS 2.1. Ventilators Ventilators are breathing support devices and can fall into different types according to their intended use and characteristics3: 1 However, placing on the market of devices which comply with MDD is limited to 27 May 2024. After this date every device placed on the market has to comply with the requirements of Regulation (EU) 2017/745 (MDR). According to the Article 120 section 5 and 6 of the MDR devices which comply with MDR may be placed on the market before its application and notified bodies which are designated and notified in accordance with MDR may carry out the conformity assessment procedures laid down in MDR and issue certificates in accordance with MDR. 2 According to Article 1(g) of the MDD, intended purpose is the use for which the device is intended according to the data supplied by the manufacturer on the labelling, in the instructions and/or in promotional materials. 3 This list of ventilators includes some standards applicable to the specific ventilator. However, it should be noted that this is not an exhaustive list and other standards also apply to these devices and should be taken into account (e.g. EN 60601-1-2, EN 60601-1-6, EN 60601-1-8, EN 60601-1-11, EN 62304, EN 62366). In addition, the current state of the art should be considered. This applies also to accessories. 3 - Ventilator for critical care: automatic equipment that is intended to augment or provide ventilation of the lungs of the patient when connected to the airway of the patient: o intended for use in an environment that provides specialized care for patients whose conditions can be life threatening and who can require comprehensive care and constant monitoring in a professional healthcare facility; o intended to be operated by a healthcare professional operator; and o intended for those patients who need differing levels of support from artificial ventilation including for ventilator-dependent patients. (See e.g. EN ISO/IEC 80601-2-12:2011 + Cor.:2011). - Home healthcare environment ventilators for ventilator-dependent patients: intended for use in the home healthcare environment; intended for use by a lay operator; intended for use with patients who are dependent on mechanical ventilation for their life support. Depending on the intended purpose can be also used in the clinical setting (See e.g. EN ISO 80601-2-72:2015). - Ventilators for emergency and transport : these ventilators are used in Emergency Medical Service environment, e.g. in ambulances, transport of patients to the hospital, patient transport from hospital to hospital or transport within the hospital. The alarm and safety concept of emergency and transport ventilators in general is designed for a permanent presence of the user. This facilitates fast recognition and response in the event of an alarm or in the event of any malfunction (See e.g. EN 794-3:1998+A2:2009). - Anaesthetic ventilator: are designed for use during anaesthesia with an anaesthetic breathing system (See e.g. EN ISO 80601-2-13:2012). Ventilators for critical care are usually invasive, which enables the ventilator machine to provide lung support for inspiration and expiration through tracheal intubation. However, most critical care ventilators allow non-invasive ventilation modes for critical care patients as well. Ventilators for non-critical care are usually non-invasive and therefore provide air pressure support to natural breathing through e.g. a facemask. Ventilators may offer different types of additional complementary functions that include:  High flow oxygen supply (nasal high flow therapy);  Monitoring systems;  Nebulisation systems. 2.2. Accessories Ventilators need to be “connected” to the patients through dedicated accessories4 to the ventilator that allow the machine to support the patient’s breathing; therefore, it is important to proof compatibility with the ventilator(s). These accessories can be placed on the market individually and usually fall into one of the following categories: 4 See MEDDEV 2.1/1 Definitions of 'medical devices', 'accessory' and 'manufacturer' (https://ec.europa.eu/docsroom/documents/10278/attachments/1/translations ). 4  Breathing systems and circuits, such as: o Circuits; o Connections/Adapters; o Tubes; o Nasal cannulas for O 2; o Masks or helmets for non-invasive ventilation; o Air compressors;  Nebulizers;  Humidifiers and filters;  Monitoring accessories, including alarms, in-built safety features. Accessories are provided either disposable or reusable and are treated as medical devices in their own right5. 2.3. Parts or components Parts or components of medical devices that do not qualify as accessories are generally not considered medical devices and thus not requiring themselves to be CE marked according to the MDD (e.g. expiratory valves or flow sensors). 3. CLASSIFICATION 3.1. Ventilators There are different types of ventilators depending on the degree of invasiveness and the setting in which they are used in (e.g. Intensive Care Unit - ICU). Ventilators fall under two different classes in accordance with rule 11 (or rule 9) of Annex IX6,7 to the MDD: - Class IIa: only applicable to non-invasive devices, e.g. continuous positive airway pressure – CPAP non-intended for critical care, or devices that only support spontaneous breathing. - Class IIb: applicable to most ventilators. The classification depends on the intended purpose of the ventilator and has important implications in the selection of appropriate conformity assessment procedure(s) for the device including timing and complexity (see section 4 for details). 3.2. Accessories Accessories are classified in their own right usually in accordance with rule 2 or 5 of Annex IX to the MDD, under Class I, IIa or IIb. 5 Art. 1(1) of the MDD 6 See MEDDEV 2.4/1 rev.9 Classification of Medical Devices - (https://ec.europa.eu/docsroom/documents/10337/attachments/1/translations). 7 Please note that if a conformity assessment under the MDR is followed, the rules of classification specified in Annex VIII to the MDR apply. Breathing support devices may be classified to class IIa or IIb (rule 12) or class III (rule 22) if they integrate or incorporate diagnostic functions which significantly determine the patient management by the device, such as closed loop systems. 5 3.3. Impact of classification on conformity assessment Given that ventilators are classified as Class IIa or Class IIb, and accessories (except for Class I non-sterile and without measuring function), will in principle need the involvement of a notified body prior to their placing on the market. Other options for the placing on the market are provided in section 4 for both ventilators and accessories. 4. REGULATORY OPTIONS FOR PLACING VENTILATORS ON THE MARKET In the context of the COVID-19 outbreak, several industries have expressed their willingness to support and scale up the production of ventilators8. There are different regulatory options9 available for supporting production or placing on the market of ventilators. These options are presented below, ordered by feasibility, to allow a swift supply in the current context. 4.1. Supplying parts, components or the finished devices to medical devices manufacturers currently placing on the market ventilators When the legal manufacturer10 has already undergone a conformity assessment for the ventilator, has obtained a certificate and is lawfully placing ventilators on the market under its own name, other producers (e.g. not currently working in the medical devices field) can support its production. Such producers can provide parts or components, or the finished device, therefore becoming suppliers or subcontractors of this manufacturer. Given that the medical devices sector is highly regulated and complex, leveraging the knowledge and responsibilities of an already established manufacturer of ventilators could be the least burdensome and fastest option to scale up the production of ventilators. 4.1.1. Producers supplying parts or components to medical devices manufacturers currently placing on the market ventilators Manufacturers of medical devices can have many suppliers, which in case of quality system certification are qualified, approved and controlled by the manufacturer. These suppliers may need to be assessed by a notified body as part of the conformity assessment procedure on the basis of their criticality and the manufacturer’s process in place to control suppliers and the verification of purchased products11. When the manufacturer wishes to use an additional supplier, this might need to be communicated in advance to the notified body. 8 Scaling up of production might also be needed for accessories. These medical devices can follow the same options explained in section 4 but small differences can be applicable in case they have a different classification (e.g. class Is). 9 This document mainly focuses on regulatory options provided by the MDD. If a conformity assessment under the MDR is followed, similar procedures will apply under Annex IX, X or XI of the MDR depending on the classification of the product. 10 Legal manufacturer refers to the definition of manufacturer established in Art. 1(f) of the MDD. 11 See Guidance for Notified Bodies auditing suppliers to medical device manufacturers – (http://www.doks.nbog.eu/Doks/NBOG_BPG_2010_1.pdf) 6 4.1.2. Producers manufacturing the ventilator itself for the medical device manufacturer currently placing on the market ventilators Manufacturers of medical devices producing ventilators may provide the specifications of a ventilator (e.g. current or older/simpler design) including parts of the technical documentation to a producer that becomes its subcontractor. The producer will manufacture the ventilator but the medical device manufacturer will keep its role of legal manufacturer according to the MDD. The legal manufacturer of the ventilator, which holds a quality system certification, qualifies, approves and controls the subcontractor that will need to be assessed by a notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on-site12) audit. Alternatively, the manufacturer of medical devices could also follow other conformity assessment routes such as the EC type-examination, as established in Annex III to the MDD, and/or EC verification, as established in Annex IV to the MDD (these routes are elaborated in 4.3.2). 4.2. Derogation procedure – placing on the market authorised by the relevant authorities of one Member State in the interest of public health The relevant authority of one Member State may decide to authorise the placing on the market of devices in the interest of protection of health, even if the applicable conformity assessment procedures have not been finalised or initiated ('national derogation'). In view of the epidemiological context as well as the exponential growth in demand for medical devices, the Commission has published a Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the Covid-19 context. Question 5 of this guidance provides information on the derogation procedures for medical devices which is established in Article 11(13) of the MDD. In particular, the guidance specifies that the Covid-19 context warrants the application of such derogations. By amendment of 23 April 202013, Article 59(1) of Medical Devices Regulation (EU) 2017/745 (MDR) empowers Member States to adopt national derogations under both the MDD and the MDR from the date of entry into force of that amendment. The relevant competent authority of the Member State in this case authorises the placing on the market within its territory and can also organise the purchase. 12 See MDCG 2020-4 Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID-19 quarantine orders and travel restrictions (https://ec.europa.eu/docsroom/documents/40705). 13 Regulation 2020/561 amending Regulation (EU) 2017/745 on medical devices as regards the dates of application of certain of its provisions. 7 In practice, this implies that each competent authority would need to assess whether the products produced by the manufacture provides an adequate level of safety in respect to the applicable legal requirements. The assessment procedures can vary among Member States and in some cases will involve the support of third parties (e.g. testing laboratories). In the exceptional COVID-19 context, the assessment procedures will ensure a short- term supply while guaranteeing patient safety14. The Member State will evaluate the available technical documentation to find evidence that essential performance and safety requirements are guaranteed in the context of use. In particular, the role of healthcare teams and health facilities is essential to allow a rational use and a continuous assessment of these crisis solutions. Once this assessment is performed, the authority has to take a decision, whether or not the respective device produced by the manufacturer may enter the national territory of the Member State. Competent authorities should inform the Commission and their counterparts in other Member States of any temporary agreement they have granted to specific devices. In addition, Article 59(3) of the MDR empowers the Commission to extend, in exceptional cases relating to public health or patient safety or health, by means of implementing acts, for a limited period of time the validity of a national derogation, granted by a Member State under the MDD or the MDR, to the territory of the Union and set the conditions under which a device may be placed on the market or put into service. This allows the Commission and the Member States to address potential shortages Union wide of vitally important medical devices in an effective manner. Timing to obtain a national derogation by a competent authority will greatly depend on the quality and adequacy of the evidence provided by the manufacturer. When technical documentation and evidence of safety of performance is adequate, this can be a feasible option to ensure short-term supply. 4.3. Manufacturing of the finished device by a producer that was not previously placing on the market ventilators If the ventilator is entirely manufactured by a producer that decides to place it on the market under its name, such producer will become the legal manufacturer in its own right. This means that the manufacturer will need to fulfil all requirements of the MDD (e.g. including the need to draw up the technical documentation and clinical evaluation related to the ventilator, and to establish and keep up to date a systematic procedure to review experience gained from devices in the post-production phase). The manufacturer who places the finished CE marked ventilator on the market under its own name needs to ensure that the device complies with the essential requirements (established in Annex I of the MDD) and provide relevant evidence. A notified body will be involved in the conformity assessment in all cases. 14 Some Member States have published guidance on their respective websites to support this assessment e.g. in case of implementation of innovative manufacturing processes such as 3D printing. 8 Given that the medical devices sector is highly regulated and complex, the scenarios presented below will be the most burdensome and therefore only applicable to increase supply in the medium-long term. 4.3.1. Medical devices manufacturers’ not currently producing ventilators request an extension of their product range. This option is available for medical devices manufacturers currently certified. It includes, for instance, medical devices manufacturers already holding a full quality management system certificate under Annex II to the MDD for other devices and wishing to add ventilators to their certification. They could seek the support from (non-medical devices) producers to act as subcontractors and extend the scope of their certificate. From a procedural point of view, the medical devices manufacturer may produce the ventilator itself or may utilise a subcontractor (i.e. producer linked or not to the medical devices field). In the latter case, the manufacturer will qualify, approve and control the subcontractor that will be assessed by the notified body as part of the conformity assessment procedure. When the manufacturer wishes to use an additional subcontractor, this will need to be communicated in advance to the notified body (i.e. as the subcontractor is considered critical11) that will assess the available information and will decide the actions to be put in place e.g. whether or not it is necessary to carry out an (on- site12) audit. Most importantly, the manufacturer will need to request an extension of the product range from its notified body. The notified body will assess the available information in relation to the new product (that include an assessment of the technical documentation and clinical evaluation) and update the certificate. The manufacturer of medical devices could also use other conformity assessment routes such as the EC Type-Examination and EC Verification and testing of every product under Annex III and IV respectively (these routes are elaborated in section 4.3.2). 4.3.2. Ventilator manufactured entirely by a producer that is not currently a legal manufacturer under the MDD Producers that do not currently qualify as legal manufacturers under the MDD and decide to place ventilators on the market under their own name need to be aware of all the legal requirements for manufactures under the MDD. It is important to mention that in the field of medical devices some Member States could have additional requirements, for instance, the need to authorise the facility of the medical device manufacturer prior to starting production. In addition to this, the involvement of a notified body will depend on the classification. In particular: 1. Class IIa ventilators can follow the following routes established in the relevant Annexes of the MDD: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and 9 regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the product to be certified prior to certification on a sampling basis15. b. Declaration of conformity (Annex VII) combined with either an assessment of the quality assurance of the production or of the product (Annex V or VI) or a EC verification (set out in Annex IV):  The assessment of the quality system performed by the notified body will be similar to the one outlined in section 1.a above.  The verification by testing of products by the notified body will be performed by examination and testing of every product. 2. Class IIb ventilators can follow the following routes: a. Annex II (excluding point 4) – which involves the assessment of the full manufacturer’s quality management system. This will require an on-site audit (which may be performed remotely in the current context) and regular surveillance audits at least annually. In addition, the notified body will assess the technical documentation and the clinical evaluation of the products to be certified prior to certification on a sampling basis15. b. EC type-examination (Annex III) combined with either an assessment of the quality assurance either of the production or of the product (Annex V or VI) or EC verification by testing of products (set out in Annex IV). EC Type-examination consists in the assessment of the technical documentation and testing of a number of features of the device type to ensure it conforms to the requirements. The additional procedures (Annex IV, V or VI) are the same as the ones described in 1.b above. The assessment of the quality management system of the manufacturer (Annex II, V and VI) can be partly fulfilled by compliance with a harmonised standard (EN ISO 13485) but this route will unlikely be fast enough to ensure short-term supply. This is due to the timelines and experience required to get a certificate under these annexes of the MDD and taking into account the current circumstances where auditing capacity is restricted by the Covid19 situation. A faster route but also time-consuming route will probably be the performance of tests on the products that might be combined with the assessment of the technical documentation, namely: - declaration of conformity (Annex VII) + verification of products (Annex IV) for Class IIa; or - EC type-examination (Annex III) + verification of products (Annex IV) for Class IIb. Through this route, the device type or device samples are tested and there is no obligation to have a certified quality management system in place and subject to regular surveillance audits. However, quality management processes are important and critical to the production of safe and functional medical devices. The conformity assessment will be 15 See Annex II, section 3.3 to the MDD 10 based on the manufacturers testing strategy that must ensure compliance with the safety and performance requirements. It should be noted that this option is burdensome and will take several months, especially to draw up an adequate technical documentation. In addition, there is only a limited number of notified bodies designated to perform EC type-examination and/or EC verification in ventilators (according to NANDO16 18 notified bodies out of 56 are authorised to perform these tests at the moment). 16 This information can be found in NANDO, by searching notified bodies under the MDD that are designated under Annex III and IV for code MD 1102 - Respiratory devices, devices including hyperbaric chambers for oxygen therapy, inhalation anaesthesia - https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13

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L_2017117EN.01000101.xml 5.5.2017    EN Official Journal of the European Union L 117/1 REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Text with EEA relevance) THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, Having regard to the Treaty on the Functioning of the European Union, and in particular Article 114 and Article 168(4)(c) thereof, Having regard to the proposal from the European Commission, After transmission of the draft legislative act to the national parliaments, Having regard to the opinion of the European Economic and Social Committee (1), After consulting the Committee of the Regions, Acting in accordance with the ordinary legislative procedure (2), Whereas: (1) Council Directive 90/385/EEC (3) and Council Directive 93/42/EEC (4) constitute the Union regulatory framework for medical devices, other than in vitro diagnostic medical devices. However, a fundamental revision of those Directives is needed to establish a robust, transparent, predictable and sustainable regulatory framework for medical devices which ensures a high level of safety and health whilst supporting innovation. (2) This Regulation aims to ensure the smooth functioning of the internal market as regards medical devices, taking as a base a high level of protection of health for patients and users, and taking into account the small- and medium-sized enterprises that are active in this sector. At the same time, this Regulation sets high standards of quality and safety for medical devices in order to meet common safety concerns as regards such products. Both objectives are being pursued simultaneously and are inseparably linked whilst one not being secondary to the other. As regards Article 114 of the Treaty on the Functioning of the European Union (TFEU), this Regulation harmonises the rules for the placing on the market and putting into service of medical devices and their accessories on the Union market thus allowing them to benefit from the principle of free movement of goods. As regards Article 168(4)(c) TFEU, this Regulation sets high standards of quality and safety for medical devices by ensuring, among other things, that data generated in clinical investigations are reliable and robust and that the safety of the subjects participating in a clinical investigation is protected. (3) This Regulation does not seek to harmonise rules relating to the further making available on the market of medical devices after they have already been put into service such as in the context of second-hand sales. (4) Key elements of the existing regulatory approach, such as the supervision of notified bodies, conformity assessment procedures, clinical investigations and clinical evaluation, vigilance and market surveillance should be significantly reinforced, whilst provisions ensuring transparency and traceability regarding medical devices should be introduced, to improve health and safety. (5) To the extent possible, guidance developed for medical devices at international level, in particular in the context of the Global Harmonization Task Force (GHTF) and its follow-up initiative, the International Medical Devices Regulators Forum (IMDRF), should be taken into account to promote the global convergence of regulations which contributes to a high level of safety protection worldwide, and to facilitate trade, in particular in the provisions on Unique Device Identification, general safety and performance requirements, technical documentation, classification rules, conformity assessment procedures and clinical investigations. (6) For historical reasons, active implantable medical devices, covered by Directive 90/385/EEC, and other medical devices, covered by Directive 93/42/EEC, were regulated in two separate legal instruments. In the interest of simplification, both directives, which have been amended several times, should be replaced by a single legislative act applicable to all medical devices other than in vitro diagnostic medical devices. (7) The scope of application of this Regulation should be clearly delimited from other Union harmonisation legislation concerning products, such as in vitro diagnostic medical devices, medicinal products, cosmetics and food. Therefore, Regulation (EC) No 178/2002 of the European Parliament and of the Council (5) should be amended to exclude medical devices from its scope. (8) It should be the responsibility of the Member States to decide on a case-by-case basis whether or not a product falls within the scope of this Regulation. In order to ensure consistent qualification decisions in that regard across all Member States, particularly with regard to borderline cases, the Commission should be allowed to, on its own initiative or at the duly substantiated request of a Member State, having consulted the Medical Device Coordination Group (‘MDCG’), decide on a case-by-case basis whether or not a specific product, category or group of products falls within the scope of this Regulation. When deliberating on the regulatory status of products in borderline cases involving medicinal products, human tissues and cells, biocidal products or food products, the Commission should ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency and the European Food Safety Authority, as relevant. (9) Since in some cases it is difficult to distinguish between medical devices and cosmetic products, the possibility of taking a Union-wide decision regarding the regulatory status of a product should also be introduced in Regulation (EC) No 1223/2009 of the European Parliament and of the Council (6). (10) Products which combine a medicinal product or substance and a medical device are regulated either under this Regulation or under Directive 2001/83/EC of the European Parliament and of the Council. (7) The two legislative acts should ensure appropriate interaction in terms of consultations during pre-market assessment, and of exchange of information in the context of vigilance activities involving such combination products. For medicinal products that integrate a medical device part, compliance with the general safety and performance requirements laid down in this Regulation for the device part should be adequately assessed in the context of the marketing authorisation for such medicinal products. Directive 2001/83/EC should therefore be amended. (11) Union legislation, in particular Regulation (EC) No 1394/2007 of the European Parliament and of the Council (8) and Directive 2004/23/EC of the European Parliament and of the Council (9), is incomplete in respect of certain products manufactured utilising derivatives of tissues or cells of human origin that are non-viable or are rendered non-viable. Such products should come under the scope of this Regulation, provided they comply with the definition of a medical device or are covered by this Regulation. (12) Certain groups of products for which a manufacturer claims only an aesthetic or another non-medical purpose but which are similar to medical devices in terms of functioning and risks profile should be covered by this Regulation. In order for manufacturers to be able to demonstrate the conformity of such products, the Commission should adopt common specifications at least with regard to application of risk management and, where necessary, clinical evaluation regarding safety. Such common specifications should be developed specifically for a group of products without an intended medical purpose and should not be used for conformity assessment of the analogous devices with a medical purpose. Devices with both a medical and a non-medical intended purpose should fulfil both the requirements applicable to devices with, and to devices without, an intended medical purpose. (13) As is the case for products that contain viable tissues or cells of human or animal origin, that are explicitly excluded from Directives 90/385/EEC and 93/42/EEC and hence from this Regulation, it should be clarified that products that contain or consist of viable biological materials or viable organisms of another origin in order to achieve or support the intended purpose of those products are not covered by this Regulation either. (14) The requirements laid down in Directive 2002/98/EC of the European Parliament and of the Council (10) should continue to apply. (15) There is scientific uncertainty about the risks and benefits of nanomaterials used for devices. In order to ensure a high level of health protection, free movement of goods and legal certainty for manufacturers, it is necessary to introduce a uniform definition for nanomaterials based on Commission Recommendation 2011/696/EU (11), with the necessary flexibility to adapt that definition to scientific and technical progress and subsequent regulatory development at Union and international level. In the design and manufacture of devices, manufacturers should take special care when using nanoparticles for which there is a high or medium potential for internal exposure. Such devices should be subject to the most stringent conformity assessment procedures. In preparation of implementing acts regulating the practical and uniform application of the corresponding requirements laid down in this Regulation, the relevant scientific opinions of the relevant scientific committees should be taken into account. (16) Safety aspects addressed by Directive 2014/30/EU of the European Parliament and of the Council (12) are an integral part of the general safety and performance requirements laid down in this Regulation for devices. Consequently, this Regulation should be considered a lex specialis in relation to that Directive. (17) This Regulation should include requirements regarding the design and manufacture of devices emitting ionizing radiation without affecting the application of Council Directive 2013/59/Euratom (13) which pursues other objectives. (18) This Regulation should include requirements for devices' design, safety and performance characteristics which are developed in such a way as to prevent occupational injuries, including protection from radiation. (19) It is necessary to clarify that software in its own right, when specifically intended by the manufacturer to be used for one or more of the medical purposes set out in the definition of a medical device, qualifies as a medical device, while software for general purposes, even when used in a healthcare setting, or software intended for life-style and well-being purposes is not a medical device. The qualification of software, either as a device or an accessory, is independent of the software's location or the type of interconnection between the software and a device. (20) The definitions in this Regulation, regarding devices themselves, the making available of devices, economic operators, users and specific processes, the conformity assessment, clinical investigations and clinical evaluations, post-market surveillance, vigilance and market surveillance, standards and other technical specifications, should be aligned with well-established practice in the field at Union and international level in order to enhance legal certainty. (21) It should be made clear that it is essential that devices offered to persons in the Union by means of information society services within the meaning of Directive (EU) 2015/1535 of the European Parliament and of the Council (14) and devices used in the context of a commercial activity to provide a diagnostic or therapeutic service to persons within the Union comply with the requirements of this Regulation, where the product in question is placed on the market or the service is provided in the Union. (22) To recognise the important role of standardisation in the field of medical devices, compliance with harmonised standards as defined in Regulation (EU) No 1025/2012 of the European Parliament and of the Council (15) should be a means for manufacturers to demonstrate conformity with the general safety and performance requirements and other legal requirements, such as those relating to quality and risk management, laid down in this Regulation. (23) Directive 98/79/EC of the European Parliament and of the Council (16) allows the Commission to adopt common technical specifications for specific categories of in vitro diagnostic medical devices. In areas where no harmonised standards exist or where they are insufficient, the Commission should be empowered to lay down common specifications which provide a means of complying with the general safety and performance requirements, and the requirements for clinical investigations and clinical evaluation and/or post-market clinical follow-up, laid down in this Regulation. (24) Common specifications (‘CS’) should be developed after consulting the relevant stakeholders and taking account of European and international standards. (25) The rules applicable to devices should be aligned, where appropriate, with the New Legislative Framework for the Marketing of Products, which consists of Regulation (EC) No 765/2008 of the European Parliament and of the Council (17) and Decision No 768/2008/EC of the European Parliament and of the Council (18). (26) The rules on Union market surveillance and control of products entering the Union market laid down in Regulation (EC) No 765/2008 apply to devices covered by this Regulation which does not prevent Member States from choosing the competent authorities to carry out those tasks. (27) It is appropriate to set out clearly the general obligations of the different economic operators, including importers and distributors, building on the New Legislative Framework for the Marketing of Products, without prejudice to the specific obligations laid down in the various parts of this Regulation, to enhance understanding of the requirements laid down in this Regulation and thus to improve regulatory compliance by the relevant operators. (28) For the purpose of this Regulation, the activities of distributors should be deemed to include acquisition, holding and supplying of devices. (29) Several of the obligations on manufacturers, such as clinical evaluation or vigilance reporting, that were set out only in the Annexes to Directives 90/385/EEC and 93/42/EEC, should be incorporated into the enacting provisions of this Regulation to facilitate its application. (30) Health institutions should have the possibility of manufacturing, modifying and using devices in-house and thereby address, on a non-industrial scale, the specific needs of target patient groups which cannot be met at the appropriate level of performance by an equivalent device available on the market. In that context, it is appropriate to provide that certain rules of this Regulation, as regards medical devices manufactured and used only within health institutions, including hospitals as well as institutions, such as laboratories and public health institutes that support the healthcare system and/or address patient needs, but which do not treat or care for patients directly, should not apply, since the aims of this Regulation would still be met in a proportionate manner. It should be noted that the concept of ‘health institution’ does not cover establishments primarily claiming to pursue health interests or healthy lifestyles, such as gyms, spas, wellness and fitness centres. As a result, the exemption applicable to health institutions does not apply to such establishments. (31) In view of the fact that natural or legal persons can claim compensation for damage caused by a defective device in accordance with applicable Union and national law, it is appropriate to require manufacturers to have measures in place to provide sufficient financial coverage in respect of their potential liability under Council Directive 85/374/EEC (19). Such measures should be proportionate to the risk class, type of device and the size of the enterprise. In this context, it is also appropriate to lay down rules concerning the facilitation, by a competent authority, of the provision of information to persons who may have been injured by a defective device. (32) To ensure that devices manufactured in series production continue to be in conformity with the requirements of this Regulation and that experience from the use of the devices they manufacture is taken into account for the production process, all manufacturers should have a quality management system and a post-market surveillance system in place which should be proportionate to the risk class and the type of the device in question. In addition, in order to minimize risks or prevent incidents related to devices, manufacturers should establish a system for risk management and a system for reporting of incidents and field safety corrective actions. (33) The risk management system should be carefully aligned with and reflected in the clinical evaluation for the device, including the clinical risks to be addressed as part of clinical investigations, clinical evaluation and post-market clinical follow up. The risk management and clinical evaluation processes should be inter-dependent and should be regularly updated. (34) It should be ensured that supervision and control of the manufacture of devices, and the post-market surveillance and vigilance activities concerning them, are carried out within the manufacturer's organisation by a person responsible for regulatory compliance who fulfils minimum conditions of qualification. (35) For manufacturers who are not established in the Union, the authorised representative plays a pivotal role in ensuring the compliance of the devices produced by those manufacturers and in serving as their contact person established in the Union. Given that pivotal role, for the purposes of enforcement it is appropriate to make the authorised representative legally liable for defective devices in the event that a manufacturer established outside the Union has not complied with its general obligations. The liability of the authorised representative provided for in this Regulation is without prejudice to the provisions of Directive 85/374/EEC, and accordingly the authorised representative should be jointly and severally liable with the importer and the manufacturer. The tasks of an authorised representative should be defined in a written mandate. Considering the role of authorised representatives, the minimum requirements they should meet should be clearly defined, including the requirement of having available a person who fulfils minimum conditions of qualification which should be similar to those for a manufacturer's person responsible for regulatory compliance. (36) To ensure legal certainty in respect of the obligations incumbent on economic operators, it is necessary to clarify when a distributor, importer or other person is to be considered the manufacturer of a device. (37) Parallel trade in products already placed on the market is a lawful form of trade within the internal market on the basis of Article 34 TFEU subject to the limitations arising from the need for protection of health and safety and from the need for protection of intellectual property rights provided for under Article 36 TFEU. Application of the principle of parallel trade is, however, subject to different interpretations in the Member States. The conditions, in particular the requirements for relabelling and repackaging, should therefore be specified in this Regulation, taking into account the case-law of the Court of Justice (20) in other relevant sectors and existing good practice in the field of medical devices. (38) The reprocessing and further use of single-use devices should only take place where permitted by national law and while complying with the requirements laid down in this Regulation. The reprocessor of a single-use device should be considered to be the manufacturer of the reprocessed device and should assume the obligations incumbent on manufacturers under this Regulation. Nevertheless, Member States should have the possibility of deciding that the obligations relating to reprocessing and re-use of single-use devices within a health institution or by an external reprocessor acting on its behalf may differ from the obligations on a manufacturer described in this Regulation. In principle, such divergence should only be permitted where reprocessing and reuse of single-use devices within a health institution or by an external reprocessor are compliant with CS that have been adopted, or, in the absence of such CS, with relevant harmonised standards and national provisions. The reprocessing of such devices should ensure an equivalent level of safety and performance to that of the corresponding initial single-use device. (39) Patients who are implanted with a device should be given clear and easily accessible essential information allowing the implanted device to be identified and other relevant information about the device, including any necessary health risk warnings or precautions to be taken, for example indications as to whether or not it is compatible with certain diagnostic devices or with scanners used for security controls. (40) Devices should, as a general rule, bear the CE marking to indicate their conformity with this Regulation so that they can move freely within the Union and be put into service in accordance with their intended purpose. Member States should not create obstacles to the placing on the market or putting into service of devices that comply with the requirements laid down in this Regulation. However, Member States should be allowed to decide whether to restrict the use of any specific type of device in relation to aspects that are not covered by this Regulation. (41) The traceability of devices by means of a Unique Device Identification system (UDI system) based on international guidance should significantly enhance the effectiveness of the post-market safety-related activities for devices, which is owing to improved incident reporting, targeted field safety corrective actions and better monitoring by competent authorities. It should also help to reduce medical errors and to fight against falsified devices. Use of the UDI system should also improve purchasing and waste disposal policies and stock-management by health institutions and other economic operators and, where possible, be compatible with other authentication systems already in place in those settings. (42) The UDI system should apply to all devices placed on the market except custom-made devices, and be based on internationally recognised principles including definitions that are compatible with those used by major trade partners. In order for the UDI system to become functional in time for the application of this Regulation, detailed rules should be laid down in this Regulation. (43) Transparency and adequate access to information, appropriately presented for the intended user, are essential in the public interest, to protect public health, to empower patients and healthcare professionals and to enable them to make informed decisions, to provide a sound basis for regulatory decision-making and to build confidence in the regulatory system. (44) One key aspect in fulfilling the objectives of this Regulation is the creation of a European database on medical devices (Eudamed) that should integrate different electronic systems to collate and process information regarding devices on the market and the relevant economic operators, certain aspects of conformity assessment, notified bodies, certificates, clinical investigations, vigilance and market surveillance. The objectives of the database are to enhance overall transparency, including through better access to information for the public and healthcare professionals, to avoid multiple reporting requirements, to enhance coordination between Member States and to streamline and facilitate the flow of information between economic operators, notified bodies or sponsors and Member States as well as between Member States among themselves and with the Commission. Within the internal market, this can be ensured effectively only at Union level and the Commission should therefore further develop and manage the European databank on medical devices set up by Commission Decision 2010/227/EU (21). (45) To facilitate the functioning of Eudamed, an internationally recognised medical device nomenclature should be available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. Furthermore, that nomenclature should be available, where reasonably practicable, free of charge also to other stakeholders. (46) Eudamed's electronic systems regarding devices on the market, the relevant economic operators and certificates should enable the public to be adequately informed about devices on the Union market. The electronic system on clinical investigations should serve as a tool for the cooperation between Member States and for enabling sponsors to submit, on a voluntary basis, a single application for several Member States and to report serious adverse events, device deficiencies and related updates. The electronic system on vigilance should enable manufacturers to report serious incidents and other reportable events and to support the coordination of the evaluation of such incidents and events by competent authorities. The electronic system regarding market surveillance should be a tool for the exchange of information between competent authorities. (47) In respect of data collated and processed through the electronic systems of Eudamed, Directive 95/46/EC of the European Parliament and of the Council (22) applies to the processing of personal data carried out in the Member States, under the supervision of the Member States' competent authorities, in particular the public independent authorities designated by the Member States. Regulation (EC) No 45/2001 of the European Parliament and of the Council (23) applies to the processing of personal data carried out by the Commission within the framework of this Regulation, under the supervision of the European Data Protection Supervisor. In accordance with Regulation (EC) No 45/2001, the Commission should be designated as the controller of Eudamed and its electronic systems. (48) For implantable devices and for class III devices, manufacturers should summarise the main safety and performance aspects of the device and the outcome of the clinical evaluation in a document that should be publicly available. (49) The summary of safety and clinical performance for a device should include in particular the place of the device in the context of diagnostic or therapeutic options taking into account the clinical evaluation of that device when compared to the diagnostic or therapeutic alternatives and the specific conditions under which that device and its alternatives can be considered. (50) The proper functioning of notified bodies is crucial for ensuring a high level of health and safety protection and citizens' confidence in the system. Designation and monitoring of notified bodies by the Member States, in accordance with detailed and strict criteria, should therefore be subject to controls at Union level. (51) Notified bodies' assessments of manufacturers' technical documentation, in particular documentation on clinical evaluation, should be critically evaluated by the authority responsible for notified bodies. That evaluation should be part of the risk-based approach to the oversight and monitoring activities of notified bodies and should be based on sampling of the relevant documentation. (52) The position of notified bodies vis-à-vis manufacturers should be strengthened, including with regard to their right and duty to carry out unannounced on-site audits and to conduct physical or laboratory tests on devices to ensure continuous compliance by manufacturers after receipt of the original certification. (53) To increase transparency with regard to the oversight of notified bodies by national authorities, the authorities responsible for notified bodies should publish information on the national measures governing the assessment, designation and monitoring of notified bodies. In accordance with good administrative practice, this information should be kept up to date by those authorities in particular to reflect relevant, significant or substantive changes to the procedures in question. (54) The Member State in which a notified body is established should be responsible for enforcing the requirements of this Regulation with regard to that notified body. (55) In view, in particular, of the responsibility of Member States for the organisation and delivery of health services and medical care, they should be allowed to lay down additional requirements on notified bodies designated for the conformity assessment of devices and established on their territory as far as issues that are not regulated in this Regulation are concerned. Any such additional requirements laid down should not affect more specific horizontal Union legislation on notified bodies and equal treatment of notified bodies. (56) For class III implantable devices and class IIb active devices intended to administer and/or remove a medicinal product, notified bodies should, except in certain cases, be obliged to request expert panels to scrutinise their clinical evaluation assessment report. Competent authorities should be informed about devices that have been granted a certificate following a conformity assessment procedure involving an expert panel. The consultation of expert panels in relation to the clinical evaluation should lead to a harmonised evaluation of high-risk medical devices by sharing expertise on clinical aspects and developing CS on categories of devices that have undergone that consultation process. (57) For class III devices and for certain class IIb devices, a manufacturer should be able to consult voluntarily an expert panel, prior to that manufacturer's clinical evaluation and/or investigation, on its clinical development strategy and on proposals for clinical investigations. (58) It is necessary, in particular for the purpose of the conformity assessment procedures, to maintain the division of devices into four product classes in line with international practice. The classification rules, which are based on the vulnerability of the human body, should take into account the potential risks associated with the technical design and manufacture of the devices. To maintain the same level of safety as provided by Directive 90/385/EEC, active implantable devices should be in the highest risk class. (59) Rules under the old regime applied to invasive devices do not sufficiently take account of the level of invasiveness and potential toxicity of certain devices which are introduced into the human body. In order to obtain a suitable risk-based classification of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body, it is necessary to introduce specific classification rules for such devices. The classification rules should take into account the place where the device performs its action in or on the human body, where it is introduced or applied, and whether a systemic absorption of the substances of which the device is composed, or of the products of metabolism in the human body of those substances occurs. (60) The conformity assessment procedure for class I devices should be carried out, as a general rule, under the sole responsibility of manufacturers in view of the low level of vulnerability associated with such devices. For class IIa, class IIb and class III devices, an appropriate level of involvement of a notified body should be compulsory. (61) The conformity assessment procedures for devices should be further strengthened and streamlined whilst the requirements for notified bodies as regards the performance of their assessments should be clearly specified to ensure a level playing field. (62) It is appropriate that certificates of free sale contain information that makes it possible to use Eudamed in order to obtain information on the device, in particular with regard to whether it is on the market, withdrawn from the market or recalled, and on any certificate on its conformity. (63) To ensure a high level of safety and performance, demonstration of compliance with the general safety and performance requirements laid down in this Regulation should be based on clinical data that, for class III devices and implantable devices should, as a general rule, be sourced from clinical investigations that have been carried out under the responsibility of a sponsor. It should be possible both for the manufacturer and for another natural or legal person to be the sponsor taking responsibility for the clinical investigation. (64) The rules on clinical investigations should be in line with well-established international guidance in this field, such as the international standard ISO 14155:2011 on good clinical practice for clinical investigations of medical devices for human subjects, so as to make it easier for the results of clinical investigations conducted in the Union to be accepted as documentation outside the Union and to make it easier for the results of clinical investigations conducted outside the Union in accordance with international guidelines to be accepted within the Union. In addition, the rules should be in line with the most recent version of the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. (65) It should be left to the Member State where a clinical investigation is to be conducted to determine the appropriate authority to be involved in the assessment of the application to conduct a clinical investigation and to organise the involvement of ethics committees within the timelines for the authorisation of that clinical investigation as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. In that context, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. (66) Where, in the course of a clinical investigation, harm caused to a subject leads to the civil or criminal liability of the investigator or the sponsor being invoked, the conditions for liability in such cases, including issues of causality and the level of damages and sanctions, should remain governed by national law. (67) An electronic system should be set up at Union level to ensure that every clinical investigation is recorded and reported in a publicly accessible database. To protect the right to the protection of personal data, recognised by Article 8 of the Charter of Fundamental Rights of the European Union (‘the Charter’), no personal data of subjects participating in a clinical investigation should be recorded in the electronic system. To ensure synergies with the area of clinical trials on medicinal products, the electronic system on clinical investigations should be interoperable with the EU database to be set up for clinical trials on medicinal products for human use. (68) Where a clinical investigation is to be conducted in more than one Member State, the sponsor should have the possibility of submitting a single application in order to reduce administrative burden. In order to allow for resource-sharing and to ensure consistency regarding the assessment of the health and safety-related aspects of the investigational device and of the scientific design of that clinical investigation, the procedure for the assessment of such single application should be coordinated between the Member States under the direction of a coordinating Member State. Such coordinated assessment should not include the assessment of intrinsically national, local and ethical aspects of a clinical investigation, including informed consent. For an initial period of seven years from the date of application of this Regulation, Member States should be able to participate on a voluntary basis in the coordinated assessment. After that period, all Member States should be obliged to participate in the coordinated assessment. The Commission, based on the experience gained from the voluntary coordination between Member States, should draw up a report on the application of the relevant provisions regarding the coordinated assessment procedure. In the event that the findings of the report are negative, the Commission should submit a proposal to extend the period of participation on a voluntary basis in the coordinated assessment procedure. (69) Sponsors should report certain adverse events and device deficiencies that occur during clinical investigations to the Member States in which those clinical investigations are being conducted. Member States should have the possibility of terminating or suspending the investigations or revoking the authorisation for those investigations, if considered necessary to ensure a high level of protection of the subjects participating in a clinical investigation. Such information should be communicated to the other Member States. (70) The sponsor of a clinical investigation should submit a summary of results of the clinical investigation that is easily understandable for the intended user together with the clinical investigation report, where applicable, within the timelines laid down in this Regulation. Where it is not possible to submit the summary of the results within the defined timelines for scientific reasons, the sponsor should justify this and specify when the results will be submitted. (71) This Regulation should cover clinical investigations intended to gather clinical evidence for the purpose of demonstrating conformity of devices and should also lay down basic requirements regarding ethical and scientific assessments for other types of clinical investigations of medical devices. (72) Incapacitated subjects, minors, pregnant women and breastfeeding women require specific protection measures. However, it should be left to Member States to determine the legally designated representatives of incapacitated subjects and minors. (73) The principles of replacement, reduction and refinement in the area of animal experimentation laid down in the Directive 2010/63/EU of the European Parliament and of the Council (24) should be observed. In particular, the unnecessary duplication of tests and studies should be avoided. (74) Manufacturers should play an active role during the post-market phase by systematically and actively gathering information from post-market experience with their devices in order to update their technical documentation and cooperate with the national competent authorities in charge of vigilance and market surveillance activities. To this end, manufacturers should establish a comprehensive post-market surveillance system, set up under their quality management system and based on a post-market surveillance plan. Relevant data and information gathered through post-market surveillance, as well as lessons learned from any implemented preventive and/or corrective actions, should be used to update any relevant part of technical documentation, such as those relating to risk assessment and clinical evaluation, and should also serve the purpose of transparency. (75) In order to better protect health and safety regarding devices on the market, the electronic system on vigilance for devices should be made more effective by creating a central portal at Union level for reporting serious incidents and field safety corrective actions. (76) Member States should take appropriate measures to raise awareness among healthcare professionals, users and patients about the importance of reporting incidents. Healthcare professionals, users and patients should be encouraged and enabled to report suspected serious incidents at national level using harmonised formats. The national competent authorities should inform manufacturers of any suspected serious incidents and, where a manufacturer confirms that such an incident has occurred, the authorities concerned should ensure that appropriate follow-up action is taken in order to minimise recurrence of such incidents. (77) The evaluation of reported serious incidents and field safety corrective actions should be conducted at national level but coordination should be ensured where similar incidents have occurred or field safety corrective actions have to be carried out in more than one Member State, with the objective of sharing resources and ensuring consistency regarding the corrective action. (78) In the context of the investigation of incidents, the competent authorities should take into account, where appropriate, the information provided by and views of relevant stakeholders, including patient and healthcare professionals' organisations and manufacturers' associations. (79) The reporting of serious adverse events or device deficiencies during clinical investigations and the reporting of serious incidents occurring after a device has been placed on the market should be clearly distinguished to avoid double reporting. (80) Rules on market surveillance should be included in this Regulation to reinforce the rights and obligations of the national competent authorities, to ensure effective coordination of their market surveillance activities and to clarify the applicable procedures. (81) Any statistically significant increase in the number or severity of incidents that are not serious or in expected side-effects that could have a significant impact on the benefit-risk analysis and which could lead to unacceptable risks should be reported to the competent authorities in order to permit their assessment and the adoption of appropriate measures. (82) An expert committee, the Medical Device Coordination Group (MDCG), composed of persons designated by the Member States based on their role and expertise in the field of medical devices including in vitro diagnostic medical devices, should be established to fulfil the tasks conferred on it by this Regulation and by Regulation (EU) 2017/746 of the European Parliament and of the Council (25), to provide advice to the Commission and to assist the Commission and the Member States in ensuring a harmonised implementation of this Regulation. The MDCG should be able to establish subgroups in order to have access to necessary in-depth technical expertise in the field of medical devices including in vitro diagnostic medical devices. When establishing subgroups, appropriate consideration should be given to the possibility of involving existing groups at Union level in the field of medical devices. (83) Expert panels and expert laboratories should be designated by the Commission on the basis of their up-to-date clinical, scientific or technical expertise, with the aim of providing scientific, technical and clinical assistance to the Commission, the MDCG, manufacturers and notified bodies in relation to the implementation of this Regulation. Moreover, expert panels should fulfil the tasks of providing an opinion on clinical evaluation assessment reports of notified bodies in the case of certain high-risk devices. (84) Closer coordination between national competent authorities through information exchange and coordinated assessments under the direction of a coordinating authority is essential for ensuring a consistently high level of health and safety protection within the internal market, in particular in the areas of clinical investigations and vigilance. The principle of coordinated exchange and assessment should also apply across other authority activities described in this Regulation, such as the designation of notified bodies and should be encouraged in the area of market surveillance of devices. Joint working, coordination and communication of activities should also lead to more efficient use of resources and expertise at national level. (85) The Commission should provide scientific, technical and corresponding logistical support to coordinating national authorities and ensure that the regulatory system for devices is effectively and uniformly implemented at Union level based on sound scientific evidence. (86) The Union and, where appropriate, the Member States should actively participate in international regulatory cooperation in the field of medical devices to facilitate the exchange of safety-related information regarding medical devices and to foster the further development of international regulatory guidelines that promote the adoption in other jurisdictions of regulations that lead to a level of health and safety protection equivalent to that set by this Regulation. (87) Member States should take all necessary measures to ensure that the provisions of this Regulation are implemented, including by laying down effective, proportionate and dissuasive penalties for their infringement. (88) Whilst this Regulation should not affect the right of Member States to levy fees for activities at national level, Member States should, in order to ensure transparency, inform the Commission and the other Member States before they decide on the level and structure of such fees. In order to further ensure transparency, the structure and level of the fees should be publicly available on request. (89) This Regulation respects the fundamental rights and observes the principles recognised in particular by the Charter and in particular human dignity, the integrity of the person, the protection of personal data, the freedom of art and science, the freedom to conduct business and the right to property. This Regulation should be applied by the Member States in accordance with those rights and principles. (90) The power to adopt delegated acts in accordance with Article 290 TFEU should be delegated to the Commission in order to amend certain non-essential provisions of this Regulation. It is of particular importance that the Commission carry out appropriate consultations during its preparatory work, including at expert level, and that those consultations be conducted in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making (26). In particular, to ensure equal participation in the preparation of delegated acts, the European Parliament and the Council receive all documents at the same time as Member States' experts, and their experts systematically have access to meetings of Commission expert groups dealing with preparation of delegated acts. (91) In order to ensure uniform conditions for the implementation of this Regulation, implementing powers should be conferred on the Commission. Those powers should be exercised in accordance with Regulation (EU) No 182/2011 of the European Parliament and of the Council (27). (92) The advisory procedure should be used for implementing acts that set out the form and presentation of the data elements of manufacturers' summaries of safety and clinical performance, and that establish the model for certificates of free sale, given that such implementing acts are of a procedural nature and do not directly have an impact on health and safety at Union level. (93) The Commission should adopt immediately applicable implementing acts where, in duly justified cases relating to the extension to the territory of the Union of a national derogation from the applicable conformity assessment procedures, imperative grounds of urgency so require. (94) In order to enable it to designate issuing entities, expert panels and expert laboratories, implementing powers should be conferred on the Commission. (95) To allow economic operators, especially SMEs, notified bodies, Member States and the Commission to adapt to the changes introduced by this Regulation and to ensure its proper application, it is appropriate to provide for a sufficient transitional period for that adaptation and for the organisational arrangements that are to be made. However, certain parts of the Regulation that directly affect Member States and the Commission should be implemented as soon as possible. It is also particularly important that, by the date of application of this Regulation, a sufficient number of notified bodies be designated in accordance with the new requirements so as to avoid any shortage of medical devices on the market. Nonetheless, it is necessary that any designation of a notified body in accordance with the requirements of this Regulation prior to the date of its application be without prejudice to the validity of the designation of those notified bodies under Directives 90/385/EEC and 93/42/EEC and to their capacity to continue issuing valid certificates under those two Directives until the date of application of this Regulation. (96) In order to ensure a smooth transition to the new rules for registration of devices and of certificates, the obligation to submit the relevant information to the electronic systems set up at Union level pursuant to this Regulation should, in the event that the corresponding IT systems are developed according to plan, only become fully effective from 18 months after the date of application of this Regulation. During this transitional period, certain provisions of Directives 90/385/EEC and 93/42/EEC should remain in force. However, in order to avoid multiple registrations, economic operators and notified bodies who register in the relevant electronic systems set up at Union level pursuant to this Regulation should be considered to be in compliance with the registration requirements adopted by the Member States pursuant to those provisions. (97) In order to provide for a smooth introduction of the UDI system, the moment of application of the obligation to place the UDI carrier on the label of the device should vary from one to five years after the date of application of this Regulation depending upon the class of the device concerned. (98) Directives 90/385/EEC and 93/42/EEC should be repealed to ensure that only one set of rules applies to the placing of medical devices on the market and the related aspects covered by this Regulation. Manufacturers' obligations as regards the making available of documentation regarding devices they placed on the market and manufacturers' and Member States' obligations as regards vigilance activities for devices placed on the market pursuant to those Directives should however continue to apply. While it should be left to Member States to decide how to organise vigilance activities, it is desirable for them to have the possibility of reporting incidents related to devices placed on the market pursuant to the Directives using the same tools as those for reporting on devices placed on the market pursuant to this Regulation. It is furthermore appropriate, in order to ensure a smooth transition from the old regime to the new regime, to provide that Commission Regulation (EU) No 207/2012 (28) and Commission Regulation (EU) No 722/2012 (29) should remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. Decision 2010/227/EU adopted in implementation of those Directives and Directive 98/79/EC should also remain in force and continue to apply until the date when Eudamed becomes fully functional. Conversely, no such maintenance in force is required for Commission Directives 2003/12/EC (30) and 2005/50/EC (31) and Commission Implementing Regulation (EU) No 920/2013 (32). (99) The requirements of this Regulation should be applicable to all devices placed on the market or put into service from the date of application of this Regulation. However, in order to provide for a smooth transition it should be possible, for a limited period of time from that date, for devices to be placed on the market or put into service by virtue of a valid certificate issued pursuant to Directive 90/385/EEC or pursuant to Directive 93/42/EEC. (100) The European Data Protection Supervisor has given an opinion (33) pursuant to Article 28(2) of Regulation (EC) No 45/2001. (101) Since the objectives of this Regulation, namely to ensure the smooth functioning of the internal market as regards medical devices and to ensure high standards of quality and safety for medical devices, thus ensuring a high level of protection of health and safety of patients, users and other persons, cannot be sufficiently achieved by the Member States but can rather, by reason of its scale and effects, be better achieved at Union level, the Union may adopt measures, in accordance with the principle of subsidiarity as set out in Article 5 of the Treaty on European Union. In accordance with the principle of proportionality, as set out in that Article, this Regulation does not go beyond what is necessary in order to achieve those objectives, HAVE ADOPTED THIS REGULATION: CHAPTER I SCOPE AND DEFINITIONS Article 1 Subject matter and scope 1.   This Regulation lays down rules concerning the placing on the market, making available on the market or putting into service of medical devices for human use and accessories for such devices in the Union. This Regulation also applies to clinical investigations concerning such medical devices and accessories conducted in the Union. 2.   This Regulation shall also apply, as from the date of application of common specifications adopted pursuant to Article 9, to the groups of products without an intended medical purpose that are listed in Annex XVI, taking into account the state of the art, and in particular existing harmonised standards for analogous devices with a medical purpose, based on similar technology. The common specifications for each of the groups of products listed in Annex XVI shall address, at least, application of risk management as set out in Annex I for the group of products in question and, where necessary, clinical evaluation regarding safety. The necessary common specifications shall be adopted by 26 May 2020. They shall apply as from six months after the date of their entry into force or from 26 May 2020, whichever is the latest. Notwithstanding Article 122, Member States' measures regarding the qualification of the products covered by Annex XVI as medical devices pursuant to Directive 93/42/EEC shall remain valid until the date of application, as referred to in the first subparagraph, of the relevant common specifications for that group of products. This Regulation also applies to clinical investigations conducted in the Union concerning the products referred to in the first subparagraph. 3.   Devices with both a medical and a non-medical intended purpose shall fulfil cumulatively the requirements applicable to devices with an intended medical purpose and those applicable to devices without an intended medical purpose. 4.   For the purposes of this Regulation, medical devices, accessories for medical devices, and products listed in Annex XVI to which this Regulation applies pursuant to paragraph 2 shall hereinafter be referred to as ‘devices’. 5.   Where justified on account of the similarity between a device with an intended medical purpose placed on the market and a product without an intended medical purpose in respect of their characteristics and risks, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list in Annex XVI, by adding new groups of products, in order to protect the health and safety of users or other persons or other aspects of public health. 6.   This Regulation does not apply to: (a) in vitro diagnostic medical devices covered by Regulation (EU) 2017/746; (b) medicinal products as defined in point 2 of Article 1 of Directive 2001/83/EC. In deciding whether a product falls under Directive 2001/83/EC or under this Regulation, particular account shall be taken of the principal mode of action of the product; (c) advanced therapy medicinal products covered by Regulation (EC) No 1394/2007; (d) human blood, blood products, plasma or blood cells of human origin or devices which incorporate, when placed on the market or put into service, such blood products, plasma or cells, except for devices referred to in paragraph 8 of this Article; (e) cosmetic products covered by Regulation (EC) No 1223/2009; (f) transplants, tissues or cells of animal origin, or their derivatives, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or are rendered non-viable; (g) transplants, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, or products containing or consisting of them; however this Regulation does apply to devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable; (h) products, other than those referred to in points (d), (f) and (g), that contain or consist of viable biological material or viable organisms, including living micro-organisms, bacteria, fungi or viruses in order to achieve or support the intended purpose of the product; (i) food covered by Regulation (EC) No 178/2002. 7.   Any device which, when placed on the market or put into service, incorporates as an integral part an in vitro diagnostic medical device as defined in point 2 of Article 2 of Regulation (EU) 2017/746, shall be governed by this Regulation. The requirements of Regulation (EU) 2017/746 shall apply to the in vitro diagnostic medical device part of the device. 8.   Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation. However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council (34), as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 9.   Any device which is intended to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal product. However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned. 10.   Any device which, when placed on the market or put into service, incorporates, as an integral part, non-viable tissues or cells of human origin or their derivatives that have an action ancillary to that of the device shall be assessed and authorised in accordance with this Regulation. In that case, the provisions for donation, procurement and testing laid down in Directive 2004/23/EC shall apply. However, if the action of those tissues or cells or their derivatives is principal and not ancillary to that of the device and the product is not governed by Regulation (EC) No 1394/2007, the product shall be governed by Directive 2004/23/EC. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 11.   This Regulation is specific Union legislation within the meaning of Article 2(3) of Directive 2014/30/EU. 12.   Devices that are also machinery within the meaning of point (a) of the second paragraph of Article 2 of Directive 2006/42/EC of the European Parliament and of the Council (35) shall, where a hazard relevant under that Directive exists, also meet the essential health and safety requirements set out in Annex I to that Directive to the extent to which those requirements are more specific than the general safety and performance requirements set out in Chapter II of Annex I to this Regulation. 13.   This Regulation shall not affect the application of Directive 2013/59/Euratom. 14.   This Regulation shall not affect the right of a Member State to restrict the use of any specific type of device in relation to aspects not covered by this Regulation. 15.   This Regulation shall not affect national law concerning the organisation, delivery or financing of health services and medical care, such as the requirement that certain devices may only be supplied on a medical prescription, the requirement that only certain health professionals or healthcare institutions may dispense or use certain devices or that their use be accompanied by specific professional counselling. 16.   Nothing in this Regulation shall restrict the freedom of the press or the freedom of expression in the media in so far as those freedoms are guaranteed in the Union and in the Member States, in particular under Article 11 of the Charter of Fundamental Rights of the European Union. Article 2 Definitions For the purposes of this Regulation, the following definitions apply: (1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: — diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, — investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, — providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: — devices for the control or support of conception; — products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (2) ‘accessory for a medical device’ means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); (3) ‘custom-made device’ means any device specifically made in accordance with a written prescription of any person authorised by national law by virtue of that person's professional qualifications which gives, under that person's responsibility, specific design characteristics, and is intended for the sole use of a particular patient exclusively to meet their individual conditions and needs. However, mass-produced devices which need to be adapted to meet the specific requirements of any professional user and devices which are mass-produced by means of industrial manufacturing processes in accordance with the written prescriptions of any authorised person shall not be considered to be custom-made devices; (4) ‘active device’ means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; (5) ‘implantable device’ means any device, including those that are partially or wholly absorbed, which is intended: — to be totally introduced into the human body, or — to replace an epithelial surface or the surface of the eye, by clinical intervention and which is intended to remain in place after the procedure. Any device intended to be partially introduced into the human body by clinical intervention and intended to remain in place after the procedure for at least 30 days shall also be deemed to be an implantable device; (6) ‘invasive device’ means any device which, in whole or in part, penetrates inside the body, either through a body orifice or through the surface of the body; (7) ‘generic device group’ means a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics; (8) ‘single-use device’ means a device that is intended to be used on one individual during a single procedure; (9) ‘falsified device’ means any device with a false presentation of its identity and/or of its source and/or its CE marking certificates or documents relating to CE marking procedures. This definition does not include unintentional non-compliance and is without prejudice to infringements of intellectual property rights; (10) ‘procedure pack’ means a combination of products packaged together and placed on the market with the purpose of being used for a specific medical purpose; (11) ‘system’ means a combination of products, either packaged together or not, which are intended to be inter-connected or combined to achieve a specific medical purpose; (12) ‘intended purpose’ means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation; (13) ‘label’ means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices; (14) ‘instructions for use’ means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use and of any precautions to be taken; (15) ‘Unique Device Identifier’ (‘UDI’) means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market; (16) ‘non-viable’ means having no potential for metabolism or multiplication; (17) ‘derivative’ means a ‘non-cellular substance’ extracted from human or animal tissue or cells through a manufacturing process. The final substance used for manufacturing of the device in this case does not contain any cells or tissues; (18) ‘nanomaterial’ means a natural, incidental or manufactured material containing particles in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1-100 nm; Fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1 nm shall also be deemed to be nanomaterials; (19) ‘particle’, for the purposes of the definition of nanomaterial in point (18), means a minute piece of matter with defined physical boundaries; (20) ‘agglomerate’, for the purposes of the definition of nanomaterial in point (18), means a collection of weakly bound particles or aggregates where the resulting external surface area is similar to the sum of the surface areas of the individual components; (21) ‘aggregate’, for the purposes of the definition of nanomaterial in point (18), means a particle comprising of strongly bound or fused particles; (22) ‘performance’ means the ability of a device to achieve its intended purpose as stated by the manufacturer; (23) ‘risk’ means the combination of the probability of occurrence of harm and the severity of that harm; (24) ‘benefit-risk determination’ means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer; (25) ‘compatibility’ is the ability of a device, including software, when used together with one or more other devices in accordance with its intended purpose, to: (a) perform without losing or compromising the ability to perform as intended, and/or (b) integrate and/or operate without the need for modification or adaption of any part of the combined devices, and/or (c) be used together without conflict/interference or adverse reaction. (26) ‘interoperability’ is the ability of two or more devices, including software, from the same manufacturer or from different manufacturers, to: (a) exchange information and use the information that has been exchanged for the correct execution of a specified function without changing the content of the data, and/or (b) communicate with each other, and/or (c) work together as intended. (27) ‘making available on the market’ means any supply of a device, other than an investigational device, for distribution, consumption or use on the Union market in the course of a commercial activity, whether in return for payment or free of charge; (28) ‘placing on the market’ means the first making available of a device, other than an investigational device, on the Union market; (29) ‘putting into service’ means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; (30) ‘manufacturer’ means a natural or legal person who manufactures or fully refurbishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark; (31) ‘fully refurbishing’, for the purposes of the definition of manufacturer, means the complete rebuilding of a device already placed on the market or put into service, or the making of a new device from used devices, to bring it into conformity with this Regulation, combined with the assignment of a new lifetime to the refurbished device; (32) ‘authorised representative’ means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under this Regulation; (33) ‘importer’ means any natural or legal person established within the Union that places a device from a third country on the Union market; (34) ‘distributor’ means any natural or legal person in the supply chain, other than the manufacturer or the importer, that makes a device available on the market, up until the point of putting into service; (35) ‘economic operator’ means a manufacturer, an authorised representative, an importer, a distributor or the person referred to in Article 22(1) and 22(3); (36) ‘health institution’ means an organisation the primary purpose of which is the care or treatment of patients or the promotion of public health; (37) ‘user’ means any healthcare professional or lay person who uses a device; (38) ‘lay person’ means an individual who does not have formal education in a relevant field of healthcare or medical discipline; (39) ‘reprocessing’ means a process carried out on a used device in order to allow its safe reuse including cleaning, disinfection, sterilisation and related procedures, as well as testing and restoring the technical and functional safety of the used device; (40) ‘conformity assessment’ means the process demonstrating whether the requirements of this Regulation relating to a device have been fulfilled; (41) ‘conformity assessment body’ means a body that performs third-party conformity assessment activities including calibration, testing, certification and inspection; (42) ‘notified body’ means a conformity assessment body designated in accordance with this Regulation; (43) ‘CE marking of conformity’ or ‘CE marking’ means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in this Regulation and other applicable Union harmonisation legislation providing for its affixing; (44) ‘clinical evaluation’ means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer; (45) ‘clinical investigation’ means any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device; (46) ‘investigational device’ means a device that is assessed in a clinical investigation; (47) ‘clinical investigation plan’ means a document that describes the rationale, objectives, design, methodology, monitoring, statistical considerations, organisation and conduct of a clinical investigation; (48) ‘clinical data’ means information concerning safety or performance that is generated from the use of a device and is sourced from the following: — clinical investigation(s) of the device concerned, — clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated, — reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated, — clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up; (49) ‘sponsor’ means any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the clinical investigation; (50) ‘subject’ means an individual who participates in a clinical investigation; (51) ‘clinical evidence’ means clinical data and clinical evaluation results pertaining to a device of a sufficient amount and quality to allow a qualified assessment of whether the device is safe and achieves the intended clinical benefit(s), when used as intended by the manufacturer; (52) ‘clinical performance’ means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer; (53) ‘clinical benefit’ means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health; (54) ‘investigator’ means an individual responsible for the conduct of a clinical investigation at a clinical investigation site; (55) ‘informed consent’ means a subject's free and voluntary expression of his or her willingness to participate in a particular clinical investigation, after having been informed of all aspects of the clinical investigation that are relevant to the subject's decision to participate or, in the case of minors and of incapacitated subjects, an authorisation or agreement from their legally designated representative to include them in the clinical investigation; (56) ‘ethics committee’ means an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations; (57) ‘adverse event’ means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device; (58) ‘serious adverse event’ means any adverse event that led to any of the following: (a) death, (b) serious deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) hospitalisation or prolongation of patient hospitalisation, (iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, (v) chronic disease, (c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect; (59) ‘device deficiency’ means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer; (60) ‘post-market surveillance’ means all activities carried out by manufacturers in cooperation with other economic operators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediately apply any necessary corrective or preventive actions; (61) ‘market surveillance’ means the activities carried out and measures taken by competent authorities to check and ensure that devices comply with the requirements set out in the relevant Union harmonisation legislation and do not endanger health, safety or any other aspect of public interest protection; (62) ‘recall’ means any measure aimed at achieving the return of a device that has already been made available to the end user; (63) ‘withdrawal’ means any measure aimed at preventing a device in the supply chain from being further made available on the market; (64) ‘incident’ means any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect; (65) ‘serious incident’ means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; (66) ‘serious public health threat’ means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time; (67) ‘corrective action’ means action taken to eliminate the cause of a potential or actual non-conformity or other undesirable situation; (68) ‘field safety corrective action’ means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market; (69) ‘field safety notice’ means a communication sent by a manufacturer to users or customers in relation to a field safety corrective action; (70) ‘harmonised standard’ means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) No 1025/2012; (71) ‘common specifications’ (CS) means a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system. Article 3 Amendment of certain definitions The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend the definition of nanomaterial set out in point (18) and the related definitions in points (19), (20) and (21) of Article 2 in the light of technical and scientific progress and taking into account definitions agreed at Union and international level. Article 4 Regulatory status of products 1.   Without prejudice to Article 2(2) of Directive 2001/83/EC, upon a duly substantiated request of a Member State, the Commission shall, after consulting the Medical Device Coordination Group established under Article 103 of this Regulation (‘MDCG’), by means of implementing acts, determine whether or not a specific product, or category or group of products, falls within the definitions of ‘medical device’ or ‘accessory for a medical device’. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3) of this Regulation. 2.   The Commission may also, on its own initiative, after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 3.   The Commission shall ensure that Member States share expertise in the fields of medical devices, in vitro diagnostic medical devices, medicinal products, human tissues and cells, cosmetics, biocides, food and, if necessary, other products, in order to determine the appropriate regulatory status of a product, or category or group of products. 4.   When deliberating on the possible regulatory status as a device of products involving medicinal products, human tissues and cells, biocides or food products, the Commission shall ensure an appropriate level of consultation of the European Medicines Agency (EMA), the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA), as relevant. CHAPTER II MAKING AVAILABLE ON THE MARKET AND PUTTING INTO SERVICE OF DEVICES, OBLIGATIONS OF ECONOMIC OPERATORS, REPROCESSING, CE MARKING, FREE MOVEMENT Article 5 Placing on the market and putting into service 1.   A device may be placed on the market or put into service only if it complies with this Regulation when duly supplied and properly installed, maintained and used in accordance with its intended purpose. 2.   A device shall meet the general safety and performance requirements set out in Annex I which apply to it, taking into account its intended purpose. 3.   Demonstration of conformity with the general safety and performance requirements shall include a clinical evaluation in accordance with Article 61. 4.   Devices that are manufactured and used within health institutions shall be considered as having been put into service. 5.   With the exception of the relevant general safety and performance requirements set out in Annex I, the requirements of this Regulation shall not apply to devices, manufactured and used only within health institutions established in the Union, provided that all of the following conditions are met: (a) the devices are not transferred to another legal entity, (b) manufacture and use of the devices occur under appropriate quality management systems, (c) the health institution justifies in its documentation that the target patient group's specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market, (d) the health institution provides information upon request on the use of such devices to its competent authority, which shall include a justification of their manufacturing, modification and use; (e) the health institution draws up a declaration which it shall make publicly available, including: (i) the name and address of the manufacturing health institution; (ii) the details necessary to identify the devices; (iii) a declaration that the devices meet the general safety and performance requirements set out in Annex I to this Regulation and, where applicable, information on which requirements are not fully met with a reasoned justification therefor, (f) the health institution draws up documentation that makes it possible to have an understanding of the manufacturing facility, the manufacturing process, the design and performance data of the devices, including the intended purpose, and that is sufficiently detailed to enable the competent authority to ascertain that the general safety and performance requirements set out in Annex I to this Regulation are met; (g) the health institution takes all necessary measures to ensure that all devices are manufactured in accordance with the documentation referred to in point (f), and (h) the health institution reviews experience gained from clinical use of the devices and takes all necessary corrective actions. Member States may require that such health institutions submit to the competent authority any further relevant information about such devices which have been manufactured and used on their territory. Member States shall retain the right to restrict the manufacture and the use of any specific type of such devices and shall be permitted access to inspect the activities of the health institutions. This paragraph shall not apply to devices that are manufactured on an industrial scale. 6.   In order to ensure the uniform application of Annex I, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 6 Distance sales 1.   A device offered by means of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to a natural or legal person established in the Union shall comply with this Regulation. 2.   Without prejudice to national law regarding the exercise of the medical profession, a device that is not placed on the market but used in the context of a commercial activity, whether in return for payment or free of charge, for the provision of a diagnostic or therapeutic service offered by means of information society services as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535 or by other means of communication, directly or through intermediaries, to a natural or legal person established in the Union shall comply with this Regulation. 3.   Upon request by a competent authority, any natural or legal person offering a device in accordance with paragraph 1 or providing a service in accordance with paragraph 2 shall make available a copy of the EU declaration of conformity of the device concerned. 4.   A Member State may, on grounds of protection of public health, require a provider of information society services, as defined in point (b) of Article 1(1) of Directive (EU) 2015/1535, to cease its activity. Article 7 Claims In the labelling, instructions for use, making available, putting into service and advertising of devices, it shall be prohibited to use text, names, trademarks, pictures and figurative or other signs that may mislead the user or the patient with regard to the device's intended purpose, safety and performance by: (a) ascribing functions and properties to the device which the device does not have; (b) creating a false impression regarding treatment or diagnosis, functions or properties which the device does not have; (c) failing to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; (d) suggesting uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. Article 8 Use of harmonised standards 1.   Devices that are in conformity with the relevant harmonised standards, or the relevant parts of those standards, the references of which have been published in the Official Journal of the European Union, shall be presumed to be in conformity with the requirements of this Regulation covered by those standards or parts thereof. The first subparagraph shall also apply to system or process requirements to be fulfilled in accordance with this Regulation by economic operators or sponsors, including those relating to quality management systems, risk management, post-market surveillance systems, clinical investigations, clinical evaluation or post-market clinical follow-up (‘PMCF’). References in this Regulation to harmonised standards shall be understood as meaning harmonised standards the references of which have been published in the Official Journal of the European Union. 2.   References in this Regulation to harmonised standards shall also include the monographs of the European Pharmacopoeia adopted in accordance with the Convention on the Elaboration of a European Pharmacopoeia, in particular on surgical sutures and on interaction between medicinal products and materials used in devices containing such medicinal products, provided that references to those monographs have been published in the Official Journal of the European Union. Article 9 Common specifications 1.   Without prejudice to Article 1(2) and 17(5) and the deadline laid down in those provisions, where no harmonised standards exist or where relevant harmonised standards are not sufficient, or where there is a need to address public health concerns, the Commission, after having consulted the MDCG, may, by means of implementing acts, adopt common specifications (CS) in respect of the general safety and performance requirements set out in Annex I, the technical documentation set out in Annexes II and III, the clinical evaluation and post-market clinical follow-up set out in Annex XIV or the requirements regarding clinical investigation set out in Annex XV. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Devices that are in conformity with the CS referred to in paragraph 1 shall be presumed to be in conformity with the requirements of this Regulation covered by those CS or the relevant parts of those CS. 3.   Manufacturers shall comply with the CS referred to in paragraph 1 unless they can duly justify that they have adopted solutions that ensure a level of safety and performance that is at least equivalent thereto. 4.   Notwithstanding paragraph 3, manufacturers of products listed in Annex XVI shall comply with the relevant CS for those products. Article 10 General obligations of manufacturers 1.   When placing their devices on the market or putting them into service, manufacturers shall ensure that they have been designed and manufactured in accordance with the requirements of this Regulation. 2.   Manufacturers shall establish, document, implement and maintain a system for risk management as described in Section 3 of Annex I. 3.   Manufacturers shall conduct a clinical evaluation in accordance with the requirements set out in Article 61 and Annex XIV, including a PMCF. 4.   Manufacturers of devices other than custom-made devices shall draw up and keep up to date technical documentation for those devices. The technical documentation shall be such as to allow the conformity of the device with the requirements of this Regulation to be assessed. The technical documentation shall include the elements set out in Annexes II and III. The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress, the Annexes II and III. 5.   Manufacturers of custom-made devices shall draw up, keep up to date and keep available for competent authorities documentation in accordance with Section 2 of Annex XIII. 6.   Where compliance with the applicable requirements has been demonstrated following the applicable conformity assessment procedure, manufacturers of devices, other than custom-made or investigational devices, shall draw up an EU declaration of conformity in accordance with Article 19, and affix the CE marking of conformity in accordance with Article 20. 7.   Manufacturers shall comply with the obligations relating to the UDI system referred to in Article 27 and with the registration obligations referred to in Articles 29 and 31. 8.   Manufacturers shall keep the technical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market. In the case of implantable devices, the period shall be at least 15 years after the last device has been placed on the market. Upon request by a competent authority, the manufacturer shall, as indicated therein, provide that technical documentation in its entirety or a summary thereof. A manufacturer with a registered place of business outside the Union shall, in order to allow its authorised representative to fulfil the tasks mentioned in Article 11(3), ensure that the authorised representative has the necessary documentation permanently available. 9.   Manufacturers shall ensure that procedures are in place to keep series production in conformity with the requirements of this Regulation. Changes in device design or characteristics and changes in the harmonised standards or CS by reference to which the conformity of a device is declared shall be adequately taken into account in a timely manner. Manufacturers of devices, other than investigational devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device. The quality management system shall cover all parts and elements of a manufacturer's organisation dealing with the quality of processes, procedures and devices. It shall govern the structure, responsibilities, procedures, processes and management resources required to implement the principles and actions necessary to achieve compliance with the provisions of this Regulation. The quality management system shall address at least the following aspects: (a) a strategy for regulatory compliance, including compliance with conformity assessment procedures and procedures for management of modifications to the devices covered by the system; (b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; (c) responsibility of the management; (d) resource management, including selection and control of suppliers and sub-contractors; (e) risk management as set out in in Section 3 of Annex I; (f) clinical evaluation in accordance with Article 61 and Annex XIV, including PMCF; (g) product realisation, including planning, design, development, production and service provision; (h) verification of the UDI assignments made in accordance with Article 27(3) to all relevant devices and ensuring consistency and validity of information provided in accordance with Article 29; (i) setting-up, implementation and maintenance of a post-market surveillance system, in accordance with Article 83; (j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; (k) processes for reporting of serious incidents and field safety corrective actions in the context of vigilance; (l) management of corrective and preventive actions and verification of their effectiveness; (m) processes for monitoring and measurement of output, data analysis and product improvement. 10.   Manufacturers of devices shall implement and keep up to date the post-market surveillance system in accordance with Article 83. 11.   Manufacturers shall ensure that the device is accompanied by the information set out in Section 23 of Annex I in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label shall be indelible, easily legible and clearly comprehensible to the intended user or patient. 12.   Manufacturers who consider or have reason to believe that a device which they have placed on the market or put into service is not in conformity with this Regulation shall immediately take the necessary corrective action to bring that device into conformity, to withdraw it or to recall it, as appropriate. They shall inform the distributors of the device in question and, where applicable, the authorised representative and importers accordingly. Where the device presents a serious risk, manufacturers shall immediately inform the competent authorities of the Member States in which they made the device available and, where applicable, the notified body that issued a certificate for the device in accordance with Article 56, in particular, of the non-compliance and of any corrective action taken. 13.   Manufacturers shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88. 14.   Manufacturers shall, upon request by a competent authority, provide it with all the information and documentation necessary to demonstrate the conformity of the device, in an official Union language determined by the Member State concerned. The competent authority of the Member State in which the manufacturer has its registered place of business may require that the manufacturer provide samples of the device free of charge or, where that is impracticable, grant access to the device. Manufacturers shall cooperate with a competent authority, at its request, on any corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market or put into service. If the manufacturer fails to cooperate or the information and documentation provided is incomplete or incorrect, the competent authority may, in order to ensure the protection of public health and patient safety, take all appropriate measures to prohibit or restrict the device's being made available on its national market, to withdraw the device from that market or to recall it until the manufacturer cooperates or provides complete and correct information. If a competent authority considers or has reason to believe that a device has caused damage, it shall, upon request, facilitate the provision of the information and documentation referred to in the first subparagraph to the potentially injured patient or user and, as appropriate, the patient's or user's successor in title, the patient's or user's health insurance company or other third parties affected by the damage caused to the patient or user, without prejudice to data protection rules and, unless there is an overriding public interest in disclosure, without prejudice to the protection of intellectual property rights. The competent authority need not comply with the obligation laid down in the third subparagraph where disclosure of the information and documentation referred to in the first subparagraph is ordinarily dealt with in the context of legal proceedings. 15.   Where manufacturers have their devices designed or manufactured by another legal or natural person the information on the identity of that person shall be part of the information to be submitted in accordance with Article 30(1). 16.   Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Manufacturers shall, in a manner that is proportionate to the risk class, type of device and the size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to more protective measures under national law. Article 11 Authorised representative 1.   Where the manufacturer of a device is not established in a Member State, the device may only be placed on the Union market if the manufacturer designates a sole authorised representative. 2.   The designation shall constitute the authorised representative's mandate, it shall be valid only when accepted in writing by the authorised representative and shall be effective at least for all devices of the same generic device group. 3.   The authorised representative shall perform the tasks specified in the mandate agreed between it and the manufacturer. The authorised representative shall provide a copy of the mandate to the competent authority, upon request. The mandate shall require, and the manufacturer shall enable, the authorised representative to perform at least the following tasks in relation to the devices that it covers: (a) verify that the EU declaration of conformity and technical documentation have been drawn up and, where applicable, that an appropriate conformity assessment procedure has been carried out by the manufacturer; (b) keep available a copy of the technical documentation, the EU declaration of conformity and, if applicable, a copy of the relevant certificate, including any amendments and supplements, issued in accordance with Article 56, at the disposal of competent authorities for the period referred to in Article 10(8); (c) comply with the registration obligations laid down in Article 31 and verify that the manufacturer has complied with the registration obligations laid down in Articles 27 and 29; (d) in response to a request from a competent authority, provide that competent authority with all the information and documentation necessary to demonstrate the conformity of a device, in an official Union language determined by the Member State concerned; (e) forward to the manufacturer any request by a competent authority of the Member State in which the authorised representative has its registered place of business for samples, or access to a device and verify that the competent authority receives the samples or is given access to the device; (f) cooperate with the competent authorities on any preventive or corrective action taken to eliminate or, if that is not possible, mitigate the risks posed by devices; (g) immediately inform the manufacturer about complaints and reports from healthcare professionals, patients and users about suspected incidents related to a device for which they have been designated; (h) terminate the mandate if the manufacturer acts contrary to its obligations under this Regulation. 4.   The mandate referred to in paragraph 3 of this Article shall not delegate the manufacturer's obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). 5.   Without prejudice to paragraph 4 of this Article, where the manufacturer is not established in a Member State and has not complied with the obligations laid down in Article 10, the authorised representative shall be legally liable for defective devices on the same basis as, and jointly and severally with, the manufacturer. 6.   An authorised representative who terminates its mandate on the ground referred to in point (h) of paragraph 3 shall immediately inform the competent authority of the Member State in which it is established and, where applicable, the notified body that was involved in the conformity assessment for the device of the termination of the mandate and the reasons therefor. 7.   Any reference in this Regulation to the competent authority of the Member State in which the manufacturer has its registered place of business shall be understood as a reference to the competent authority of the Member State in which the authorised representative, designated by a manufacturer referred to in paragraph 1, has its registered place of business. Article 12 Change of authorised representative The detailed arrangements for a change of authorised representative shall be clearly defined in an agreement between the manufacturer, where practicable the outgoing authorised representative, and the incoming authorised representative. That agreement shall address at least the following aspects: (a) the date of termination of the mandate of the outgoing authorised representative and date of beginning of the mandate of the incoming authorised representative; (b) the date until which the outgoing authorised representative may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the obligation of the outgoing authorised representative after the end of the mandate to forward to the manufacturer or incoming authorised representative any complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device for which it had been designated as authorised representative. Article 13 General obligations of importers 1.   Importers shall place on the Union market only devices that are in conformity with this Regulation. 2.   In order to place a device on the market, importers shall verify that: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) a manufacturer is identified and that an authorised representative in accordance with Article 11 has been designated by the manufacturer; (c) the device is labelled in accordance with this Regulation and accompanied by the required instructions for use; (d) where applicable, a UDI has been assigned by the manufacturer in accordance with Article 27. Where an importer considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not place the device on the market until it has been brought into conformity and shall inform the manufacturer and the manufacturer's authorised representative. Where the importer considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which the importer is established. 3.   Importers shall indicate on the device or on its packaging or in a document accompanying the device their name, registered trade name or registered trade mark, their registered place of business and the address at which they can be contacted, so that their location can be established. They shall ensure that any additional label does not obscure any information on the label provided by the manufacturer. 4.   Importers shall verify that the device is registered in the electronic system in accordance with Article 29. Importers shall add their details to the registration in accordance with Article 31. 5.   Importers shall ensure that, while a device is under their responsibility, storage or transport conditions do not jeopardise its compliance with the general safety and performance requirements set out in Annex I and shall comply with the conditions set by the manufacturer, where available. 6.   Importers shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and provide the manufacturer, authorised representative and distributors with any information requested by them, in order to allow them to investigate complaints. 7.   Importers who consider or have reason to believe that a device which they have placed on the market is not in conformity with this Regulation shall immediately inform the manufacturer and its authorised representative. Importers shall co-operate with the manufacturer, the manufacturer's authorised representative and the competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or recall it is taken. Where the device presents a serious risk, they shall also immediately inform the competent authorities of the Member States in which they made the device available and, if applicable, the notified body that issued a certificate in accordance with Article 56 for the device in question, giving details, in particular, of the non-compliance and of any corrective action taken. 8.   Importers who have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device which they have placed on the market shall immediately forward this information to the manufacturer and its authorised representative. 9.   Importers shall, for the period referred to in Article 10(8), keep a copy of the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56. 10.   Importers shall cooperate with competent authorities, at the latters' request, on any action taken to eliminate or, if that is not possible, mitigate the risks posed by devices which they have placed on the market. Importers, upon request by a competent authority of the Member State in which the importer has its registered place of business, shall provide samples of the device free of charge or, where that is impracticable, grant access to the device. Article 14 General obligations of distributors 1.   When making a device available on the market, distributors shall, in the context of their activities, act with due care in relation to the requirements applicable. 2.   Before making a device available on the market, distributors shall verify that all of the following requirements are met: (a) the device has been CE marked and that the EU declaration of conformity of the device has been drawn up; (b) the device is accompanied by the information to be supplied by the manufacturer in accordance with Article 10(11); (c) for imported devices, the importer has complied with the requirements set out in Article 13(3); (d) that, where applicable, a UDI has been assigned by the manufacturer. In order to meet the requirements referred to in points (a), (b) and (d) of the first subparagraph the distributor may apply a sampling method that is representative of the devices supplied by that distributor. Where a distributor considers or has reason to believe that a device is not in conformity with the requirements of this Regulation, it shall not make the device available on the market until it has been brought into conformity, and shall inform the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. Where the distributor considers or has reason to believe that the device presents a serious risk or is a falsified device, it shall also inform the competent authority of the Member State in which it is established. 3.   Distributors shall ensure that, while the device is under their responsibility, storage or transport conditions comply with the conditions set by the manufacturer. 4.   Distributors that consider or have reason to believe that a device which they have made available on the market is not in conformity with this Regulation shall immediately inform the manufacturer and, where applicable, the manufacturer's authorised representative and the importer. Distributors shall co-operate with the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer, and with competent authorities to ensure that the necessary corrective action to bring that device into conformity, to withdraw or to recall it, as appropriate, is taken. Where the distributor considers or has reason to believe that the device presents a serious risk, it shall also immediately inform the competent authorities of the Member States in which it made the device available, giving details, in particular, of the non-compliance and of any corrective action taken. 5.   Distributors that have received complaints or reports from healthcare professionals, patients or users about suspected incidents related to a device they have made available, shall immediately forward this information to the manufacturer and, where applicable, the manufacturer's authorised representative, and the importer. They shall keep a register of complaints, of non-conforming devices and of recalls and withdrawals, and keep the manufacturer and, where available, the authorised representative and the importer informed of such monitoring and provide them with any information upon their request. 6.   Distributors shall, upon request by a competent authority, provide it with all the information and documentation that is at their disposal and is necessary to demonstrate the conformity of a device. Distributors shall be considered to have fulfilled the obligation referred to in the first subparagraph when the manufacturer or, where applicable, the authorised representative for the device in question provides the required information. Distributors shall cooperate with competent authorities, at their request, on any action taken to eliminate the risks posed by devices which they have made available on the market. Distributors, upon request by a competent authority, shall provide free samples of the device or, where that is impracticable, grant access to the device. Article 15 Person responsible for regulatory compliance 1.   Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom-made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. 2.   Micro and small enterprises within the meaning of Commission Recommendation 2003/361/EC (36) shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal. 3.   The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the devices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; (b) the technical documentation and the EU declaration of conformity are drawn up and kept up-to-date; (c) the post-market surveillance obligations are complied with in accordance with Article 10(10); (d) the reporting obligations referred to in Articles 87 to 91 are fulfilled; (e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV is issued. 4.   If a number of persons are jointly responsible for regulatory compliance in accordance with paragraphs 1, 2 and 3, their respective areas of responsibility shall be stipulated in writing. 5.   The person responsible for regulatory compliance shall suffer no disadvantage within the manufacturer's organisation in relation to the proper fulfilment of his or her duties, regardless of whether or not they are employees of the organisation. 6.   Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Article 16 Cases in which obligations of manufacturers apply to importers, distributors or other persons 1.   A distributor, importer or other natural or legal person shall assume the obligations incumbent on manufacturers if it does any of the following: (a) makes available on the market a device under its name, registered trade name or registered trade mark, except in cases where a distributor or importer enters into an agreement with a manufacturer whereby the manufacturer is identified as such on the label and is responsible for meeting the requirements placed on manufacturers in this Regulation; (b) changes the intended purpose of a device already placed on the market or put into service; (c) modifies a device already placed on the market or put into service in such a way that compliance with the applicable requirements may be affected. The first subparagraph shall not apply to any person who, while not considered a manufacturer as defined in point (30) of Article 2, assembles or adapts for an individual patient a device already on the market without changing its intended purpose. 2.   For the purposes of point (c) of paragraph 1, the following shall not be considered to be a modification of a device that could affect its compliance with the applicable requirements: (a) provision, including translation, of the information supplied by the manufacturer, in accordance with Section 23 of Annex I, relating to a device already placed on the market and of further information which is necessary in order to market the device in the relevant Member State; (b) changes to the outer packaging of a device already placed on the market, including a change of pack size, if the repackaging is necessary in order to market the device in the relevant Member State and if it is carried out in such conditions that the original condition of the device cannot be affected by it. In the case of devices placed on the market in sterile condition, it shall be presumed that the original condition of the device is adversely affected if the packaging that is necessary for maintaining the sterile condition is opened, damaged or otherwise negatively affected by the repackaging. 3.   A distributor or importer that carries out any of the activities mentioned in points (a) and (b) of paragraph 2 shall indicate on the device or, where that is impracticable, on its packaging or in a document accompanying the device, the activity carried out together with its name, registered trade name or registered trade mark, registered place of business and the address at which it can be contacted, so that its location can be established. Distributors and importers shall ensure that they have in place a quality management system that includes procedures which ensure that the translation of information is accurate and up-to-date, and that the activities mentioned in points (a) and (b) of paragraph 2 are performed by a means and under conditions that preserve the original condition of the device and that the packaging of the repackaged device is not defective, of poor quality or untidy. The quality management system shall cover, inter alia, procedures ensuring that the distributor or importer is informed of any corrective action taken by the manufacturer in relation to the device in question in order to respond to safety issues or to bring it into conformity with this Regulation. 4.   At least 28 days prior to making the relabelled or repackaged device available on the market, distributors or importers carrying out any of the activities mentioned in points (a) and (b) of paragraph 2 shall inform the manufacturer and the competent authority of the Member State in which they plan to make the device available of the intention to make the relabelled or repackaged device available and, upon request, shall provide the manufacturer and the competent authority with a sample or mock-up of the relabelled or repackaged device, including any translated label and instructions for use. Within the same period of 28 days, the distributor or importer shall submit to the competent authority a certificate, issued by a notified body designated for the type of devices that are subject to activities mentioned in points (a) and (b) of paragraph 2, attesting that the quality management system of the distributer or importer complies with the requirements laid down in paragraph 3. Article 17 Single-use devices and their reprocessing 1.   Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 2.   Any natural or legal person who reprocesses a single-use device to make it suitable for further use within the Union shall be considered to be the manufacturer of the reprocessed device and shall assume the obligations incumbent on manufacturers laid down in this Regulation, which include obligations relating to the traceability of the reprocessed device in accordance with Chapter III of this Regulation. The reprocessor of the device shall be considered to be a producer for the purpose of Article 3(1) of Directive 85/374/EEC. 3.   By way of derogation from paragraph 2, as regards single-use devices that are reprocessed and used within a health institution, Member States may decide not to apply all of the rules relating to manufacturers' obligations laid down in this Regulation provided that they ensure that: (a) the safety and performance of the reprocessed device is equivalent to that of the original device and the requirements in points (a), (b), (d), (e), (f), (g) and (h) of Article 5(5) are complied with; (b) the reprocessing is performed in accordance with CS detailing the requirements concerning: — risk management, including the analysis of the construction and material, related properties of the device (reverse engineering) and procedures to detect changes in the design of the original device as well as of its planned application after reprocessing, — the validation of procedures for the entire process, including cleaning steps, — the product release and performance testing, — the quality management system, — the reporting of incidents involving devices that have been reprocessed, and — the traceability of reprocessed devices. Member States shall encourage, and may require, health institutions to provide information to patients on the use of reprocessed devices within the health institution and, where appropriate, any other relevant information on the reprocessed devices that patients are treated with. Member States shall notify the Commission and the other Member States of the national provisions introduced pursuant to this paragraph and the grounds for introducing them. The Commission shall keep the information publicly available. 4.   Member States may choose to apply the provisions referred to in paragraph 3 also as regards single-use devices that are reprocessed by an external reprocessor at the request of a health institution, provided that the reprocessed device in its entirety is returned to that health institution and the external reprocessor complies with the requirements referred to in points (a) and (b) of paragraph 3. 5.   The Commission shall adopt, in accordance with Article 9(1), the necessary CS referred to in point (b) of paragraph 3 by 26 May 2020. Those CS shall be consistent with the latest scientific evidence and shall address the application of the general requirements on safety and performance laid down in in this Regulation. In the event that those CS are not adopted by 26 May 2020, reprocessing shall be performed in accordance with any relevant harmonised standards and national provisions that cover the aspects outlined in point (b) of paragraph 3. Compliance with CS or, in the absence of CS, with any relevant harmonised standards and national provisions, shall be certified by a notified body. 6.   Only single-use devices that have been placed on the market in accordance with this Regulation, or prior to 26 May 2020 in accordance with Directive 93/42/EEC, may be reprocessed. 7.   Only reprocessing of single-use devices that is considered safe according to the latest scientific evidence may be carried out. 8.   The name and address of the legal or natural person referred to in paragraph 2 and the other relevant information referred to in Section 23 of Annex I shall be indicated on the label and, where applicable, in the instructions for use of the reprocessed device. The name and address of the manufacturer of the original single-use device shall no longer appear on the label, but shall be mentioned in the instructions for use of the reprocessed device. 9.   A Member State that permits reprocessing of single-use devices may maintain or introduce national provisions that are stricter than those laid down in this Regulation and which restrict or prohibit, within its territory, the following: (a) the reprocessing of single-use devices and the transfer of single-use devices to another Member State or to a third country with a view to their reprocessing; (b) the making available or further use of reprocessed single-use devices. Member States shall notify the Commission and the other Member States of those national provisions. The Commission shall make such information publicly available. 10.   The Commission shall by 27 May 2024 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. On the basis of that report, the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 18 Implant card and information to be supplied to the patient with an implanted device 1.   The manufacturer of an implantable device shall provide together with the device the following: (a) information allowing the identification of the device, including the device name, serial number, lot number, the UDI, the device model, as well as the name, address and the website of the manufacturer; (b) any warnings, precautions or measures to be taken by the patient or a healthcare professional with regard to reciprocal interference with reasonably foreseeable external influences, medical examinations or environmental conditions; (c) any information about the expected lifetime of the device and any necessary follow-up; (d) any other information to ensure safe use of the device by the patient, including the information in point (u) of Section 23.4 of Annex I. The information referred to in the first subparagraph shall be provided, for the purpose of making it available to the particular patient who has been implanted with the device, by any means that allow rapid access to that information and shall be stated in the language(s) determined by the concerned Member State. The information shall be written in a way that is readily understood by a lay person and shall be updated where appropriate. Updates of the information shall be made available to the patient via the website mentioned in point (a) of the first subparagraph. In addition, the manufacturer shall provide the information referred to in point (a) of the first subparagraph on an implant card delivered with the device. 2.   Member States shall require health institutions to make the information referred to in paragraph 1 available, by any means that allow rapid access to that information, to any patients who have been implanted with the device, together with the implant card, which shall bear their identity. 3.   The following implants shall be exempted from the obligations laid down in this Article: sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors. The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend this list by adding other types of implants to it or by removing implants therefrom. Article 19 EU declaration of conformity 1.   The EU declaration of conformity shall state that the requirements specified in this Regulation have been fulfilled in relation to the device that is covered. The manufacturer shall continuously update the EU declaration of conformity. The EU declaration of conformity shall, as a minimum, contain the information set out in Annex IV and shall be translated into an official Union language or languages required by the Member State(s) in which the device is made available. 2.   Where, concerning aspects not covered by this Regulation, devices are subject to other Union legislation which also requires an EU declaration of conformity by the manufacturer that fulfilment of the requirements of that legislation has been demonstrated, a single EU declaration of conformity shall be drawn up in respect of all Union acts applicable to the device. The declaration shall contain all the information required for identification of the Union legislation to which the declaration relates. 3.   By drawing up the EU declaration of conformity, the manufacturer shall assume responsibility for compliance with the requirements of this Regulation and all other Union legislation applicable to the device. 4.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the EU declaration of conformity set out in Annex IV in the light of technical progress. Article 20 CE marking of conformity 1.   Devices, other than custom-made or investigational devices, considered to be in conformity with the requirements of this Regulation shall bear the CE marking of conformity, as presented in Annex V. 2.   The CE marking shall be subject to the general principles set out in Article 30 of Regulation (EC) No 765/2008. 3.   The CE marking shall be affixed visibly, legibly and indelibly to the device or its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE marking shall be affixed to the packaging. The CE marking shall also appear in any instructions for use and on any sales packaging. 4.   The CE marking shall be affixed before the device is placed on the market. It may be followed by a pictogram or any other mark indicating a special risk or use. 5.   Where applicable, the CE marking shall be followed by the identification number of the notified body responsible for the conformity assessment procedures set out in Article 52. The identification number shall also be indicated in any promotional material which mentions that a device fulfils the requirements for CE marking. 6.   Where devices are subject to other Union legislation which also provides for the affixing of the CE marking, the CE marking shall indicate that the devices also fulfil the requirements of that other legislation. Article 21 Devices for special purposes 1.   Member States shall not create obstacles to: (a) investigational devices being supplied to an investigator for the purpose of a clinical investigation if they meet the conditions laid down in Articles 62 to 80 and Article 82, in the implementing acts adopted pursuant to Article 81 and in Annex XV; (b) custom-made devices being made available on the market if Article 52(8) and Annex XIII have been complied with. The devices referred to in the first subparagraph shall not bear the CE marking, with the exception of the devices referred to in Article 74. 2.   Custom-made devices shall be accompanied by the statement referred to in Section 1 of Annex XIII, which shall be made available to the particular patient or user identified by name, an acronym or a numerical code. Member States may require that the manufacturer of a custom-made device submit to the competent authority a list of such devices which have been made available in their territory. 3.   At trade fairs, exhibitions, demonstrations or similar events, Member States shall not create obstacles to the showing of devices which do not comply with this Regulation, provided a visible sign clearly indicates that such devices are intended for presentation or demonstration purposes only and cannot be made available until they have been brought into compliance with this Regulation. Article 22 Systems and procedure packs 1.   Natural or legal persons shall draw up a statement if they combine devices bearing a CE marking with the following other devices or products, in a manner that is compatible with the intended purpose of the devices or other products and within the limits of use specified by their manufacturers, in order to place them on the market as a system or procedure pack: (a) other devices bearing the CE marking; (b) in vitro diagnostic medical devices bearing the CE marking in conformity with Regulation (EU) 2017/746; (c) other products which are in conformity with legislation that applies to those products only where they are used within a medical procedure or their presence in the system or procedure pack is otherwise justified. 2.   In the statement made pursuant to paragraph 1, the natural or legal person concerned shall declare that: (a) they verified the mutual compatibility of the devices and, if applicable other products, in accordance with the manufacturers' instructions and have carried out their activities in accordance with those instructions; (b) they packaged the system or procedure pack and supplied relevant information to users incorporating the information to be supplied by the manufacturers of the devices or other products which have been put together; (c) the activity of combining devices and, if applicable, other products as a system or procedure pack was subject to appropriate methods of internal monitoring, verification and validation. 3.   Any natural or legal person who sterilises systems or procedure packs referred to in paragraph 1 for the purpose of placing them on the market shall, at their choice, apply one of the procedures set out in Annex IX or the procedure set out in Part A of Annex XI. The application of those procedures and the involvement of the notified body shall be limited to the aspects of the procedure relating to ensuring sterility until the sterile packaging is opened or damaged. The natural or legal person shall draw up a statement declaring that sterilisation has been carried out in accordance with the manufacturer's instructions. 4.   Where the system or procedure pack incorporates devices which do not bear the CE marking or where the chosen combination of devices is not compatible in view of their original intended purpose, or where the sterilisation has not been carried out in accordance with the manufacturer's instructions, the system or procedure pack shall be treated as a device in its own right and shall be subject to the relevant conformity assessment procedure pursuant to Article 52. The natural or legal person shall assume the obligations incumbent on manufacturers. 5.   The systems or procedure packs referred to in paragraph 1 of this Article shall not themselves bear an additional CE marking but they shall bear the name, registered trade name or registered trade mark of the person referred to in paragraphs 1 and 3 of this Article as well as the address at which that person can be contacted, so that the person's location can be established. Systems or procedure packs shall be accompanied by the information referred to in Section 23 of Annex I. The statement referred to in paragraph 2 of this Article shall be kept at the disposal of the competent authorities, after the system or procedure pack has been put together, for the period that is applicable under Article 10(8) to the devices that have been combined. Where those periods differ, the longest period shall apply. Article 23 Parts and components 1.   Any natural or legal person who makes available on the market an item specifically intended to replace an identical or similar integral part or component of a device that is defective or worn in order to maintain or restore the function of the device without changing its performance or safety characteristics or its intended purpose, shall ensure that the item does not adversely affect the safety and performance of the device. Supporting evidence shall be kept available for the competent authorities of the Member States. 2.   An item that is intended specifically to replace a part or component of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation. Article 24 Free movement Except where otherwise provided for in this Regulation, Member States shall not refuse, prohibit or restrict the making available on the market or putting into service within their territory of devices which comply with the requirements of this Regulation. CHAPTER III IDENTIFICATION AND TRACEABILITY OF DEVICES, REGISTRATION OF DEVICES AND OF ECONOMIC OPERATORS, SUMMARY OF SAFETY AND CLINICAL PERFORMANCE, EUROPEAN DATABASE ON MEDICAL DEVICES Article 25 Identification within the supply chain 1.   Distributors and importers shall co-operate with manufacturers or authorised representatives to achieve an appropriate level of traceability of devices. 2.   Economic operators shall be able to identify the following to the competent authority, for the period referred to in Article 10(8): (a) any economic operator to whom they have directly supplied a device; (b) any economic operator who has directly supplied them with a device; (c) any health institution or healthcare professional to which they have directly supplied a device. Article 26 Medical devices nomenclature To facilitate the functioning of the European database on medical devices (‘Eudamed’) as referred to in Article 33, the Commission shall ensure that an internationally recognised medical devices nomenclature is available free of charge to manufacturers and other natural or legal persons required by this Regulation to use that nomenclature. The Commission shall also endeavour to ensure that that nomenclature is available to other stakeholders free of charge, where reasonably practicable. Article 27 Unique Device Identification system 1.   The Unique Device Identification system (‘UDI system’) described in Part C of Annex VI shall allow the identification and facilitate the traceability of devices, other than custom-made and investigational devices, and shall consist of the following: (a) production of a UDI that comprises the following: (i) a UDI device identifier (‘UDI-DI’) specific to a manufacturer and a device, providing access to the information laid down in Part B of Annex VI; (ii) a UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI; (b) placing of the UDI on the label of the device or on its packaging; (c) storage of the UDI by economic operators, health institutions and healthcare professionals, in accordance with the conditions laid down in paragraphs 8 and 9 of this Article respectively; (d) establishment of an electronic system for Unique Device Identification (‘UDI database’) in accordance with Article 28. 2.   The Commission shall, by means of implementing acts, designate one or several entities to operate a system for assignment of UDIs pursuant to this Regulation (‘issuing entity’). That entity or those entities shall satisfy all of the following criteria: (a) the entity is an organisation with legal personality; (b) its system for the assignment of UDIs is adequate to identify a device throughout its distribution and use in accordance with the requirements of this Regulation; (c) its system for the assignment of UDIs conforms to the relevant international standards; (d) the entity gives access to its system for the assignment of UDIs to all interested users in accordance with a set of predetermined and transparent terms and conditions; (e) the entity undertakes to do the following: (i) operate its system for the assignment of UDIs for at least 10 years after its designation; (ii) make available to the Commission and to the Member States, upon request, information concerning its system for the assignment of UDIs; (iii) remain in compliance with the criteria for designation and the terms of designation. When designating issuing entities, the Commission shall endeavour to ensure that UDI carriers, as defined in Part C of Annex VI, are universally readable regardless of the system used by the issuing entity, with a view to minimising financial and administrative burdens for economic operators and health institutions. 3.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall assign to the device and, if applicable, to all higher levels of packaging, a UDI created in compliance with the rules of the issuing entity designated by the Commission in accordance with paragraph 2. Before a device, other than a custom-made or investigational device, is placed on the market the manufacturer shall ensure that the information referred to in Part B of Annex VI of the device in question are correctly submitted and transferred to the UDI database referred to in Article 28. 4.   UDI carriers shall be placed on the label of the device and on all higher levels of packaging. Higher levels of packaging shall not be understood to include shipping containers. 5.   The UDI shall be used for reporting serious incidents and field safety corrective actions in accordance with Article 87. 6.   The Basic UDI-DI, as defined in Part C of Annex VI, of the device shall appear on the EU declaration of conformity referred to in Article 19. 7.   As part of the technical documentation referred to in Annex II, the manufacturer shall keep up-to-date a list of all UDIs that it has assigned. 8.   Economic operators shall store and keep, preferably by electronic means, the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to: — class III implantable devices; — the devices, categories or groups of devices determined by a measure referred to in point (a) of paragraph 11. 9.   Health institutions shall store and keep preferably by electronic means the UDI of the devices which they have supplied or with which they have been supplied, if those devices belong to class III implantable devices. For devices other than class III implantable devices, Member States shall encourage, and may require, health institutions to store and keep, preferably by electronic means, the UDI of the devices with which they have been supplied. Member States shall encourage, and may require, healthcare professionals to store and keep preferably by electronic means, the UDI of the devices with which they have been supplied with. 10.   The Commission is empowered to adopt delegated acts in accordance with Article 115: (a) amending the list of information set out in Part B of Annex VI in the light of technical progress; and (b) amending Annex VI in the light of international developments and technical progress in the field of Unique Device Identification. 11.   The Commission may, by means of implementing acts, specify the detailed arrangements and the procedural aspects for the UDI system with a view to ensuring its harmonised application in relation to any of the following: (a) determining the devices, categories or groups of devices to which the obligation laid down in paragraph 8 is to apply; (b) specifying the data to be included in the UDI-PI of specific devices or device groups; The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). 12.   When adopting the measures referred to in paragraph 11, the Commission shall take into account all of the following: (a) confidentiality and data protection as referred to in Articles 109 and 110 respectively; (b) the risk-based approach; (c) the cost-effectiveness of the measures; (d) the convergence of UDI systems developed at international level; (e) the need to avoid duplications in the UDI system; (f) the needs of the healthcare systems of the Member States, and where possible, compatibility with other medical device identification systems that are used by stakeholders. Article 28 UDI database 1.   The Commission, after consulting the MDCG shall set up and manage a UDI database to validate, collate, process and make available to the public the information mentioned in Part B of Annex VI. 2.   When designing the UDI database, the Commission shall take into account the general principles set out in Section 5 of Part C of Annex VI. The UDI database shall be designed in particular such that no UDI-PIs and no commercially confidential product information can be included therein. 3.   The core data elements to be provided to the UDI database, referred to in Part B of Annex VI, shall be accessible to the public free of charge. 4.   The technical design of the UDI database shall ensure maximum accessibility to information stored therein, including multi-user access and automatic uploads and downloads of that information. The Commission shall provide for technical and administrative support to manufacturers and other users of the UDI database. Article 29 Registration of devices 1.   Before placing a device, other than a custom-made device, on the market, the manufacturer shall, in accordance with the rules of the issuing entity referred to in Article 27(2), assign a Basic UDI-DI as defined in Part C of Annex VI to the device and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 2.   Before placing on the market a system or procedure pack pursuant to Article 22(1) and (3), that is not a custom-made device, the natural or legal person responsible shall assign to the system or procedure pack, in compliance with the rules of the issuing entity, a Basic UDI-DI and shall provide it to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that system or procedure pack. 3.   For devices that are the subject of a conformity assessment as referred to in Article 52(3) and in the second and third subparagraphs of Article 52(4), the assignment of a Basic UDI-DI referred to in paragraph 1 of this Article shall be done before the manufacturer applies to a notified body for that assessment. For the devices referred to in the first subparagraph, the notified body shall include a reference to the Basic UDI-DI on the certificate issued in accordance with point (a) of Section 4 of Chapter I of Annex XII and confirm in Eudamed that the information referred to in Section 2.2 of Part A of Annex VI is correct. After the issuing of the relevant certificate and before placing the device on the market, the manufacturer shall provide the Basic UDI-DI to the UDI database together with the other core data elements referred to in Part B of Annex VI related to that device. 4.   Before placing a device on the market, other than a custom-made device, the manufacturer shall enter or if, already provided, verify in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and shall thereafter keep the information updated. Article 30 Electronic system for registration of economic operators 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to create the single registration number referred to in Article 31(2) and to collate and process information that is necessary and proportionate to identify the manufacturer and, where applicable, the authorised representative and the importer. The details regarding the information to be provided to that electronic system by the economic operators are laid down in Section 1 of Part A of Annex VI. 2.   Member States may maintain or introduce national provisions on registration of distributors of devices which have been made available on their territory. 3.   Within two weeks of placing a device, other than a custom-made device, on the market, importers shall verify that the manufacturer or authorised representative has provided to the electronic system the information referred to in paragraph 1. Where applicable, importers shall inform the relevant authorised representative or manufacturer if the information referred to in paragraph 1 is not included or is incorrect. Importers shall add their details to the relevant entry/entries. Article 31 Registration of manufacturers, authorised representatives and importers 1.   Before placing a device, other than a custom-made device, on the market, manufacturers, authorised representatives and importers shall, in order to register, submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already registered in accordance with this Article. In cases where the conformity assessment procedure requires the involvement of a notified body pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI shall be provided to that electronic system before applying to the notified body. 2.   After having verified the data entered pursuant to paragraph 1, the competent authority shall obtain a single registration number (‘SRN’) from the electronic system referred to in Article 30 and issue it to the manufacturer, the authorised representative or the importer. 3.   The manufacturer shall use the SRN when applying to a notified body for conformity assessment and for accessing Eudamed in order to fulfil its obligations under Article 29. 4.   Within one week of any change occurring in relation to the information referred to in paragraph 1 of this Article, the economic operator shall update the data in the electronic system referred to in Article 30. 5.   Not later than one year after submission of the information in accordance with paragraph 1, and every second year thereafter, the economic operator shall confirm the accuracy of the data. In the event of a failure to do so within six months of those deadlines, any Member State may take appropriate corrective measures within its territory until that economic operator complies with that obligation. 6.   Without prejudice to the economic operator's responsibility for the data, the competent authority shall verify the confirmed data referred to in Section 1 of Part A of Annex VI. 7.   The data entered pursuant to paragraph 1 of this Article in the electronic system referred to in Article 30 shall be accessible to the public. 8.   The competent authority may use the data to charge the manufacturer, the authorised representative or the importer a fee pursuant to Article 111. Article 32 Summary of safety and clinical performance 1.   For implantable devices and for class III devices, other than custom-made or investigational devices, the manufacturer shall draw up a summary of safety and clinical performance. The summary of safety and clinical performance shall be written in a way that is clear to the intended user and, if relevant, to the patient and shall be made available to the public via Eudamed. The draft of the summary of safety and clinical performance shall be part of the documentation to be submitted to the notified body involved in the conformity assessment pursuant to Article 52 and shall be validated by that body. After its validation, the notified body shall upload the summary to Eudamed. The manufacturer shall mention on the label or instructions for use where the summary is available. 2.   The summary of safety and clinical performance shall include at least the following aspects: (a) the identification of the device and the manufacturer, including the Basic UDI-DI and, if already issued, the SRN; (b) the intended purpose of the device and any indications, contraindications and target populations; (c) a description of the device, including a reference to previous generation(s) or variants if such exist, and a description of the differences, as well as, where relevant, a description of any accessories, other devices and products, which are intended to be used in combination with the device; (d) possible diagnostic or therapeutic alternatives; (e) reference to any harmonised standards and CS applied; (f) the summary of clinical evaluation as referred to in Annex XIV, and relevant information on post-market clinical follow-up; (g) suggested profile and training for users; (h) information on any residual risks and any undesirable effects, warnings and precautions. 3.   The Commission may, by means of implementing acts, set out the form and the presentation of the data elements to be included in the summary of safety and clinical performance. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). Article 33 European database on medical devices 1.   The Commission, after consulting the MDCG, shall set up, maintain and manage the European database on medical devices (‘Eudamed’) for the following purposes: (a) to enable the public to be adequately informed about devices placed on the market, the corresponding certificates issued by notified bodies and about the relevant economic operators; (b) to enable unique identification of devices within the internal market and to facilitate their traceability; (c) to enable the public to be adequately informed about clinical investigations and to enable sponsors of clinical investigations to comply with obligations under Articles 62 to 80, Article 82, and any acts adopted pursuant to Article 81; (d) to enable manufacturers to comply with the information obligations laid down in Articles 87 to 90 or in any acts adopted pursuant to Article 91; (e) to enable the competent authorities of the Member States and the Commission to carry out their tasks relating to this Regulation on a well-informed basis and to enhance the cooperation between them. 2.   Eudamed shall include the following electronic systems: (a) the electronic system for registration of devices referred to in Article 29(4); (b) the UDI-database referred to in Article 28; (c) the electronic system on registration of economic operators referred to in Article 30; (d) the electronic system on notified bodies and on certificates referred to in Article 57; (e) the electronic system on clinical investigations referred to in Article 73; (f) the electronic system on vigilance and post-market surveillance referred to in Article 92; (g) the electronic system on market surveillance referred to in Article 100. 3.   When designing Eudamed the Commission shall give due consideration to compatibility with national databases and national web-interfaces to allow for import and export of data. 4.   The data shall be entered into Eudamed by the Member States, notified bodies, economic operators and sponsors as specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall provide for technical and administrative support to users of Eudamed. 5.   All the information collated and processed by Eudamed shall be accessible to the Member States and to the Commission. The information shall be accessible to notified bodies, economic operators, sponsors and the public to the extent specified in the provisions on the electronic systems referred to in paragraph 2. The Commission shall ensure that public parts of Eudamed are presented in a user-friendly and easily-searchable format. 6.   Eudamed shall contain personal data only insofar as necessary for the electronic systems referred to in paragraph 2 of this Article to collate and process information in accordance with this Regulation. Personal data shall be kept in a form which permits identification of data subjects for periods no longer than those referred to in Article 10(8). 7.   The Commission and the Member States shall ensure that data subjects may effectively exercise their rights to information, of access, to rectification and to object in accordance with Regulation (EC) No 45/2001 and Directive 95/46/EC, respectively. They shall also ensure that data subjects may effectively exercise the right of access to data relating to them, and the right to have inaccurate or incomplete data corrected and erased. Within their respective responsibilities, the Commission and the Member States shall ensure that inaccurate and unlawfully processed data are deleted, in accordance with the applicable legislation. Corrections and deletions shall be carried out as soon as possible, but no later than 60 days after a request is made by a data subject. 8.   The Commission shall, by means of implementing acts, lay down the detailed arrangements necessary for the setting up and maintenance of Eudamed. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). When adopting those implementing acts, the Commission shall ensure that, as far as possible, the system is developed in such a way as to avoid having to enter the same information twice within the same module or in different modules of the system. 9.   In relation to its responsibilities under this Article and the processing of personal data involved therein, the Commission shall be considered to be the controller of Eudamed and its electronic systems. Article 34 Functionality of Eudamed 1.   The Commission shall, in collaboration with the MDCG, draw up the functional specifications for Eudamed. The Commission shall draw up a plan for the implementation of those specifications by 26 May 2018. That plan shall seek to ensure that Eudamed is fully functional at a date that allows the Commission to publish the notice referred to in paragraph 3 of this Article by 25 March 2020 and that all other relevant deadlines laid down in Article 123 of this Regulation and in Article 113 of Regulation (EU) 2017/746 are met. 2.   The Commission shall, on the basis of an independent audit report, inform the MDCG when it has verified that Eudamed has achieved full functionality and Eudamed meets the functional specifications drawn up pursuant to paragraph 1. 3.   The Commission shall, after consultation with the MDCG and when it is satisfied that the conditions referred to in paragraph 2 have been fulfilled, publish a notice to that effect in the Official Journal of the European Union. CHAPTER IV NOTIFIED BODIES Article 35 Authorities responsible for notified bodies 1.   Any Member State that intends to designate a conformity assessment body as a notified body, or has designated a notified body, to carry out conformity assessment activities under this Regulation shall appoint an authority (‘authority responsible for notified bodies’), which may consist of separate constituent entities under national law and shall be responsible for setting up and carrying out the necessary procedures for the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, including subcontractors and subsidiaries of those bodies. 2.   The authority responsible for notified bodies shall be established, organised and operated so as to safeguard the objectivity and impartiality of its activities and to avoid any conflicts of interests with conformity assessment bodies. 3.   The authority responsible for notified bodies shall be organised in a manner such that each decision relating to designation or notification is taken by personnel different from those who carried out the assessment. 4.   The authority responsible for notified bodies shall not perform any activities that notified bodies perform on a commercial or competitive basis. 5.   The authority responsible for notified bodies shall safeguard the confidential aspects of the information it obtains. However, it shall exchange information on notified bodies with other Member States, the Commission and, when required, with other regulatory authorities. 6.   The authority responsible for notified bodies shall have a sufficient number of competent personnel permanently available for the proper performance of its tasks. Where the authority responsible for notified bodies is a different authority from the national competent authority for medical devices, it shall ensure that the national authority responsible for medical devices is consulted on relevant matters. 7.   Member States shall make publicly available general information on their measures governing the assessment, designation and notification of conformity assessment bodies and for the monitoring of notified bodies, and on changes which have a significant impact on such tasks. 8.   The authority responsible for notified bodies shall participate in the peer-review activities provided for in Article 48. Article 36 Requirements relating to notified bodies 1.   Notified bodies shall fulfil the tasks for which they are designated in accordance with this Regulation. They shall satisfy the organisational and general requirements and the quality management, resource and process requirements that are necessary to fulfil those tasks. In particular, notified bodies shall comply with Annex VII. In order to meet the requirements referred to in the first subparagraph, notified bodies shall have permanent availability of sufficient administrative, technical and scientific personnel in accordance with Section 3.1.1 of Annex VII and personnel with relevant clinical expertise in accordance with Section 3.2.4 of Annex VII, where possible employed by the notified body itself. The personnel referred to in Sections 3.2.3 and 3.2.7 of Annex VII shall be employed by the notified body itself and shall not be external experts or subcontractors. 2.   Notified bodies shall make available and submit upon request all relevant documentation, including the manufacturer's documentation, to the authority responsible for notified bodies to allow it to conduct its assessment, designation, notification, monitoring and surveillance activities and to facilitate the assessment outlined in this Chapter. 3.   In order to ensure the uniform application of the requirements set out in Annex VII, the Commission may adopt implementing acts, to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 37 Subsidiaries and subcontracting 1.   Where a notified body subcontracts specific tasks connected with conformity assessment or has recourse to a subsidiary for specific tasks connected with conformity assessment, it shall verify that the subcontractor or the subsidiary meets the applicable requirements set out in Annex VII and shall inform the authority responsible for notified bodies accordingly. 2.   Notified bodies shall take full responsibility for the tasks performed on their behalf by subcontractors or subsidiaries. 3.   Notified bodies shall make publicly available a list of their subsidiaries. 4.   Conformity assessment activities may be subcontracted or carried out by a subsidiary provided that the legal or natural person that applied for conformity assessment has been informed accordingly. 5.   Notified bodies shall keep at the disposal of the authority responsible for notified bodies all relevant documents concerning the verification of the qualifications of the subcontractor or the subsidiary and the work carried out by them under this Regulation. Article 38 Application by conformity assessment bodies for designation 1.   Conformity assessment bodies shall submit an application for designation to the authority responsible for notified bodies. 2.   The application shall specify the conformity assessment activities as defined in this Regulation, and the types of devices for which the body is applying to be designated, and shall be supported by documentation demonstrating compliance with Annex VII. In respect of the organisational and general requirements and the quality management requirements set out in Sections 1 and 2 of Annex VII, a valid accreditation certificate and the corresponding evaluation report delivered by a national accreditation body in accordance with Regulation (EC) No 765/2008 may be submitted and shall be taken into consideration during the assessment described in Article 39. However, the applicant shall make available all the documentation referred to in the first subparagraph to demonstrate compliance with those requirements upon request. 3.   The notified body shall update the documentation referred to in paragraph 2 whenever relevant changes occur, in order to enable the authority responsible for notified bodies to monitor and verify continuous compliance with all the requirements set out in Annex VII. Article 39 Assessment of the application 1.   The authority responsible for notified bodies shall within 30 days check that the application referred to in Article 38 is complete and shall request the applicant to provide any missing information. Once the application is complete that authority shall send it to the Commission. The authority responsible for notified bodies shall review the application and supporting documentation in accordance with its own procedures and shall draw up a preliminary assessment report. 2.   The authority responsible for notified bodies shall submit the preliminary assessment report to the Commission which shall immediately transmit it to the MDCG. 3.   Within 14 days of the submission referred to in paragraph 2 of this Article, the Commission, in conjunction with the MDCG, shall appoint a joint assessment team made up of three experts, unless the specific circumstances require a different number of experts, chosen from the list referred to in Article 40(2). One of the experts shall be a representative of the Commission who shall coordinate the activities of the joint assessment team. The other two experts shall come from Member States other than the one in which the applicant conformity assessment body is established. The joint assessment team shall be comprised of experts who are competent to assess the conformity assessment activities and the types of devices which are the subject of the application or, in particular when the assessment procedure is initiated in accordance with Article 47(3), to ensure that the specific concern can be appropriately assessed. 4.   Within 90 days of its appointment, the joint assessment team shall review the documentation submitted with the application in accordance with Article 38. The joint assessment team may provide feedback to, or require clarification from, the authority responsible for notified bodies on the application and on the planned on-site assessment. The authority responsible for notified bodies together with the joint assessment team shall plan and conduct an on-site assessment of the applicant conformity assessment body and, where relevant, of any subsidiary or subcontractor, located inside or outside the Union, to be involved in the conformity assessment process. The on-site assessment of the applicant body shall be led by the authority responsible for notified bodies. 5.   Findings regarding non-compliance of an applicant conformity assessment body with the requirements set out in Annex VII shall be raised during the assessment process and discussed between the authority responsible for notified bodies and the joint assessment team with a view to reaching consensus and resolving any diverging opinions, with respect to the assessment of the application. At the end of the on-site assessment, the authority responsible for notified bodies shall list for the applicant conformity assessment body the non-compliances resulting from the assessment and summarise the assessment by the joint assessment team. Within a specified timeframe, the applicant conformity assessment body shall submit to the national authority a corrective and preventive action plan to address the non-compliances. 6.   The joint assessment team shall document any remaining diverging opinions with respect to the assessment within 30 days of completion of the on-site assessment and send them to the authority responsible for notified bodies. 7.   The authority responsible for notified bodies shall following receipt of a corrective and preventive action plan from the applicant body assess whether non-compliances identified during the assessment have been appropriately addressed. This plan shall indicate the root cause of the identified non-compliances and shall include a timeframe for implementation of the actions therein. The authority responsible for notified bodies shall having confirmed the corrective and preventive action plan forward it and its opinion thereon to the joint assessment team. The joint assessment team may request of the authority responsible for notified bodies further clarification and modifications. The authority responsible for notified bodies shall draw up its final assessment report which shall include: — the result of the assessment, — confirmation that the corrective and preventive actions have been appropriately addressed and, where required, implemented, — any remaining diverging opinion with the joint assessment team, and, where applicable, — the recommended scope of designation. 8.   The authority responsible for notified bodies shall submit its final assessment report and, if applicable, the draft designation to the Commission, the MDCG and the joint assessment team. 9.   The joint assessment team shall provide a final opinion regarding the assessment report prepared by the authority responsible for notified bodies and, if applicable, the draft designation within 21 days of receipt of those documents to the Commission, which shall immediately submit that final opinion to the MDCG. Within 42 days of receipt of the opinion of the joint assessment team, the MDCG shall issue a recommendation with regard to the draft designation, which the authority responsible for notified bodies shall duly take into consideration for its decision on the designation of the notified body. 10.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements specifying procedures and reports for the application for designation referred to in Article 38 and the assessment of the application set out in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 40 Nomination of experts for joint assessment of applications for notification 1.   The Member States and the Commission shall nominate experts qualified in the assessment of conformity assessment bodies in the field of medical devices to participate in the activities referred to in Articles 39 and 48. 2.   The Commission shall maintain a list of the experts nominated pursuant to paragraph 1 of this Article, together with information on their specific field of competence and expertise. That list shall be made available to Member States competent authorities through the electronic system referred to in Article 57. Article 41 Language requirements All documents required pursuant to Articles 38 and 39 shall be drawn up in a language or languages which shall be determined by the Member State concerned. Member States, in applying the first paragraph, shall consider accepting and using a commonly understood language in the medical field, for all or part of the documentation concerned. The Commission shall provide translations of the documentation pursuant to Articles 38 and 39, or parts thereof into an official Union language, such as is necessary for that documentation to be readily understood by the joint assessment team appointed in accordance with Article 39(3). Article 42 Designation and notification procedure 1.   Member States may only designate conformity assessment bodies for which the assessment pursuant to Article 39 was completed and which comply with Annex VII. 2.   Member States shall notify the Commission and the other Member States of the conformity assessment bodies they have designated, using the electronic notification tool within the database of notified bodies developed and managed by the Commission (NANDO). 3.   The notification shall clearly specify, using the codes referred to in paragraph 13 of this Article, the scope of the designation indicating the conformity assessment activities as defined in this Regulation and the types of devices which the notified body is authorised to assess and, without prejudice to Article 44, any conditions associated with the designation. 4.   The notification shall be accompanied by the final assessment report of the authority responsible for notified bodies, the final opinion of the joint assessment team referred to in Article 39(9) and the recommendation of the MDCG. Where the notifying Member State does not follow the recommendation of the MDCG, it shall provide a duly substantiated justification. 5.   The notifying Member State shall, without prejudice to Article 44, inform the Commission and the other Member States of any conditions associated with the designation and provide documentary evidence regarding the arrangements in place to ensure that the notified body will be monitored regularly and will continue to satisfy the requirements set out in Annex VII. 6.   Within 28 days of the notification referred to in paragraph 2, a Member State or the Commission may raise written objections, setting out its arguments, with regard either to the notified body or to its monitoring by the authority responsible for notified bodies. Where no objection is raised, the Commission shall publish in NANDO the notification within 42 days of its having been notified as referred to in paragraph 2. 7.   When a Member State or the Commission raises objections in accordance with paragraph 6, the Commission shall bring the matter before the MDCG within 10 days of the expiry of the period referred to in paragraph 6. After consulting the parties involved, the MDCG shall give its opinion at the latest within 40 days of the matter having been brought before it. Where the MDCG is of the opinion that the notification can be accepted, the Commission shall publish in NANDO the notification within 14 days. 8.   Where the MDCG, after having been consulted in accordance with paragraph 7, confirms the existing objection or raises another objection, the notifying Member State shall provide a written response to the MDCG opinion within 40 days of its receipt. The response shall address the objections raised in the opinion, and set out the reasons for the notifying Member State's decision to designate or not designate the conformity assessment body. 9.   Where the notifying Member State decides to uphold its decision to designate the conformity assessment body, having given its reasons in accordance with paragraph 8, the Commission shall publish in NANDO the notification within 14 days of being informed thereof. 10.   When publishing the notification in NANDO, the Commission shall also add to the electronic system referred to in Article 57 the information relating to the notification of the notified body along with the documents mentioned in paragraph 4 of this Article and the opinion and responses referred to in paragraphs 7 and 8 of this Article. 11.   The designation shall become valid the day after the notification is published in NANDO. The published notification shall state the scope of lawful conformity assessment activity of the notified body. 12.   The conformity assessment body concerned may perform the activities of a notified body only after the designation has become valid in accordance with paragraph 11. 13.   The Commission shall by 26 November 2017, by means of implementing acts, draw up a list of codes and corresponding types of devices for the purpose of specifying the scope of the designation of notified bodies. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). The Commission, after consulting the MDCG, may update this list based, inter alia, on information arising from the coordination activities described in Article 48. Article 43 Identification number and list of notified bodies 1.   The Commission shall assign an identification number to each notified body for which the notification becomes valid in accordance with Article 42(11). It shall assign a single identification number even when the body is notified under several Union acts. If they are successfully designated in accordance with this Regulation, bodies notified pursuant to Directives 90/385/EEC and 93/42/EEC shall retain the identification number assigned to them pursuant to those Directives. 2.   The Commission shall make the list of the bodies notified under this Regulation, including the identification numbers that have been assigned to them and the conformity assessment activities as defined in this Regulation and the types of devices for which they have been notified, accessible to the public in NANDO. It shall also make this list available on the electronic system referred to in Article 57. The Commission shall ensure that the list is kept up to date. Article 44 Monitoring and re-assessment of notified bodies 1.   Notified bodies shall, without delay, and at the latest within 15 days, inform the authority responsible for notified bodies of relevant changes which may affect their compliance with the requirements set out in Annex VII or their ability to conduct the conformity assessment activities relating to the devices for which they have been designated. 2.   The authorities responsible for notified bodies shall monitor the notified bodies established on their territory and their subsidiaries and subcontractors to ensure ongoing compliance with the requirements and the fulfilment of its obligations set out in this Regulation. Notified bodies shall, upon request by their authority responsible for notified bodies, supply all relevant information and documents, required to enable the authority, the Commission and other Member States to verify compliance. 3.   Where the Commission or the authority of a Member State submits a request to a notified body established on the territory of another Member State relating to a conformity assessment carried out by that notified body, it shall send a copy of that request to the authority responsible for notified bodies of that other Member State. The notified body concerned shall respond without delay and within 15 days at the latest to the request. The authority responsible for notified bodies of the Member State in which the body is established shall ensure that requests submitted by authorities of any other Member State or by the Commission are resolved by the notified body unless there is a legitimate reason for not doing so in which case the matter may be referred to the MDCG. 4.   At least once a year, the authorities responsible for notified bodies shall re-assess whether the notified bodies established on their respective territory and, where appropriate, the subsidiaries and subcontractors under the responsibility of those notified bodies still satisfy the requirements and fulfil their obligations set out in Annex VII. That review shall include an on-site audit of each notified body and, where necessary, of its subsidiaries and subcontractors. The authority responsible for notified bodies shall conduct its monitoring and assessment activities according to an annual assessment plan to ensure that it can effectively monitor the continued compliance of the notified body with the requirements of this Regulation. That plan shall provide a reasoned schedule for the frequency of assessment of the notified body and, in particular, associated subsidiaries and subcontractors. The authority shall submit its annual plan for monitoring or assessment for each notified body for which it is responsible to the MDCG and to the Commission. 5.   The monitoring of notified bodies by the authority responsible for notified bodies shall include observed audits of notified body personnel, including where necessary any personnel from subsidiaries and subcontractors, as that personnel is in the process of conducting quality management system assessments at a manufacturer's facility. 6.   The monitoring of notified bodies conducted by the authority responsible for notified bodies shall consider data arising from market surveillance, vigilance and post-market surveillance to help guide its activities. The authority responsible for notified bodies shall provide for a systematic follow-up of complaints and other information, including from other Member States, which may indicate non-fulfilment of the obligations by a notified body or its deviation from common or best practice. 7.   The authority responsible for notified bodies may in addition to regular monitoring or on-site assessments conduct short-notice, unannounced or ‘for-cause’ reviews if needed to address a particular issue or to verify compliance. 8.   The authority responsible for notified bodies shall review the assessments by notified bodies of manufacturers' technical documentation, in particular the clinical evaluation documentation as further outlined in Article 45. 9.   The authority responsible for notified bodies shall document and record any findings regarding non-compliance of the notified body with the requirements set out in Annex VII and shall monitor the timely implementation of corrective and preventive actions. 10.   Three years after notification of a notified body, and again every fourth year thereafter, a complete re-assessment to determine whether the notified body still satisfies the requirements set out in Annex VII shall be conducted by the authority responsible for notified bodies of the Member State in which the body is established and by a joint assessment team appointed for the purpose of the procedure described in Articles 38 and 39. 11.   The Commission is empowered to adopt delegated acts in accordance with Article 115 in order to amend paragraph 10 to modify the frequency at which the complete re-assessment referred to in that paragraph is to be carried out. 12.   The Member States shall report to the Commission and to the MDCG, at least once a year, on their monitoring and on-site assessment activities regarding notified bodies and, where applicable, subsidiaries and subcontractors. The report shall provide details of the outcome of those activities, including activities pursuant to paragraph 7, and shall be treated as confidential by the MDCG and the Commission; however it shall contain a summary which shall be made publicly available. The summary of the report shall be uploaded to the electronic system referred to in Article 57. Article 45 Review of notified body assessment of technical documentation and clinical evaluation documentation 1.   The authority responsible for notified bodies, as part of its ongoing monitoring of notified bodies, shall review an appropriate number of notified body assessments of manufacturers' technical documentation, in particular the clinical evaluation documentation as referred to in points (c) and (d) of Section 6.1 of Annex II to verify the conclusions drawn by the notified body based on the information presented by the manufacturer. The reviews by the authority responsible for notified bodies shall be conducted both off-site and on-site. 2.   The sampling of files to be reviewed in accordance with paragraph 1 shall be planned and representative of the types and risk of devices certified by the notified body, in particular high-risk devices, and be appropriately justified and documented in a sampling plan, which shall be made available by the authority responsible for notified bodies to the MDCG upon request. 3.   The authority responsible for notified bodies shall review whether the assessment by the notified body was conducted appropriately and shall check the procedures used, associated documentation and the conclusions drawn by the notified body. Such checking shall include the technical documentation and clinical evaluation documentation of the manufacturer upon which the notified body has based its assessment. Such reviews shall be conducted utilising CS. 4.   Those reviews shall also form part of the re-assessment of notified bodies in accordance with Article 44(10) and the joint assessment activities referred to in Article 47(3). The reviews shall be conducted utilising appropriate expertise. 5.   Based on the reports of the reviews and assessments by the authority responsible for notified bodies or joint assessment teams, on input from the market surveillance, vigilance and post-market surveillance activities described in Chapter VII, on the continuous monitoring of technical progress, or on the identification of concerns and emerging issues concerning the safety and performance of devices, the MDCG may recommend that the sampling, carried out under this Article, cover a greater or lesser proportion of the technical documentation and clinical evaluation documentation assessed by a notified body. 6.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements, associated documents for, and coordination of, the review of assessments of technical documentation and clinical evaluation documentation, as referred to in this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 46 Changes to designations and notifications 1.   The authority responsible for notified bodies shall notify the Commission and the other Member States of any relevant changes to the designation of a notified body. The procedures described in Article 39 and in Article 42 shall apply to extensions of the scope of the designation. For changes to the designation other than extensions of its scope, the procedures laid down in the following paragraphs shall apply. 2.   The Commission shall immediately publish the amended notification in NANDO. The Commission shall immediately enter information on the changes to the designation of the notified body in the electronic system referred to in Article 57. 3.   Where a notified body decides to cease its conformity assessment activities it shall inform the authority responsible for notified bodies and the manufacturers concerned as soon as possible and in the case of a planned cessation one year before ceasing its activities. The certificates may remain valid for a temporary period of nine months after cessation of the notified body's activities on condition that another notified body has confirmed in writing that it will assume responsibilities for the devices covered by those certificates. The new notified body shall complete a full assessment of the devices affected by the end of that period before issuing new certificates for those devices. Where the notified body has ceased its activity, the authority responsible for notified bodies shall withdraw the designation. 4.   Where a authority responsible for notified bodies has ascertained that a notified body no longer meets the requirements set out in Annex VII, or that it is failing to fulfil its obligations or has not implemented the necessary corrective measures, the authority shall suspend, restrict, or fully or partially withdraw the designation, depending on the seriousness of the failure to meet those requirements or fulfil those obligations. A suspension shall not exceed a period of one year, renewable once for the same period. The authority responsible for notified bodies shall immediately inform the Commission and the other Member States of any suspension, restriction or withdrawal of a designation. 5.   Where its designation has been suspended, restricted, or fully or partially withdrawn, the notified body shall inform the manufacturers concerned at the latest within 10 days. 6.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall take appropriate steps to ensure that the files of the notified body concerned are kept and make them available to authorities in other Member States responsible for notified bodies and to authorities responsible for market surveillance at their request. 7.   In the event of restriction, suspension or withdrawal of a designation, the authority responsible for notified bodies shall: (a) assess the impact on the certificates issued by the notified body; (b) submit a report on its findings to the Commission and the other Member States within three months of having notified the changes to the designation; (c) require the notified body to suspend or withdraw, within a reasonable period of time determined by the authority, any certificates which were unduly issued to ensure the safety of devices on the market; (d) enter into the electronic system referred to in Article 57 information in relation to certificates of which it has required their suspension or withdrawal; (e) inform the competent authority for medical devices of the Member State in which the manufacturer has its registered place of business through the electronic system referred to in Article 57 of the certificates for which it has required suspension or withdrawal. That competent authority shall take the appropriate measures, where necessary to avoid a potential risk to the health or safety of patients, users or others. 8.   With the exception of certificates unduly issued, and where a designation has been suspended or restricted, the certificates shall remain valid in the following circumstances: (a) the authority responsible for notified bodies has confirmed, within one month of the suspension or restriction, that there is no safety issue in relation to certificates affected by the suspension or restriction, and the authority responsible for notified bodies has outlined a timeline and actions anticipated to remedy the suspension or restriction; or (b) the authority responsible for notified bodies has confirmed that no certificates relevant to the suspension will be issued, amended or re-issued during the course of the suspension or restriction, and states whether the notified body has the capability of continuing to monitor and remain responsible for existing certificates issued for the period of the suspension or restriction. In the event that the authority responsible for notified bodies determines that the notified body does not have the capability to support existing certificates issued, the manufacturer shall provide, to the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business, within three months of the suspension or restriction, a written confirmation that another qualified notified body is temporarily assuming the functions of the notified body to monitor and remain responsible for the certificates during the period of suspension or restriction. 9.   With the exception of certificates unduly issued, and where a designation has been withdrawn, the certificates shall remain valid for a period of nine months in the following circumstances: (a) where the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its registered place of business has confirmed that there is no safety issue associated with the devices in question; and (b) another notified body has confirmed in writing that it will assume immediate responsibilities for those devices and will have completed assessment of them within twelve months of the withdrawal of the designation. In the circumstances referred to in the first subparagraph, the competent authority for medical devices of the Member State in which the manufacturer of the device covered by the certificate has its place of business may extend the provisional validity of the certificates for further periods of three months, which altogether shall not exceed twelve months. The authority or the notified body assuming the functions of the notified body affected by the change of designation shall immediately inform the Commission, the other Member States and the other notified bodies thereof. Article 47 Challenge to the competence of notified bodies 1.   The Commission, in conjunction with the MDCG, shall investigate all cases where concerns have been brought to its attention regarding the continued fulfilment by a notified body, or of one or more of its subsidiaries or subcontractors, of the requirements set out in Annex VII or the obligations to which they are subject. It shall ensure that the relevant authority responsible for notified bodies is informed and is given an opportunity to investigate those concerns. 2.   The notifying Member State shall provide the Commission, on request, with all information regarding the designation of the notified body concerned. 3.   The Commission, in conjunction with the MDCG, may initiate, as applicable, the assessment procedure described in Article 39(3) and (4), where there is reasonable concern about the ongoing compliance of a notified body or a subsidiary or subcontractor of the notified body with the requirements set out in Annex VII and where the investigation by the authority responsible for notified bodies is not deemed to have fully addressed the concerns or upon request of the authority responsible for notified bodies. The reporting and outcome of that assessment shall follow the principles of Article 39. Alternatively, depending on the severity of the issue, the Commission, in conjunction with the MDCG, may request that the authority responsible for notified bodies allow the participation of up to two experts from the list established pursuant to Article 40 in an on-site assessment as part of the planned monitoring and assessment activities in accordance with Article 44 and as outlined in the annual assessment plan described in Article 44(4). 4.   Where the Commission ascertains that a notified body no longer meets the requirements for its designation, it shall inform the notifying Member State accordingly and request it to take the necessary corrective measures, including the suspension, restriction or withdrawal of the designation if necessary. Where the Member State fails to take the necessary corrective measures, the Commission may, by means of implementing acts, suspend, restrict or withdraw the designation. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). It shall notify the Member State concerned of its decision and update NANDO and the electronic system referred to in Article 57. 5.   The Commission shall ensure that all confidential information obtained in the course of its investigations is treated accordingly. Article 48 Peer review and exchange of experience between authorities responsible for notified bodies 1.   The Commission shall provide for the organisation of exchange of experience and coordination of administrative practice between the authorities responsible for notified bodies. Such exchange shall cover elements including: (a) development of best practice documents relating to the activities of the authorities responsible for notified bodies; (b) development of guidance documents for notified bodies in relation to the implementation of this Regulation; (c) training and qualification of the experts referred to in Article 40; (d) monitoring of trends relating to changes to notified body designations and notifications and trends in certificate withdrawals and transfers between notified bodies; (e) monitoring of the application and applicability of scope codes referred to in Article 42(13); (f) development of a mechanism for peer reviews between authorities and the Commission; (g) methods of communication to the public on the monitoring and surveillance activities of authorities and the Commission on notified bodies. 2.   The authorities responsible for notified bodies shall participate in a peer review every third year through the mechanism developed pursuant to paragraph 1 of this Article. Such reviews shall normally be conducted in parallel with the on-site joint assessments described in Article 39. Alternatively, an authority may make the choice of having such reviews take place as part of its monitoring activities referred to in Article 44. 3.   The Commission shall participate in the organisation and provide support to the implementation of the peer review mechanism. 4.   The Commission shall compile an annual summary report of the peer review activities, which shall be made publicly available. 5.   The Commission may, by means of implementing acts, adopt measures setting out the detailed arrangements and related documents for the peer review mechanism and training and qualification as referred to in paragraph 1 of this Article. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 49 Coordination of notified bodies The Commission shall ensure that appropriate coordination and cooperation between notified bodies is put in place and operated in the form of a coordination group of notified bodies in the field of medical devices, including in vitro diagnostic medical devices. This group shall meet on a regular basis and at least annually. The bodies notified under this Regulation shall participate in the work of that group. The Commission may establish the specific arrangements for the functioning of the coordination group of notified bodies. Article 50 List of standard fees Notified bodies shall establish lists of their standard fees for the conformity assessment activities that they carry out and shall make those lists publicly available. CHAPTER V CLASSIFICATION AND CONFORMITY ASSESSMENT SECTION 1 Classification Article 51 Classification of devices 1.   Devices shall be divided into classes I, IIa, IIb and III, taking into account the intended purpose of the devices and their inherent risks. Classification shall be carried out in accordance with Annex VIII. 2.   Any dispute between the manufacturer and the notified body concerned, arising from the application of Annex VIII, shall be referred for a decision to the competent authority of the Member State in which the manufacturer has its registered place of business. In cases where the manufacturer has no registered place of business in the Union and has not yet designated an authorised representative, the matter shall be referred to the competent authority of the Member State in which the authorised representative referred to in the last indent of point (b) of the second paragraph of Section 2.2 of Annex IX has its registered place of business. Where the notified body concerned is established in a Member State other than that of the manufacturer, the competent authority shall adopt its decision after consultation with the competent authority of the Member State that designated the notified body. The competent authority of the Member State in which the manufacturer has its registered place of business shall notify the MDCG and the Commission of its decision. The decision shall be made available upon request. 3.   At the request of a Member State the Commission shall after consulting the MDCG, decide, by means of implementing acts, on the following: (a) application of Annex VIII to a given device, or category or group of devices, with a view to determining the classification of such devices; (b) that a device, or category or group of devices, shall for reasons of public health based on new scientific evidence, or based on any information which becomes available in the course of the vigilance and market surveillance activities be reclassified, by way of derogation from Annex VIII. 4.   The Commission may also, on its own initiative and after consulting the MDCG, decide, by means of implementing acts, on the issues referred to in points (a) and (b) of paragraph 3. 5.   In order to ensure the uniform application of Annex VIII, and taking account of the relevant scientific opinions of the relevant scientific committees, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. 6.   The implementing acts referred to in paragraphs 3, 4 and 5 of this Article shall be adopted in accordance with the examination procedure referred to in Article 114(3). SECTION 2 Conformity assessment Article 52 Conformity assessment procedures 1.   Prior to placing a device on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 2.   Prior to putting into service a device that is not placed on the market, manufacturers shall undertake an assessment of the conformity of that device, in accordance with the applicable conformity assessment procedures set out in Annexes IX to XI. 3.   Manufacturers of class III devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Annex X coupled with a conformity assessment as specified in Annex XI. 4.   Manufacturers of class IIb devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device per generic device group. However, for class IIb implantable devices, except sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors, the assessment of the technical documentation as specified in Section 4 of Annex IX shall apply for every device. Alternatively, the manufacturer may choose to apply a conformity assessment based on type examination as specified in Annex X coupled with a conformity assessment based on product conformity verification as specified in Annex XI. 5.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in the second subparagraph of paragraph 4 of this Article, being used in other class IIb implantable devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend that list by adding other types of class IIb implantable devices to that list or removing devices therefrom. 6.   Manufacturers of class IIa devices, other than custom-made or investigational devices, shall be subject to a conformity assessment as specified in Chapters I and III of Annex IX, and including an assessment of the technical documentation as specified in Section 4 of that Annex of at least one representative device for each category of devices. Alternatively, the manufacturer may choose to draw up the technical documentation set out in Annexes II and III coupled with a conformity assessment as specified in Section 10 or Section 18 of Annex XI. The assessment of the technical documentation shall apply for at least one representative device for each category of devices. 7.   Manufacturers of class I devices, other than custom-made or investigational devices, shall declare the conformity of their products by issuing the EU declaration of conformity referred to in Article 19 after drawing up the technical documentation set out in Annexes II and III. If those devices are placed on the market in sterile condition, have a measuring function or are reusable surgical instruments, the manufacturer shall apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI. However, the involvement of the notified body in those procedures shall be limited: (a) in the case of devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions; (b) in the case of devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements; (c) in the case of reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use. 8.   Manufacturers of custom-made devices shall follow the procedure set out in Annex XIII and draw up the statement set out in Section 1 of that Annex before placing such devices on the market. In addition to the procedure applicable pursuant to the first subparagraph, manufacturers of class III custom-made implantable devices shall be subject to the conformity assessment as specified in Chapter I of Annex IX. Alternatively, the manufacturer may choose to apply a conformity assessment as specified in Part A of Annex XI. 9.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices referred to in the first subparagraph of Article 1(8), the procedure specified in Section 5.2 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 10.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7 of this Article, in the case of devices that are covered by this Regulation in accordance with point (f) or (g) of Article 1(6) and with the first subparagraph of Article 1(10), the procedure specified in Section 5.3 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 11.   In addition to the procedures applicable pursuant to paragraph 3, 4, 6, or 7, in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the procedure specified in Section 5.4 of Annex IX or Section 6 of Annex X, as applicable, shall also apply. 12.   The Member State in which the notified body is established may require that all or certain documents, including the technical documentation, audit, assessment and inspection reports, relating to the procedures referred to in paragraphs 1 to 7 and 9 to 11 be made available in an official Union language(s) determined by that Member State. In the absence of such requirement, those documents shall be available in any official Union language acceptable to the notified body. 13.   Investigational devices shall be subject to the requirements set out in Articles 62 to 81. 14.   The Commission may, by means of implementing acts, specify detailed arrangements and procedural aspects with a view to ensuring the harmonised application of the conformity assessment procedures by the notified bodies for any of the following aspects: (a) the frequency and the sampling basis of the assessment of the technical documentation on a representative basis as set out in the third paragraph of Section 2.3 and in Section 3.5 of Annex IX in the case of class IIa and class IIb devices, and in Section 10.2 of Annex XI in the case of class IIa devices; (b) the minimum frequency of unannounced on-site audits and sample tests to be conducted by notified bodies in accordance with Section 3.4 of Annex IX, taking into account the risk-class and the type of device; (c) the physical, laboratory or other tests to be carried out by notified bodies in the context of sample tests, assessment of the technical documentation and type examination in accordance with Sections 3.4 and 4.3 of Annex IX, Section 3 of Annex X and Section 15 of Annex XI. The implementing acts referred to in the first subparagraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 53 Involvement of notified bodies in conformity assessment procedures 1.   Where the conformity assessment procedure requires the involvement of a notified body, the manufacturer may apply to a notified body of its choice, provided that the chosen notified body is designated for conformity assessment activities related to the types of devices concerned. The manufacturer may not lodge an application in parallel with another notified body for the same conformity assessment procedure. 2.   The notified body concerned shall, by means of the electronic system referred to in Article 57, inform the other notified bodies of any manufacturer that withdraws its application prior to the notified body's decision regarding the conformity assessment. 3.   When applying to a notified body under paragraph 1, manufacturers shall declare whether they have withdrawn an application with another notified body prior to the decision of that notified body and provide information about any previous application for the same conformity assessment that has been refused by another notified body. 4.   The notified body may require any information or data from the manufacturer, which is necessary in order to properly conduct the chosen conformity assessment procedure. 5.   Notified bodies and the personnel of notified bodies shall carry out their conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific field and shall be free from all pressures and inducements, particularly financial, which might influence their judgement or the results of their conformity assessment activities, especially as regards persons or groups with an interest in the results of those activities. Article 54 Clinical evaluation consultation procedure for certain class III and class IIb devices 1.   In addition to the procedures applicable pursuant to Article 52, a notified body shall also follow the procedure regarding clinical evaluation consultation as specified in Section 5.1 of Annex IX or as referred to in Section 6 of Annex X, as applicable, when performing a conformity assessment of the following devices: (a) class III implantable devices, and (b) class IIb active devices intended to administer and/or remove a medicinal product, as referred to in Section 6.4 of Annex VIII (Rule 12). 2.   The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not adversely affect the benefit-risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device. 3.   The notified body shall notify the competent authorities, the authority responsible for notified bodies and the Commission through the electronic system referred to in Article 57 of whether or not the procedure referred to in paragraph 1 of this Article is to be applied. That notification shall be accompanied by the clinical evaluation assessment report. 4.   The Commission shall draw up an annual overview of devices which have been subject to the procedure specified in Section 5.1 of Annex IX and referred to in Section 6 of Annex X. The annual overview shall include the notifications in accordance with paragraph 3 of this Article and point (e) of Section 5.1 of Annex IX and a listing of the cases where the notified body did not follow the advice from the expert panel. The Commission shall submit this overview to the European Parliament, to the Council and to the MDCG. 5.   The Commission shall by 27 May 2025 draw up a report on the operation of this Article and submit it to the European Parliament and to the Council. The report shall take into account the annual overviews and any available relevant recommendations from the MDCG. On the basis of that report the Commission shall, if appropriate, make proposals for amendments to this Regulation. Article 55 Mechanism for scrutiny of conformity assessments of certain class III and class IIb devices 1.   A notified body shall notify the competent authorities of certificates it has granted to devices for which the conformity assessment has been performed pursuant to Article 54(1). Such notification shall take place through the electronic system referred to in Article 57 and shall include the summary of safety and clinical performance pursuant to Article 32, the assessment report by the notified body, the instructions for use referred to in Section 23.4 of Annex I, and, where applicable, the scientific opinion of the expert panels referred to in Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. In the case of divergent views between the notified body and the expert panels, a full justification shall also be included. 2.   A competent authority and, where applicable, the Commission may, based on reasonable concerns apply further procedures in accordance with Article 44, 45, 46, 47 or 94 and, where deemed necessary, take appropriate measures in accordance with Articles 95 and 97. 3.   The MDCG and, where applicable, the Commission, may, based on reasonable concerns, request scientific advice from the expert panels in relation to the safety and performance of any device. Article 56 Certificates of conformity 1.   The certificates issued by the notified bodies in accordance with Annexes IX, X and XI shall be in an official Union language determined by the Member State in which the notified body is established or otherwise in an official Union language acceptable to the notified body. The minimum content of the certificates shall be as set out in Annex XII. 2.   The certificates shall be valid for the period they indicate, which shall not exceed five years. On application by the manufacturer, the validity of the certificate may be extended for further periods, each not exceeding five years, based on a re-assessment in accordance with the applicable conformity assessment procedures. Any supplement to a certificate shall remain valid as long as the certificate which it supplements is valid. 3.   Notified bodies may impose restrictions to the intended purpose of a device to certain groups of patients or require manufacturers to undertake specific PMCF studies pursuant to Part B of Annex XIV. 4.   Where a notified body finds that the requirements of this Regulation are no longer met by the manufacturer, it shall, taking account of the principle of proportionality, suspend or withdraw the certificate issued or impose any restrictions on it unless compliance with such requirements is ensured by appropriate corrective action taken by the manufacturer within an appropriate deadline set by the notified body. The notified body shall give the reasons for its decision. 5.   The notified body shall enter in the electronic system referred to in Article 57 any information regarding certificates issued, including amendments and supplements thereto, and regarding suspended, reinstated, withdrawn or refused certificates and restrictions imposed on certificates. Such information shall be accessible to the public. 6.   In the light of technical progress, the Commission is empowered to adopt delegated acts in accordance with Article 115 amending the minimum content of the certificates set out in Annex XII. Article 57 Electronic system on notified bodies and on certificates of conformity 1.   The Commission, after consulting the MDCG, shall set up and manage an electronic system to collate and process the following information: (a) the list of subsidiaries referred to in Article 37(3); (b) the list of experts referred to in Article 40(2); (c) the information relating to the notification referred to in Article 42(10) and the amended notifications referred to in Article 46(2); (d) the list of notified bodies referred to in Article 43(2); (e) the summary of the report referred to in Article 44(12); (f) the notifications for conformity assessments and certificates referred to in Articles 54(3) and 55(1); (g) withdrawal or refusals of applications for the certificates as referred to in Article 53(2) and Section 4.3 of Annex VII; (h) the information regarding certificates referred to in Article 56(5); (i) the summary of safety and clinical performance referred to in Article 32. 2.   The information collated and processed by the electronic system shall be accessible to the competent authorities of the Member States, to the Commission, where appropriate to the notified bodies and where provided elsewhere in this regulation or in Regulation (EU) 2017/746 to the public. Article 58 Voluntary change of notified body 1.   In cases where a manufacturer terminates its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device, the detailed arrangements for the change of notified body shall be clearly defined in an agreement between the manufacturer, the incoming notified body and, where practicable the outgoing notified body. That agreement shall cover at least the following aspects: (a) the date on which the certificates issued by the outgoing notified body become invalid; (b) the date until which the identification number of the outgoing notified body may be indicated in the information supplied by the manufacturer, including any promotional material; (c) the transfer of documents, including confidentiality aspects and property rights; (d) the date after which the conformity assessment tasks of the outgoing notified body is assigned to the incoming notified body; (e) the last serial number or lot number for which the outgoing notified body is responsible. 2.   The outgoing notified body shall withdraw the certificates it has issued for the device concerned on the date on which they become invalid. Article 59 Derogation from the conformity assessment procedures 1.   By way of derogation from Article 52, any competent authority may authorise, on a duly justified request, the placing on the market or putting into service within the territory of the Member State concerned, of a specific device for which the procedures referred to in that Article have not been carried out but use of which is in the interest of public health or patient safety or health. 2.   The Member State shall inform the Commission and the other Member States of any decision to authorise the placing on the market or putting into service of a device in accordance with paragraph 1 where such authorisation is granted for use other than for a single patient. 3.   Following a notification pursuant to paragraph 2 of this Article, the Commission, in exceptional cases relating to public health or patient safety or health, may, by means of implementing acts, extend for a limited period of time the validity of an authorisation granted by a Member State in accordance with paragraph 1 of this Article to the territory of the Union and set the conditions under which the device may be placed on the market or put into service. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). On duly justified imperative grounds of urgency relating to the health and safety of humans, the Commission shall adopt immediately applicable implementing acts in accordance with the procedure referred to in Article 114(4). Article 60 Certificate of free sale 1.   For the purpose of export and upon request by a manufacturer or an authorised representative, the Member State in which the manufacturer or the authorised representative has its registered place of business shall issue a certificate of free sale declaring that the manufacturer or the authorised representative, as applicable, has its registered place of business on its territory and that the device in question bearing the CE marking in accordance with this Regulation may be marketed in the Union. The certificate of free sale shall set out the Basic UDI-DI of the device as provided to the UDI database under Article 29. Where a notified body has issued a certificate pursuant to Article 56, the certificate of free sale shall set out the unique number identifying the certificate issued by the notified body, as referred to in Section 3 of Chapter II of Annex XII. 2.   The Commission may, by means of implementing acts, establish a model for certificates of free sale, taking into account international practice as regards the use of certificates of free sale. Those implementing acts shall be adopted in accordance with the advisory procedure referred to in Article 114(2). CHAPTER VI CLINICAL EVALUATION AND CLINICAL INVESTIGATIONS Article 61 Clinical evaluation 1.   Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III. The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose. To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV. 2.   For all class III devices and for the class IIb devices referred to in point (b) of Article 54(1), the manufacturer may, prior to its clinical evaluation and/or investigation, consult an expert panel as referred to in Article 106, with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation. The manufacturer shall give due consideration to the views expressed by the expert panel. Such consideration shall be documented in the clinical evaluation report referred to in paragraph 12 of this Article. The manufacturer may not invoke any rights to the views expressed by the expert panel with regard to any future conformity assessment procedure. 3.   A clinical evaluation shall follow a defined and methodologically sound procedure based on the following: (a) a critical evaluation of the relevant scientific literature currently available relating to the safety, performance, design characteristics and intended purpose of the device, where the following conditions are satisfied: — it is demonstrated that the device subject to clinical evaluation for the intended purpose is equivalent to the device to which the data relate, in accordance with Section 3 of Annex XIV, and — the data adequately demonstrate compliance with the relevant general safety and performance requirements; (b) a critical evaluation of the results of all available clinical investigations, taking duly into consideration whether the investigations were performed under Articles 62 to 80, any acts adopted pursuant to Article 81, and Annex XV; and (c) a consideration of currently available alternative treatment options for that purpose, if any. 4.   In the case of implantable devices and class III devices, clinical investigations shall be performed, except if: — the device has been designed by modifications of a device already marketed by the same manufacturer, — the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and — the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements. In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device. In addition, clinical investigations need not be performed in the cases referred to in paragraph 6. 5.   A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph: — the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and — the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body. 6.   The requirement to perform clinical investigations pursuant to paragraph 4 shall not apply to implantable devices and class III devices: (a) which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation: — is based on sufficient clinical data, and — is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available; or (b) that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific CS, where such a CS is available. 7.   Cases in which paragraph 4 is not applied by virtue of paragraph 6 shall be justified in the clinical evaluation report by the manufacturer and in the clinical evaluation assessment report by the notified body. 8.   Where justified in view of well-established technologies, similar to those used in the exempted devices listed in point (b) of paragraph 6 of this Article, being used in other devices, or where justified in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the list of exempted devices referred to in the second subparagraph of Article 52(4) and in point (b) of paragraph 6 of this Article, by adding other types of implantable or class III devices to that list or removing devices therefrom. 9.   In the case of the products without an intended medical purpose listed in Annex XVI, the requirement to demonstrate a clinical benefit in accordance with this Chapter and Annexes XIV and XV shall be understood as a requirement to demonstrate the performance of the device. Clinical evaluations of those products shall be based on relevant data concerning safety, including data from post-market surveillance, PMCF, and, where applicable, specific clinical investigation. Clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified. 10.   Without prejudice to paragraph 4, where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation referred to in Annex II why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation, to be adequate. 11.   The clinical evaluation and its documentation shall be updated throughout the life cycle of the device concerned with clinical data obtained from the implementation of the manufacturer's PMCF plan in accordance with Part B of Annex XIV and the post-market surveillance plan referred to in Article 84. For class III devices and implantable devices, the PMCF evaluation report and, if indicated, the summary of safety and clinical performance referred to in Article 32 shall be updated at least annually with such data. 12.   The clinical evaluation, its results and the clinical evidence derived from it shall be documented in a clinical evaluation report as referred to in Section 4 of Annex XIV, which, except for custom-made devices, shall be part of the technical documentation referred to in Annex II relating to the device concerned. 13.   Where necessary to ensure the uniform application of Annex XIV, the Commission may, having due regard to technical and scientific progress, adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 62 General requirements regarding clinical investigations conducted to demonstrate conformity of devices 1.   Clinical investigations shall be designed, authorised, conducted, recorded and reported in accordance with the provisions of this Article and of Articles 63 to 80, the acts adopted pursuant to Article 81, and Annex XV, where carried out as part of the clinical evaluation for conformity assessment purposes, for one or more of the following purposes: (a) to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer; (b) to establish and verify the clinical benefits of a device as specified by its manufacturer; (c) to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device. 2.   Where the sponsor of a clinical investigation is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication with that legal representative shall be deemed to be a communication with the sponsor. Member States may choose not to apply the first subparagraph to clinical investigations to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical investigation who shall be the addressee for all communications with the sponsor provided for in this Regulation. 3.   Clinical investigations shall be designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust. Clinical investigations shall be subject to scientific and ethical review. The ethical review shall be performed by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by ethics committees are compatible with the procedures set out in this Regulation for the assessment of the application for authorisation of a clinical investigation. At least one lay person shall participate in the ethical review. 4.   A clinical investigation as referred to in paragraph 1 may be conducted only where all of the following conditions are met: (a) the clinical investigation is the subject of an authorisation by the Member State(s) in which the clinical investigation is to be conducted, in accordance with this Regulation, unless otherwise stated; (b) an ethics committee, set up in accordance with national law, has not issued a negative opinion in relation to the clinical investigation, which is valid for that entire Member State under its national law; (c) the sponsor, or its legal representative or a contact person pursuant to paragraph 2, is established in the Union; (d) vulnerable populations and subjects are appropriately protected in accordance with Articles 64 to 68; (e) the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored; (f) the subject or, where the subject is not able to give informed consent, his or her legally designated representative has given informed consent in accordance with Article 63; (g) the subject or, where the subject is not able to give informed consent, his or her legally designated representative, has been provided with the contact details of an entity where further information can be received in case of need; (h) the rights of the subject to physical and mental integrity, to privacy and to the protection of the data concerning him or her in accordance with Directive 95/46/EC are safeguarded; (i) the clinical investigation has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are specifically defined in the clinical investigation plan and constantly monitored; (j) the medical care provided to the subjects is the responsibility of an appropriately qualified medical doctor or, where appropriate, a qualified dental practitioner or any other person entitled by national law to provide the relevant patient care under clinical investigation conditions; (k) no undue influence, including that of a financial nature, is exerted on the subject, or, where applicable, on his or her legally designated representatives, to participate in the clinical investigation; (l) the investigational device(s) in question conform(s) to the applicable general safety and performance requirements set out in Annex I apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, technical and biological safety testing and pre-clinical evaluation, as well as provisions in the field of occupational safety and accident prevention, taking into consideration the state of the art; (m) the requirements of Annex XV are fulfilled. 5.   Any subject, or, where the subject is not able to give informed consent, his or her legally designated representative, may, without any resulting detriment and without having to provide any justification, withdraw from the clinical investigation at any time by revoking his or her informed consent. Without prejudice to Directive 95/46/EC, the withdrawal of the informed consent shall not affect the activities already carried out and the use of data obtained based on informed consent before its withdrawal. 6.   The investigator shall be a person exercising a profession which is recognised in the Member State concerned as qualifying for the role of investigator on account of having the necessary scientific knowledge and experience in patient care. Other personnel involved in conducting a clinical investigation shall be suitably qualified, by education, training or experience in the relevant medical field and in clinical research methodology, to perform their tasks. 7.   The facilities where the clinical investigation is to be conducted shall be suitable for the clinical investigation and shall be similar to the facilities where the device is intended to be used. Article 63 Informed consent 1.   Informed consent shall be written, dated and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document or the record, as appropriate, by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical investigation. 2.   Information given to the subject or, where the subject is not able to give informed consent, his or her legally designated representative for the purposes of obtaining his or her informed consent shall: (a) enable the subject or his or her legally designated representative to understand: (i) the nature, objectives, benefits, implications, risks and inconveniences of the clinical investigations; (ii) the subject's rights and guarantees regarding his or her protection, in particular his or her right to refuse to participate in and the right to withdraw from the clinical investigation at any time without any resulting detriment and without having to provide any justification; (iii) the conditions under which the clinical investigations is to be conducted, including the expected duration of the subject's participation in the clinical investigation; and (iv) the possible treatment alternatives, including the follow-up measures if the participation of the subject in the clinical investigation is discontinued; (b) be kept comprehensive, concise, clear, relevant, and understandable to the subject or his or her legally designated representative; (c) be provided in a prior interview with a member of the investigating team who is appropriately qualified under national law; (d) include information about the applicable damage compensation system referred to in Article 69; and (e) include the Union-wide unique single identification number of the clinical investigation referred to in Article 70(1) and information about the availability of the clinical investigation results in accordance with paragraph 6 of this Article. 3.   The information referred to in paragraph 2 shall be prepared in writing and be available to the subject or, where the subject is not able to give informed consent, his or her legally designated representative. 4.   In the interview referred to in point (c) of paragraph 2, special attention shall be paid to the information needs of specific patient populations and of individual subjects, as well as to the methods used to give the information. 5.   In the interview referred to in point (c) of paragraph 2, it shall be verified that the subject has understood the information. 6.   The subject shall be informed that a clinical investigation report and a summary presented in terms understandable to the intended user will be made available pursuant to Article 77(5) in the electronic system on clinical investigations referred to in Article 73 irrespective of the outcome of the clinical investigation, and shall be informed, to the extent possible, when they have become available. 7.   This Regulation is without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical investigation. Article 64 Clinical investigations on incapacitated subjects 1.   In the case of incapacitated subjects who have not given, or have not refused to give, informed consent before the onset of their incapacity, a clinical investigation may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the incapacitated subjects have received the information referred to in Article 63(2) in a way that is adequate in view of their capacity to understand it; (c) the explicit wish of an incapacitated subject who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to subjects or their legally designated representatives, except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical investigations on persons able to give informed consent, or by other research methods; (f) the clinical investigation relates directly to a medical condition from which the subject suffers; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the incapacitated subject outweighing the risks and burdens involved. 2.   The subject shall as far as possible take part in the informed consent procedure. Article 65 Clinical investigations on minors A clinical investigation on minors may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the informed consent of their legally designated representative has been obtained; (b) the minors have received the information referred to in Article 63(2) in a way adapted to their age and mental maturity and from investigators or members of the investigating team who are trained or experienced in working with children; (c) the explicit wish of a minor who is capable of forming an opinion and assessing the information referred to in Article 63(2) to refuse participation in, or to withdraw from, the clinical investigation at any time, is respected by the investigator; (d) no incentives or financial inducements are given to the subject or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation; (e) the clinical investigation is intended to investigate treatments for a medical condition that only occurs in minors or the clinical investigation is essential with respect to minors to validate data obtained in clinical investigations on persons able to give informed consent or by other research methods; (f) the clinical investigation either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors; (g) there are scientific grounds for expecting that participation in the clinical investigation will produce a direct benefit to the minor subject outweighing the risks and burdens involved; (h) the minor shall take part in the informed consent procedure in a way adapted to his or her age and mental maturity; (i) if during a clinical investigation the minor reaches the age of legal competence to give informed consent as defined in national law, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical investigation. Article 66 Clinical investigations on pregnant or breastfeeding women A clinical investigation on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 62(4), all of the following conditions are met: (a) the clinical investigation has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved; (b) where research is undertaken on breastfeeding women, particular care is taken to avoid any adverse impact on the health of the child; (c) no incentives or financial inducements are given to the subject except for compensation for expenses and loss of earnings directly related to the participation in the clinical investigation. Article 67 Additional national measures Member States may maintain additional measures regarding persons performing mandatory military service, persons deprived of liberty, persons who, due to a judicial decision, cannot take part in clinical investigations, or persons in residential care institutions. Article 68 Clinical investigations in emergency situations 1.   By way of derogation from point (f) of Article 62(4), from points (a) and (b) of Article 64(1) and from points (a) and (b) of Article 65, informed consent to participate in a clinical investigation may be obtained, and information on the clinical investigation may be given, after the decision to include the subject in the clinical investigation, provided that that decision is taken at the time of the first intervention on the subject, in accordance with the clinical investigation plan for that clinical investigation and that all of the following conditions are fulfilled: (a) due to the urgency of the situation, caused by a sudden life-threatening or other sudden serious medical condition, the subject is unable to provide prior informed consent and to receive prior information on the clinical investigation; (b) there are scientific grounds to expect that participation of the subject in the clinical investigation will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject, or in the diagnosis of its condition; (c) it is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his or her legally designated representative; (d) the investigator certifies that he or she is not aware of any objections to participate in the clinical investigation previously expressed by the subject; (e) the clinical investigation relates directly to the subject's medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the subject or from his or her legally designated representative and to supply prior information, and the clinical investigation is of such a nature that it may be conducted exclusively in emergency situations; (f) the clinical investigation poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject's condition. 2.   Following an intervention pursuant to paragraph 1 of this Article, informed consent in accordance with Article 63 shall be sought to continue the participation of the subject in the clinical investigation, and information on the clinical investigation shall be given, in accordance with the following requirements: (a) regarding incapacitated subjects and minors, the informed consent shall be sought by the investigator from his or her legally designated representative without undue delay and the information referred to in Article 63(2) shall be given as soon as possible to the subject and to his or her legally designated representative; (b) regarding other subjects, the informed consent shall be sought by the investigator without undue delay from the subject or his or her legally designated representative, whichever can be done sooner, and the information referred to in Article 63(2) shall be given as soon as possible to the subject or his or her legally designated representative, as applicable. For the purposes of point (b) where informed consent has been obtained from the legally designated representative, informed consent to continue the participation in the clinical investigation shall be obtained from the subject as soon as he or she is capable of giving informed consent. 3.   If the subject or, where applicable, his or her legally designated representative does not give consent, he or she shall be informed of the right to object to the use of data obtained from the clinical investigation. Article 69 Damage compensation 1.   Member States shall ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical investigation conducted on their territory are in place in the form of insurance, a guarantee, or a similar arrangement that is equivalent as regards its purpose and which is appropriate to the nature and the extent of the risk. 2.   The sponsor and the investigator shall make use of the system referred to in paragraph 1 in the form appropriate for the Member State in which the clinical investigation is conducted. Article 70 Application for clinical investigations 1.   The sponsor of a clinical investigation shall submit an application to the Member State(s) in which the clinical investigation is to be conducted (referred to for the purposes of this Article as ‘Member State concerned’) accompanied by the documentation referred to in Chapter II of Annex XV. The application shall be submitted by means of the electronic system referred to in Article 73, which shall generate a Union-wide unique single identification number for the clinical investigation, which shall be used for all relevant communication in relation to that clinical investigation. Within 10 days of it receiving the application, the Member State concerned shall notify the sponsor as to whether the clinical investigation falls within the scope of this Regulation and as to whether the application dossier is complete in accordance with Chapter II of Annex XV. 2.   Within one week of any change occurring in relation to the documentation referred to in Chapter II of Annex XV, the sponsor shall update the relevant data in the electronic system referred to in Article 73 and make that change to the documentation clearly identifiable. The Member State concerned shall be notified of the update by means of that electronic system. 3.   Where the Member State concerned finds that the clinical investigation applied for does not fall within the scope of this Regulation or that the application dossier is not complete, it shall inform the sponsor thereof and shall set a time limit of maximum 10 days for the sponsor to comment or to complete the application by means of the electronic system referred to in Article 73. The Member State concerned may extend this period by a maximum of 20 days where appropriate. Where the sponsor has not provided comments nor completed the application within the time limit referred to in the first subparagraph, the application shall be deemed to have lapsed. Where the sponsor considers the application does fall under the scope of this Regulation and/or is complete but the Member State concerned does not, the application shall be considered to have been rejected. The Member State concerned shall provide for an appeal procedure in respect of such refusal. The Member State concerned shall notify the sponsor within five days of receipt of the comments or of the requested additional information, whether the clinical investigation is considered as falling within the scope of this Regulation and the application is complete. 4.   The Member State concerned may also extend the period referred to in paragraph 1 and 3 each by a further five days. 5.   For the purposes of this Chapter, the date on which the sponsor is notified in accordance with paragraph 1 or 3 shall be the validation date of the application. Where the sponsor is not notified, the validation date shall be the last day of the periods referred to in paragraphs 1, 3 and 4 respectively. 6.   During the period when the application is being assessed, the Member State may request additional information from the sponsor. The expiry of the period laid down in point (b) of paragraph 7 shall be suspended from the date of the first request until such time as the additional information has been received. 7.   The sponsor may start the clinical investigation in the following circumstances: (a) in the case of investigational class I devices or in the case of non-invasive class IIa and class IIb devices, unless otherwise stated by national law, immediately after the validation date of the application pursuant to paragraph 5, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation; (b) in the case of investigational devices, other than those referred to in point (a), as soon as the Member State concerned has notified the sponsor of its authorisation, and provided that a negative opinion which is valid for the entire Member State, under national law, has not been issued by an ethics committee in the Member State concerned in respect of the clinical investigation. The Member State shall notify the sponsor of the authorisation within 45 days of the validation date referred to in paragraph 5. The Member State may extend this period by a further 20 days for the purpose of consulting with experts. 8.   The Commission is empowered to adopt delegated acts in accordance with Article 115 amending, in the light of technical progress and global regulatory developments, the requirements laid down in Chapter II of Annex XV. 9.   In order to ensure the uniform application of the requirements laid down in Chapter II of Annex XV, the Commission may adopt implementing acts to the extent necessary to resolve issues of divergent interpretation and of practical application. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 71 Assessment by Member States 1.   Member States shall ensure that the persons validating and assessing the application, or deciding on it, do not have conflicts of interest, are independent of the sponsor, the investigators involved and of natural or legal persons financing the clinical investigation, as well as free of any other undue influence. 2.   Member States shall ensure that the assessment is done jointly by an appropriate number of persons who collectively have the necessary qualifications and experience. 3.   Member States shall assess whether the clinical investigation is designed in such a way that potential remaining risks to subjects or third persons, after risk minimization, are justified, when weighed against the clinical benefits to be expected. They shall, while taking into account applicable CS or harmonised standards, examine in particular: (a) the demonstration of compliance of the investigational device(s) with the applicable general safety and performance requirements, apart from the aspects covered by the clinical investigation, and whether, with regard to those aspects, every precaution has been taken to protect the health and safety of the subjects. This includes, where appropriate, assurance of technical and biological safety testing and pre-clinical evaluation; (b) whether the risk-minimisation solutions employed by the sponsor are described in harmonised standards and, in those cases where the sponsor does not use harmonised standards, whether the risk-minimisation solutions provide a level of protection that is equivalent to that provided by harmonised standards; (c) whether the measures planned for the safe installation, putting into service and maintenance of the investigational device are adequate; (d) the reliability and robustness of the data generated in the clinical investigation, taking account of statistical approaches, design of the investigation and methodological aspects, including sample size, comparator and endpoints; (e) whether the requirements of Annex XV are met; (f) in the case of devices for sterile use, evidence of the validation of the manufacturer's sterilisation procedures or information on the reconditioning and sterilisation procedures which have to be conducted by the investigation site; (g) the demonstration of the safety, quality and usefulness of any components of animal or human origin or of substances, which may be considered medicinal products in accordance with Directive 2001/83/EC. 4.   Member States shall refuse the authorisation of the clinical investigation if: (a) the application dossier submitted pursuant to Article 70(1) remains incomplete; (b) the device or the submitted documents, especially the investigation plan and the investigator's brochure, do not correspond to the state of scientific knowledge, and the clinical investigation, in particular, is not suitable for providing evidence for the safety, performance characteristics or benefit of the device on subjects or patients, (c) the requirements of Article 62 are not met, or (d) any assessment under paragraph 3 is negative. Member States shall provide for an appeal procedure in respect of a refusal pursuant to the first subparagraph. Article 72 Conduct of a clinical investigation 1.   The sponsor and the investigator shall ensure that the clinical investigation is conducted in accordance with the approved clinical investigation plan. 2.   In order to verify that the rights, safety and well-being of subjects are protected, that the reported data are reliable and robust, and that the conduct of the clinical investigation is in compliance with the requirements of this Regulation, the sponsor shall ensure adequate monitoring of the conduct of a clinical investigation. The extent and nature of the monitoring shall be determined by the sponsor on the basis of an assessment that takes into consideration all characteristics of the clinical investigation including the following: (a) the objective and methodology of the clinical investigation; and (b) the degree of deviation of the intervention from normal clinical practice. 3.   All clinical investigation information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified while the confidentiality of records and the personal data of the subjects remain protected in accordance with the applicable law on personal data protection. 4.   Appropriate technical and organisational measures shall be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves transmission over a network. 5.   Member States shall inspect, at an appropriate level, investigation site(s) to check that clinical investigations are conducted in accordance with the requirements of this Regulation and with the approved investigation plan. 6.   The sponsor shall establish a procedure for emergency situations which enables the immediate identification and, where necessary, an immediate recall of the devices used in the investigation. Article 73 Electronic system on clinical investigations 1.   The Commission shall, in collaboration with the Member States, set up, manage and maintain an electronic system: (a) to create the single identification numbers for clinical investigations referred to in Article 70(1); (b) to be used as an entry point for the submission of all applications or notifications for clinical investigations referred to in Articles 70, 74, 75 and 78 and for all other submission of data, or processing of data in this context; (c) for the exchange of information relating to clinical investigations in accordance with this Regulation between the Member States and between them and the Commission including the exchange of information referred to in Articles 70 and 76; (d) for information to be provided by the sponsor in accordance with Article 77, including the clinical investigation report and its summary as required in paragraph 5 of that Article; (e) for reporting on serious adverse events and device deficiencies and related updates referred to in Article 80. 2.   When setting up the electronic system referred in paragraph 1 of this Article, the Commission shall ensure that it is interoperable with the EU database for clinical trials on medicinal products for human use set up in accordance with Article 81 of Regulation (EU) No 536/2014 of the European Parliament and of the Council (37) as concerns combined clinical investigations of devices with a clinical trial under that Regulation. 3.   The information referred to in point (c) of paragraph 1 shall only be accessible to the Member States and the Commission. The information referred to in the other points of that paragraph shall be accessible to the public, unless, for all or parts of that information, confidentiality of the information is justified on any of the following grounds: (a) protection of personal data in accordance with Regulation (EC) No 45/2001; (b) protection of commercially confidential information, especially in the investigators brochure, in particular through taking into account the status of the conformity assessment for the device, unless there is an overriding public interest in disclosure; (c) effective supervision of the conduct of the clinical investigation by the Member State(s) concerned. 4.   No personal data of subjects shall be publicly available. 5.   The user interface of the electronic system referred to in paragraph 1 shall be available in all official languages of the Union. Article 74 Clinical investigations regarding devices bearing the CE marking 1.   Where a clinical investigation is to be conducted to further assess, within the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), (‘PMCF investigation’), and where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned at least 30 days prior to its commencement by means of the electronic system referred to in Article 73. The sponsor shall include the documentation referred to in Chapter II of Annex XV as part of the notification. Points (b) to (k) and (m) of Article 62(4), Article 75, Article 76, Article 77, Article 80(5) and the relevant provisions of Annex XV shall apply to PMCF investigations. 2.   Where a clinical investigation is to be conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), Articles 62 to 81 shall apply. Article 75 Substantial modifications to clinical investigations 1.   If a sponsor intends to introduce modifications to a clinical investigation that are likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation, it shall notify, within one week, by means of the electronic system referred to in Article 73 the Member State(s) in which the clinical investigation is being or is to be conducted of the reasons for and the nature of those modifications. The sponsor shall include an updated version of the relevant documentation referred to in Chapter II of Annex XV as part of the notification. Changes to the relevant documentation shall be clearly identifiable. 2.   The Member State shall assess any substantial modification to the clinical investigation in accordance with the procedure laid down in Article 71. 3.   The sponsor may implement the modifications referred to in paragraph 1 at the earliest 38 days after the notification referred to in that paragraph, unless: (a) the Member State in which the clinical investigation is being or is to be conducted has notified the sponsor of its refusal based on the grounds referred to in Article 71(4) or on considerations of public health, subject and user safety or health, of public policy, or (b) an ethics committee in that Member State has issued a negative opinion in relation to the substantial modification to the clinical investigation, which, in accordance with national law, is valid for that entire Member State. 4.   The Member State(s) concerned may extend the period referred to in paragraph 3 by a further seven days, for the purpose of consulting with experts. Article 76 Corrective measures to be taken by Member States and information exchange between Member States 1.   Where a Member State in which a clinical investigation is being or is to be conducted has grounds for considering that the requirements set out in this Regulation are not met, it may take at least any of the following measures on its territory: (a) revoke the authorisation for the clinical investigation; (b) suspend or terminate the clinical investigation; (c) require the sponsor to modify any aspect of the clinical investigation. 2.   Before the Member State concerned takes any of the measures referred to in paragraph 1 it shall, except where immediate action is required, ask the sponsor or the investigator or both for their opinion. That opinion shall be delivered within seven days. 3.   Where a Member State has taken a measure referred to in paragraph 1 of this Article or has refused a clinical investigation, or has been notified by the sponsor of the early termination of a clinical investigation on safety grounds, that Member State shall communicate the corresponding decision and the grounds therefor to all Member States and the Commission by means of the electronic system referred to in Article 73. 4.   Where an application is withdrawn by the sponsor prior to a decision by a Member State, that information shall be made available through the electronic system referred to in Article 73 to all Member States and the Commission. Article 77 Information from the sponsor at the end of a clinical investigation or in the event of a temporary halt or early termination 1.   If the sponsor has temporarily halted a clinical investigation or has terminated a clinical investigation early, it shall inform within 15 days the Member State in which that clinical investigation has been temporarily halted or terminated early, through the electronic system referred to in Article 73, of the temporary halt or early termination, providing a justification. In the event that the sponsor has temporarily halted or terminated early the clinical investigation on safety grounds, it shall inform all Member States in which that clinical investigation is being conducted thereof within 24 hours. 2.   The end of a clinical investigation shall be deemed to coincide with the last visit of the last subject unless another point in time for such end is set out in the clinical investigation plan. 3.   The sponsor shall notify each Member State in which a clinical investigation was being conducted of the end of that clinical investigation in that Member State. That notification shall be made within 15 days of the end of the clinical investigation in relation to that Member State. 4.   If an investigation is conducted in more than one Member State, the sponsor shall notify all Member States in which that clinical investigation was conducted of the end of the clinical investigation in all Member States. That notification shall be made within 15 days of that end of the clinical investigation. 5.   Irrespective of the outcome of the clinical investigation, within one year of the end of the clinical investigation or within three months of the early termination or temporary halt, the sponsor shall submit to the Member States in which a clinical investigation was conducted a clinical investigation report as referred to in Section 2.8 of Chapter I and Section 7 of Chapter III of Annex XV. The clinical investigation report shall be accompanied by a summary presented in terms that are easily understandable to the intended user. Both the report and summary shall be submitted by the sponsor by means of the electronic system referred to in Article 73. Where, for scientific reasons, it is not possible to submit the clinical investigation report within one year of the end of the investigation, it shall be submitted as soon as it is available. In such case, the clinical investigation plan referred to in Section 3 of Chapter II of Annex XV shall specify when the results of the clinical investigation are going to be available, together with a justification. 6.   The Commission shall issue guidelines regarding the content and structure of the summary of the clinical investigation report. In addition, the Commission may issue guidelines for the formatting and sharing of raw data, for cases where the sponsor decides to share raw data on a voluntary basis. Those guidelines may take as a basis and adapt, where possible, existing guidelines for sharing of raw data in the field of clinical investigations. 7.   The summary and the clinical investigation report referred to in paragraph 5 of this Article shall become publicly accessible through the electronic system referred to in Article 73, at the latest when the device is registered in accordance with Article 29 and before it is placed on the market. In cases of early termination or temporary halt, the summary and the report shall become publicly accessible immediately after submission. If the device is not registered in accordance with Article 29 within one year of the summary and the report having been entered into the electronic system pursuant to paragraph 5 of this Article, they shall become publicly accessible at that point in time. Article 78 Coordinated assessment procedure for clinical investigations 1.   By means of the electronic system referred to in Article 73, the sponsor of a clinical investigation to be conducted in more than one Member State may submit, for the purpose of Article 70, a single application that, upon receipt, is transmitted electronically to all Member States in which the clinical investigation is to be conducted. 2.   The sponsor shall propose in the single application referred to in paragraph 1 that one of the Member States in which the clinical investigation is to be conducted acts as coordinating Member State. The Member States in which the clinical investigation is to be conducted shall, within six days of submission of the application, agree on one of them taking the role of the coordinating Member State. If they do not agree on a coordinating Member State, the coordinating Member State proposed by the sponsor shall assume that role. 3.   Under the direction of the coordinating Member State referred to in paragraph 2, the Member States concerned shall coordinate their assessment of the application, in particular of the documentation referred to in Chapter II of Annex XV. However, the completeness of the documentation referred to in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV shall be assessed separately by each Member State concerned in accordance with Article 70(1) to (5). 4.   With regard to documentation other than that referred to in the second subparagraph of paragraph 3, the coordinating Member State shall: (a) within six days of receipt of the single application, notify the sponsor that it is the coordinating Member State (‘notification date’); (b) for the purpose of the validation of the application, take into account any considerations submitted within seven days of the notification date by any Member State concerned; (c) within 10 days of the notification date, assess whether the clinical investigation falls within the scope of this Regulation and whether the application is complete, and shall notify the sponsor accordingly. Article 70(1) and (3) to (5) shall apply to the coordinating Member State in relation to that assessment; (d) establish the results of its assessment in a draft assessment report to be transmitted within 26 days of the validation date to the Member States concerned. By day 38 after the validation date, the other Member States concerned shall transmit their comments and proposals on the draft assessment report and the underlying application to the coordinating Member State which shall take due account of those comments and proposals in its finalisation of the final assessment report, to be transmitted within 45 days of the validation date to the sponsor and the other Member States concerned. The final assessment report shall be taken into account by all Member States concerned when deciding on the sponsor's application in accordance with Article 70(7). 5.   As regards the assessment of the documentation referred to in the second subparagraph of paragraph 3, each Member State concerned may request, on a single occasion, additional information from the sponsor. The sponsor shall submit the requested additional information within the period set by the Member State concerned, which shall not exceed 12 days from the receipt of the request. The expiry of the last deadline pursuant to point (d) of paragraph 4 shall be suspended from the date of the request until such time as the additional information has been received. 6.   For class IIb and class III devices, the coordinating Member State may also extend the periods referred to in paragraph 4 by a further 50 days, for the purpose of consulting with experts. 7.   The Commission may, by means of implementing acts, further specify the procedures and timescales for coordinated assessments to be taken into account by Member States concerned when deciding on the sponsor's application. Such implementing acts may also set out the procedures and timescales for coordinated assessment in the case of substantial modifications pursuant to paragraph 12 of this Article, in the case of reporting of adverse events pursuant to Article 80(4) and in the case of clinical investigations of combination products between medical devices and medicinal products, where the latter are under a concurrent coordinated assessment of a clinical trial under Regulation (EU) No 536/2014. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 8.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the conduct of the clinical investigation is acceptable or acceptable subject to compliance with specific conditions, that conclusion shall be deemed to be the conclusion of all Member States concerned. Notwithstanding the first subparagraph, a Member State concerned may only disagree with the conclusion of the coordinating Member State concerning the area of coordinated assessment on the following grounds: (a) when it considers that participation in the clinical investigation would lead to a subject receiving treatment inferior to that received in normal clinical practice in that Member State concerned; (b) infringement of national law; or (c) considerations as regards subject safety and data reliability and robustness submitted under point (b) of paragraph 4. Where one of the Member States concerned disagrees with the conclusion on the basis of the second subparagraph of this paragraph, it shall communicate its disagreement, together with a detailed justification, through the electronic system referred to in Article 73, to the Commission, to all other Member States concerned and to the sponsor. 9.   Where the conclusion of the coordinating Member State concerning the area of coordinated assessment is that the clinical investigation is not acceptable, that conclusion shall be deemed to be the conclusion of all Member States concerned. 10.   A Member State concerned shall refuse to authorise a clinical investigation if it disagrees with the conclusion of the coordinating Member State as regards any of the grounds referred to in the second subparagraph of paragraph 8, or if it finds, on duly justified grounds, that the aspects addressed in Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV are not complied with, or where an ethics committee has issued a negative opinion in relation to that clinical investigation, which is valid, in accordance with national law, for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal. 11.   Each Member State concerned shall notify the sponsor through the electronic system referred to in Article 73 as to whether the clinical investigation is authorised, whether it is authorised subject to conditions, or whether authorisation has been refused. Notification shall be done by way of one single decision within five days of the transmission, pursuant to point (d) of paragraph 4, by the coordinating Member State of the final assessment report. Where an authorisation of a clinical investigation is subject to conditions, those conditions may only be such that, by their nature, they cannot be fulfilled at the time of that authorisation. 12.   Any substantial modifications as referred to in Article 75 shall be notified to the Member States concerned by means of the electronic system referred to in Article 73. Any assessment as to whether there are grounds for disagreement as referred to in the second subparagraph of paragraph 8 of this Article shall be carried out under the direction of the coordinating Member State, except for substantial modifications concerning Sections 1.13, 3.1.3, 4.2, 4.3 and 4.4 of Chapter II of Annex XV, which shall be assessed separately by each Member State concerned. 13.   The Commission shall provide administrative support to the coordinating Member State in the accomplishment of its tasks under this Chapter. 14.   The procedure set out in this Article shall, until 27 May 2027, be applied only by those of the Member States in which the clinical investigation is to be conducted which have agreed to apply it. After 27 May 2027, all Member States shall be required to apply that procedure. Article 79 Review of coordinated assessment procedure By 27 May 2026, the Commission shall submit to the European Parliament and to the Council a report on experience gained from the application of Article 78 and, if necessary, propose a review of Article 78(14) and point (h) of Article 123(3). Article 80 Recording and reporting of adverse events that occur during clinical investigations 1.   The sponsor shall fully record all of the following: (a) any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation of the results of that clinical investigation; (b) any serious adverse event; (c) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (d) any new findings in relation to any event referred to in points (a) to (c). 2.   The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of the following by means of the electronic system referred to in Article 73: (a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; (b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (c) any new findings in relation to any event referred to in points (a) and (b). The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the sponsor may submit an initial report that is incomplete followed up by a complete report. Upon request by any Member State in which the clinical investigation is being conducted, the sponsor shall provide all information referred to in paragraph 1. 3.   The sponsor shall also report to the Member States in which the clinical investigation is being conducted any event referred to in paragraph 2 of this Article that occurred in third countries in which a clinical investigation is performed under the same clinical investigation plan as the one applying to a clinical investigation covered by this Regulation by means of the electronic system referred to in Article 73. 4.   In the case of a clinical investigation for which the sponsor has used the single application referred to in Article 78, the sponsor shall report any event as referred to in paragraph 2 of this Article by means of the electronic system referred to in Article 73. Upon receipt, this report shall be transmitted electronically to all Member States in which the clinical investigation is being conducted. Under the direction of the coordinating Member State referred to in Article 78(2), the Member States shall coordinate their assessment of serious adverse events and device deficiencies to determine whether to modify, suspend or terminate the clinical investigation or whether to revoke the authorisation for that clinical investigation. This paragraph shall not affect the rights of the other Member States to perform their own evaluation and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating Member State and the Commission shall be kept informed of the outcome of any such evaluation and the adoption of any such measures. 5.   In the case of PMCF investigations referred to in Article 74(1), the provisions on vigilance laid down in Articles 87 to 90 and in the acts adopted pursuant to Article 91 shall apply instead of this Article. 6.   Notwithstanding paragraph 5, this Article shall apply where a causal relationship between the serious adverse event and the preceding investigational procedure has been established. Article 81 Implementing acts The Commission may, by means of implementing acts, establish the detailed arrangements and procedural aspects necessary for the implementation of this Chapter as regards the following: (a) harmonised electronic forms for the application for clinical investigations and their assessment as referred to in Articles 70 and 78, taking into account specific categories or groups of devices; (b) the functioning of the electronic system referred to in Article 73; (c) harmonised electronic forms for the notification of PMCF investigations as referred to in Article 74(1), and of substantial modifications as referred to in Article 75; (d) the exchange of information between Member States as referred to in Article 76; (e) harmonised electronic forms for the reporting of serious adverse events and device deficiencies as referred to in Article 80; (f) the timelines for the reporting of serious adverse events and device deficiencies, taking into account the severity of the event to be reported as referred to in Article 80; (g) uniform application of the requirements regarding the clinical evidence or data needed to demonstrate compliance with the general safety and performance requirements set out in Annex I. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 82 Requirements regarding other clinical investigations 1.   Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), shall comply with the provisions of Article 62 (2) and (3), points (b), (c), (d), (f), (h), and (l) of Article 62(4) and Article 62(6). 2.   In order to protect the rights, safety, dignity and well-being of subjects and the scientific and ethical integrity of clinical investigations not performed for any of the purposes listed in Article 62(1), each Member State shall define any additional requirements for such investigations, as appropriate for each Member State concerned. CHAPTER VII POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE SECTION 1 Post-market surveillance Article 83 Post-market surveillance system of the manufacturer 1.   For each device, manufacturers shall plan, establish, document, implement, maintain and update a post-market surveillance system in a manner that is proportionate to the risk class and appropriate for the type of device. That system shall be an integral part of the manufacturer's quality management system referred to in Article 10(9). 2.   The post-market surveillance system shall be suited to actively and systematically gathering, recording and analysing relevant data on the quality, performance and safety of a device throughout its entire lifetime, and to drawing the necessary conclusions and to determining, implementing and monitoring any preventive and corrective actions. 3.   Data gathered by the manufacturer's post-market surveillance system shall in particular be used: (a) to update the benefit-risk determination and to improve the risk management as referred to in Chapter I of Annex I; (b) to update the design and manufacturing information, the instructions for use and the labelling; (c) to update the clinical evaluation; (d) to update the summary of safety and clinical performance referred to in Article 32; (e) for the identification of needs for preventive, corrective or field safety corrective action; (f) for the identification of options to improve the usability, performance and safety of the device; (g) when relevant, to contribute to the post-market surveillance of other devices; and (h) to detect and report trends in accordance with Article 88. The technical documentation shall be updated accordingly. 4.   If, in the course of the post-market surveillance, a need for preventive or corrective action or both is identified, the manufacturer shall implement the appropriate measures and inform the competent authorities concerned and, where applicable, the notified body. Where a serious incident is identified or a field safety corrective action is implemented, it shall be reported in accordance with Article 87. Article 84 Post-market surveillance plan The post-market surveillance system referred to in Article 83 shall be based on a post-market surveillance plan, the requirements for which are set out in Section 1.1 of Annex III. For devices other than custom-made devices, the post-market surveillance plan shall be part of the technical documentation specified in Annex II. Article 85 Post-market surveillance report Manufacturers of class I devices shall prepare a post-market surveillance report summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. The report shall be updated when necessary and made available to the competent authority upon request. Article 86 Periodic safety update report 1.   Manufacturers of class IIa, class IIb and class III devices shall prepare a periodic safety update report (‘PSUR’) for each device and where relevant for each category or group of devices summarising the results and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan referred to in Article 84 together with a rationale and description of any preventive and corrective actions taken. Throughout the lifetime of the device concerned, that PSUR shall set out: (a) the conclusions of the benefit-risk determination; (b) the main findings of the PMCF; and (c) the volume of sales of the device and an estimate evaluation of the size and other characteristics of the population using the device and, where practicable, the usage frequency of the device. Manufacturers of class IIb and class III devices shall update the PSUR at least annually. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. Manufacturers of class IIa devices shall update the PSUR when necessary and at least every two years. That PSUR shall, except in the case of custom-made devices, be part of the technical documentation as specified in Annexes II and III. For custom-made devices, the PSUR shall be part of the documentation referred to in Section 2 of Annex XIII. 2.   For class III devices or implantable devices, manufacturers shall submit PSURs by means of the electronic system referred to in Article 92 to the notified body involved in the conformity assessment in accordance with Article 52. The notified body shall review the report and add its evaluation to that electronic system with details of any action taken. Such PSURs and the evaluation by the notified body shall be made available to competent authorities through that electronic system. 3.   For devices other than those referred to in paragraph 2, manufacturers shall make PSURs available to the notified body involved in the conformity assessment and, upon request, to competent authorities. SECTION 2 Vigilance Article 87 Reporting of serious incidents and field safety corrective actions 1.   Manufacturers of devices made available on the Union market, other than investigational devices, shall report, to the relevant competent authorities, in accordance with Articles 92(5) and (7), the following: (a) any serious incident involving devices made available on the Union market, except expected side-effects which are clearly documented in the product information and quantified in the technical documentation and are subject to trend reporting pursuant to Article 88; (b) any field safety corrective action in respect of devices made available on the Union market, including any field safety corrective action undertaken in a third country in relation to a device which is also legally made available on the Union market, if the reason for the field safety corrective action is not limited to the device made available in the third country. The reports referred to in the first subparagraph shall be submitted through the electronic system referred to in Article 92. 2.   As a general rule, the period for the reporting referred to in paragraph 1 shall take account of the severity of the serious incident. 3.   Manufacturers shall report any serious incident as referred to in point (a) of paragraph 1 immediately after they have established the causal relationship between that incident and their device or that such causal relationship is reasonably possible and not later than 15 days after they become aware of the incident. 4.   Notwithstanding paragraph 3, in the event of a serious public health threat the report referred to in paragraph 1 shall be provided immediately, and not later than 2 days after the manufacturer becomes aware of that threat. 5.   Notwithstanding paragraph 3, in the event of death or an unanticipated serious deterioration in a person's state of health the report shall be provided immediately after the manufacturer has established or as soon as it suspects a causal relationship between the device and the serious incident but not later than 10 days after the date on which the manufacturer becomes aware of the serious incident. 6.   Where necessary to ensure timely reporting, the manufacturer may submit an initial report that is incomplete followed up by a complete report. 7.   If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report within the timeframe required in accordance with paragraphs 2 to 5. 8.   Except in cases of urgency in which the manufacturer needs to undertake field safety corrective action immediately, the manufacturer shall, without undue delay, report the field safety corrective action referred to in point (b) of paragraph 1 in advance of the field safety corrective action being undertaken. 9.   For similar serious incidents that occur with the same device or device type and for which the root cause has been identified or a field safety corrective action implemented or where the incidents are common and well documented, the manufacturer may provide periodic summary reports instead of individual serious incident reports, on condition that the coordinating competent authority referred to in Article 89(9), in consultation with the competent authorities referred to in point (a) of Article 92(8), has agreed with the manufacturer on the format, content and frequency of the periodic summary reporting. Where a single competent authority is referred to in points (a) and (b) of Article 92(8), the manufacturer may provide periodic summary reports following agreement with that competent authority. 10.   The Member States shall take appropriate measures such as organising targeted information campaigns, to encourage and enable healthcare professionals, users and patients to report to the competent authorities suspected serious incidents referred to in point (a) of paragraph 1. The competent authorities shall record centrally at national level reports they receive from healthcare professionals, users and patients. 11.   Where a competent authority of a Member State obtains such reports on suspected serious incidents referred to in point (a) of paragraph 1 from healthcare professionals, users or patients, it shall take the necessary steps to ensure that the manufacturer of the device concerned is informed of the suspected serious incident without delay. Where the manufacturer of the device concerned considers that the incident is a serious incident, it shall provide a report in accordance with paragraphs 1 to 5 of this Article on that serious incident to the competent authority of the Member State in which that serious incident occurred and shall take the appropriate follow-up action in accordance with Article 89. Where the manufacturer of the device concerned considers that the incident is not a serious incident or is an expected undesirable side-effect, which will be covered by trend reporting in accordance with Article 88, it shall provide an explanatory statement. If the competent authority does not agree with the conclusion of the explanatory statement, it may require the manufacturer to provide a report in accordance with paragraphs 1 to 5 of this Article and require it to ensure that appropriate follow-up action is taken in accordance with Article 89. Article 88 Trend reporting 1.   Manufacturers shall report, by means of the electronic system referred to in Article 92, any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side-effects that could have a significant impact on the benefit-risk analysis referred to in Sections 1 and 5 of Annex I and which have led or may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. The significant increase shall be established in comparison to the foreseeable frequency or severity of such incidents in respect of the device, or category or group of devices, in question during a specific period as specified in the technical documentation and product information. The manufacturer shall specify how to manage the incidents referred to in the first subparagraph and the methodology used for determining any statistically significant increase in the frequency or severity of such incidents, as well as the observation period, in the post-market surveillance plan referred to in Article 84. 2.   The competent authorities may conduct their own assessments on the trend reports referred to in paragraph 1 and require the manufacturer to adopt appropriate measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. Each competent authority shall inform the Commission, the other competent authorities and the notified body that issued the certificate, of the results of such assessment and of the adoption of such measures. Article 89 Analysis of serious incidents and field safety corrective actions 1.   Following the reporting of a serious incident pursuant to Article 87(1), the manufacturer shall, without delay, perform the necessary investigations in relation to the serious incident and the devices concerned. This shall include a risk assessment of the incident and field safety corrective action taking into account criteria as referred to in paragraph 3 of this Article as appropriate. The manufacturer shall co-operate with the competent authorities and where relevant with the notified body concerned during the investigations referred to in the first subparagraph and shall not perform any investigation which involves altering the device or a sample of the batch concerned in a way which may affect any subsequent evaluation of the causes of the incident, prior to informing the competent authorities of such action. 2.   Member States shall take the necessary steps to ensure that any information regarding a serious incident that has occurred within their territory, or a field safety corrective action that has been or is to be undertaken within their territory, and that is brought to their knowledge in accordance with Article 87 is evaluated centrally at national level by their competent authority, if possible together with the manufacturer, and, where relevant, the notified body concerned. 3.   In the context of the evaluation referred to in paragraph 2, the competent authority shall evaluate the risks arising from the reported serious incident and evaluate any related field safety corrective actions, taking into account the protection of public health and criteria such as causality, detectability and probability of recurrence of the problem, frequency of use of the device, probability of occurrence of direct or indirect harm, the severity of that harm, the clinical benefit of the device, intended and potential users, and population affected. The competent authority shall also evaluate the adequacy of the field safety corrective action envisaged or undertaken by the manufacturer and the need for, and kind of, any other corrective action, in particular taking into account the principle of inherent safety contained in Annex I. Upon request by the national competent authority, manufacturers shall provide all documents necessary for the risk assessment. 4.   The competent authority shall monitor the manufacturer's investigation of a serious incident. Where necessary, a competent authority may intervene in a manufacturer's investigation or initiate an independent investigation. 5.   The manufacturer shall provide a final report to the competent authority setting out its findings from the investigation by means of the electronic system referred to in Article 92. The report shall set out conclusions and where relevant indicate corrective actions to be taken. 6.   In the case of devices referred to in the first subparagraph of Article 1(8) and where the serious incident or field safety corrective action may be related to a substance which, if used separately, would be considered to be a medicinal product, the evaluating competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall, inform the national competent authority or the EMA, depending on which issued the scientific opinion on that substance under Article 52(9), of that serious incident or field safety corrective action. In the case of devices covered by this Regulation in accordance with point (g) of Article 1(6) and where the serious incident or field safety corrective action may be related to the derivatives of tissues or cells of human origin utilised for the manufacture of the device, and in the case of devices falling under this Regulation pursuant to Article 1(10), the competent authority or the coordinating competent authority referred to in paragraph 9 of this Article shall inform the competent authority for human tissues and cells that was consulted by the notified body in accordance with Article 52(10). 7.   After carrying out the evaluation in accordance with paragraph 3 of this Article, the evaluating competent authority shall, through the electronic system referred to in Article 92, inform, without delay, the other competent authorities of the corrective action taken or envisaged by the manufacturer or required of it to minimise the risk of recurrence of the serious incident, including information on the underlying events and the outcome of its assessment. 8.   The manufacturer shall ensure that information about the field safety corrective action taken is brought without delay to the attention of users of the device in question by means of a field safety notice. The field safety notice shall be edited in an official Union language or languages determined by the Member State in which the field safety corrective action is taken. Except in cases of urgency, the content of the draft field safety notice shall be submitted to the evaluating competent authority or, in the cases referred to in paragraph 9, to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice shall be consistent in all Member States. The field safety notice shall allow the correct identification of the device or devices involved, in particular by including the relevant UDIs, and the correct identification, in particular, by including the SRN, if already issued, of the manufacturer that has undertaken the field safety corrective action. The field safety notice shall explain, in a clear manner, without understating the level of risk, the reasons for the field safety corrective action with reference to the device malfunction and associated risks for patients, users or other persons, and shall clearly indicate all the actions to be taken by users. The manufacturer shall enter the field safety notice in the electronic system referred to in Article 92 through which that notice shall be accessible to the public. 9.   The competent authorities shall actively participate in a procedure in order to coordinate their assessments referred to in paragraph 3 in the following cases: (a) where there is concern regarding a particular serious incident or cluster of serious incidents relating to the same device or type of device of the same manufacturer in more than one Member State; (b) where the appropriateness of a field safety corrective action that is proposed by a manufacturer in more than one Member State is in question. That coordinated procedure shall cover the following: — designation of a coordinating competent authority on a case by case basis, when required; — defining the coordinated assessment process, including the tasks and responsibilities of the coordinating competent authority and the involvement of other competent authorities. Unless otherwise agreed between the competent authorities, the coordinating competent authority shall be the competent authority of the Member State in which the manufacturer has its registered place of business. The coordinating competent authority shall, through the electronic system referred to in Article 92, inform the manufacturer, the other competent authorities and the Commission that it has assumed the role of coordinating authority. 10.   The designation of a coordinating competent authority shall not affect the rights of the other competent authorities to perform their own assessment and to adopt measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. The coordinating competent authority and the Commission shall be kept informed of the outcome of any such assessment and the adoption of any such measures. 11.   The Commission shall provide administrative support to the coordinating competent authority in the accomplishment of its tasks under this Chapter. Article 90 Analysis of vigilance data The Commission shall, in collaboration with the Member States, put in place systems and processes to actively monitor the data available in the electronic system referred to in Article 92, in order to identify trends, patterns or signals in the data that may reveal new risks or safety concerns. Where a previously unknown risk is identified or the frequency of an anticipated risk significantly and adversely changes the benefit-risk determination, the competent authority or, where appropriate, the coordinating competent authority shall inform the manufacturer, or where applicable the authorised representative, which shall then take the necessary corrective actions. Article 91 Implementing acts The Commission may, by means of implementing acts, and after consultation of the MDCG, adopt the detailed arrangements and procedural aspects necessary for the implementation of Articles 85 to 90 and 92 as regards the following: (a) the typology of serious incidents and field safety corrective actions in relation to specific devices, or categories or groups of devices; (b) the reporting of serious incidents and field safety corrective actions and field safety notices, and the provision of periodic summary reports, post-market surveillance reports, PSURs and trend reports by manufacturers as referred to in Articles 85, 86, 87, 88 and 89 respectively; (c) standard structured forms for electronic and non-electronic reporting, including a minimum data set for reporting of suspected serious incidents by healthcare professionals, users and patients; (d) timelines for the reporting of field safety corrective actions, and for the provision by manufacturers of periodic summary reports and trend reports, taking into account the severity of the incident to be reported as referred to in Article 87; (e) harmonised forms for the exchange of information between competent authorities as referred to in Article 89; (f) procedures for the designation of a coordinating competent authority; the coordinated evaluation process, including tasks and responsibilities of the coordinating competent authority and involvement of other competent authorities in this process. The implementing acts referred to in the first paragraph shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 92 Electronic system on vigilance and on post-market surveillance 1.   The Commission shall, in collaboration with the Member States, set up and manage an electronic system to collate and process the following information: (a) the reports by manufacturers on serious incidents and field safety corrective actions referred to in Article 87(1) and Article 89(5); (b) the periodic summary reports by manufacturers referred to in Article 87(9); (c) the reports by manufacturers on trends referred to in Article 88; (d) the PSURs referred to in Article 86; (e) the field safety notices by manufacturers referred to in Article 89(8); (f) the information to be exchanged between the competent authorities of the Member States and between them and the Commission in accordance with Article 89(7) and (9). That electronic system shall include relevant links to the UDI database. 2.   The information referred to in paragraph 1 of this Article shall be made available through the electronic system to the competent authorities of the Member States and to the Commission. The notified bodies shall also have access to that information to the extent that it relates to devices for which they issued a certificate in accordance with Article 53. 3.   The Commission shall ensure that healthcare professionals and the public have appropriate levels of access to the electronic system referred to in paragraph 1. 4.   On the basis of arrangements between the Commission and competent authorities of third countries or international organisations, the Commission may grant those competent authorities or international organisations access to the electronic system referred to in paragraph 1 at the appropriate level. Those arrangements shall be based on reciprocity and make provision for confidentiality and data protection equivalent to those applicable in the Union. 5.   The reports on serious incidents referred to in point (a) of Article 87(1) shall be automatically transmitted, upon receipt, via the electronic system referred to in paragraph 1 of this Article, to the competent authority of the Member State in which the incident occurred. 6.   The trend reports referred to in Article 88(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the Member State in which the incidents occurred. 7.   The reports on field safety corrective actions referred to in point (b) of Article 87(1) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authorities of the following Member States: (a) the Member States in which the field safety corrective action is being or is to be undertaken; (b) the Member State in which the manufacturer has its registered place of business. 8.   The periodic summary reports referred to in Article 87(9) shall be automatically transmitted upon receipt via the electronic system referred to in paragraph 1 of this Article to the competent authority of: (a) the Member State or Member States participating in the coordination procedure in accordance with Article 89(9) and which have agreed on the periodic summary report; (b) the Member State in which the manufacturer has its registered place of business. 9.   The information referred to in paragraphs 5 to 8 of this Article shall be automatically transmitted, upon receipt, through the electronic system referred to in paragraph 1 of this Article, to the notified body that issued the certificate for the device in question in accordance with Article 56. SECTION 3 Market surveillance Article 93 Market surveillance activities 1.   The competent authorities shall perform appropriate checks on the conformity characteristics and performance of devices including, where appropriate, a review of documentation and physical or laboratory checks on the basis of adequate samples. The competent authorities shall, in particular, take account of established principles regarding risk assessment and risk management, vigilance data and complaints. 2.   The competent authorities shall draw up annual surveillance activity plans and allocate a sufficient number of material and competent human resources in order to carry out those activities taking into account the European market surveillance programme developed by the MDCG pursuant to Article 105 and local circumstances. 3.   In order to fulfil the obligations laid down in paragraph 1, the competent authorities: (a) may require economic operators to, inter alia, make available the documentation and information necessary for the purpose of carrying out the authorities' activities and, where justified, to provide the necessary samples of devices or access to devices free of charge; and (b) shall carry out both announced and, if necessary, unannounced inspections of the premises of economic operators, as well as suppliers and/or subcontractors, and, where necessary, at the facilities of professional users. 4.   The competent authorities shall prepare an annual summary of the results of their surveillance activities and make it accessible to other competent authorities by means of the electronic system referred to in Article 100. 5.   The competent authorities may confiscate, destroy or otherwise render inoperable devices that present an unacceptable risk or falsified devices where they deem it necessary to do so in the interests of the protection of public health. 6.   Following each inspection carried out for the purposes referred to in paragraph 1, the competent authority shall draw up a report on the findings of the inspection that concern compliance with the legal and technical requirements applicable under this Regulation. The report shall set out any corrective actions needed. 7.   The competent authority which carried out the inspection shall communicate the content of the report referred to in paragraph 6 of this Article to the economic operator that has been the subject of the inspection. Before adopting the final report, the competent authority shall give that economic operator the opportunity to submit comments. That final inspection report shall be entered in the electronic system provided for in Article 100. 8.   The Member States shall review and assess the functioning of their market surveillance activities. Such reviews and assessments shall be carried out at least every four years and the results thereof shall be communicated to the other Member States and the Commission. Each Member State shall make a summary of the results accessible to the public by means of the electronic system referred to in Article 100. 9.   The competent authorities of the Member States shall coordinate their market surveillance activities, cooperate with each other and share with each other and with the Commission the results thereof, to provide for a harmonised and high level of market surveillance in all Member States. Where appropriate, the competent authorities of the Member States shall agree on work-sharing, joint market surveillance activities and specialisation. 10.   Where more than one authority in a Member State is responsible for market surveillance and external border controls, those authorities shall cooperate with each other, by sharing information relevant to their role and functions. 11.   Where appropriate, the competent authorities of the Member States shall cooperate with the competent authorities of third countries with a view to exchanging information and technical support and promoting activities relating to market surveillance. Article 94 Evaluation of devices suspected of presenting an unacceptable risk or other non-compliance Where the competent authorities of a Member State, based on data obtained by vigilance or market surveillance activities or on other information, have reason to believe that a device: (a) may present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health; or (b) otherwise does not comply with the requirements laid down in this Regulation, they shall carry out an evaluation of the device concerned covering all requirements laid down in this Regulation relating to the risk presented by the device, or to any other non-compliance of the device. The relevant economic operators shall cooperate with the competent authorities. Article 95 Procedure for dealing with devices presenting an unacceptable risk to health and safety 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities find that the device presents an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall without delay require the manufacturer of the devices concerned, its authorised representative and all other relevant economic operators to take all appropriate and duly justified corrective action to bring the device into compliance with the requirements of this Regulation relating to the risk presented by the device and, in a manner that is proportionate to the nature of the risk, to restrict the making available of the device on the market, to subject the making available of the device to specific requirements, to withdraw the device from the market, or to recall it, within a reasonable period that is clearly defined and communicated to the relevant economic operator. 2.   The competent authorities shall, without delay, notify the Commission, the other Member States and, where a certificate has been issued in accordance with Article 56 for the device concerned, the notified body that issued that certificate, of the results of the evaluation and of the actions which they have required the economic operators to take, by means of the electronic system referred to in Article 100. 3.   The economic operators as referred to in paragraph 1 shall, without delay, ensure that all appropriate corrective action is taken throughout the Union in respect of all the devices concerned that they have made available on the market. 4.   Where the economic operator as referred to in paragraph 1 does not take adequate corrective action within the period referred to in paragraph 1, the competent authorities shall take all appropriate measures to prohibit or restrict the making available of the device on their national market, to withdraw the device from that market or to recall it. The competent authorities shall notify the Commission, the other Member States and the notified body referred to in paragraph 2 of this Article, without delay, of those measures, by means of the electronic system referred to in Article 100. 5.   The notification referred to in paragraph 4 shall include all available details, in particular the data necessary for the identification and tracing of the non-compliant device, the origin of the device, the nature of and the reasons for the non-compliance alleged and the risk involved, the nature and duration of the national measures taken and the arguments put forward by the relevant economic operator. 6.   Member States other than the Member State initiating the procedure shall, without delay, inform the Commission and the other Member States, by means of the electronic system referred to in Article 100, of any additional relevant information at their disposal relating to the non-compliance of the device concerned and of any measures adopted by them in relation to the device concerned. In the event of disagreement with the notified national measure, they shall, without delay, inform the Commission and the other Member States of their objections, by means of the electronic system referred to in Article 100. 7.   Where, within two months of receipt of the notification referred to in paragraph 4, no objection has been raised by either a Member State or the Commission in respect of any measures taken by a Member State, those measures shall be deemed to be justified. In that case, all Member States shall ensure that corresponding appropriate restrictive or prohibitive measures, including withdrawing, recalling or limiting the availability of the device on their national market, are taken without delay in respect of the device concerned. Article 96 Procedure for evaluating national measures at Union level 1.   Where, within two months of receipt of the notification referred to in Article 95(4), objections are raised by a Member State against a measure taken by another Member State, or where the Commission considers the measure to be contrary to Union law, the Commission shall, after consulting the competent authorities concerned and, where necessary, the economic operators concerned, evaluate that national measure. On the basis of the results of that evaluation, the Commission may decide, by means of implementing acts, whether or not the national measure is justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 2.   Where the Commission considers the national measure to be justified as referred to in paragraph 1 of this Article, the second subparagraph of Article 95(7) shall apply. If the Commission considers the national measure to be unjustified, the Member State concerned shall withdraw the measure. Where the Commission does not adopt a decision pursuant to paragraph 1 of this Article within eight months of receipt of the notification referred to in Article 95(4), the national measure shall be considered to be justified. 3.   Where a Member State or the Commission considers that the risk to health and safety emanating from a device cannot be mitigated satisfactorily by means of measures taken by the Member State or Member States concerned, the Commission, at the request of a Member State or on its own initiative, may take, by means of implementing acts, the necessary and duly justified measures to ensure the protection of health and safety, including measures restricting or prohibiting the placing on the market and putting into service of the device concerned. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 97 Other non-compliance 1.   Where, having performed an evaluation pursuant to Article 94, the competent authorities of a Member State find that a device does not comply with the requirements laid down in this Regulation but does not present an unacceptable risk to the health or safety of patients, users or other persons, or to other aspects of the protection of public health, they shall require the relevant economic operator to bring the non-compliance concerned to an end within a reasonable period that is clearly defined and communicated to the economic operator and that is proportionate to the non-compliance. 2.   Where the economic operator does not bring the non-compliance to an end within the period referred to in paragraph 1 of this Article, the Member State concerned shall, without delay, take all appropriate measures to restrict or prohibit the product being made available on the market or to ensure that it is recalled or withdrawn from the market. That Member State shall inform the Commission and the other Member States, without delay, of those measures, by means of the electronic system referred to in Article 100. 3.   In order to ensure the uniform application of this Article, the Commission may, by means of implementing acts, specify appropriate measures to be taken by competent authorities to address given types of non-compliance. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 98 Preventive health protection measures 1.   Where a Member State, after having performed an evaluation which indicates a potential risk related to a device or a specific category or group of devices, considers that, in order to protect the health and safety of patients, users or other persons or other aspects of public health, the making available on the market or putting into service of a device or a specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled, it may take any necessary and justified measures. 2.   The Member State referred to in paragraph 1 shall immediately notify the Commission and all other Member States, giving the reasons for its decision, by means of the electronic system referred to in Article 100. 3.   The Commission, in consultation with the MDCG and, where necessary, the economic operators concerned, shall assess the national measures taken. The Commission may decide, by means of implementing acts, whether the national measures are justified or not. In the absence of a Commission decision within six months of their notification, the national measures shall be considered to be justified. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 4.   Where the assessment referred to in paragraph 3 of this Article demonstrates that the making available on the market or putting into service of a device, specific category or group of devices should be prohibited, restricted or made subject to particular requirements or that such device or category or group of devices should be withdrawn from the market or recalled in all Member States in order to protect the health and safety of patients, users or other persons or other aspects of public health, the Commission may adopt implementing acts to take the necessary and duly justified measures. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 99 Good administrative practice 1.   Any measure adopted by the competent authorities of the Member States pursuant to Articles 95 to 98 shall state the exact grounds on which it is based. Where such a measure is addressed to a specific economic operator, the competent authority shall notify without delay the economic operator concerned of that measure, and shall at the same time inform that economic operator of the remedies available under the law or the administrative practice of the Member State concerned and of the time limits to which such remedies are subject. Where the measure is of general applicability, it shall be appropriately published. 2.   Except in cases where immediate action is necessary for reasons of unacceptable risk to human health or safety, the economic operator concerned shall be given the opportunity to make submissions to the competent authority within an appropriate period of time that is clearly defined before any measure is adopted. Where action has been taken without the economic operator having had the opportunity to make submissions as referred to in the first subparagraph, it shall be given the opportunity to make submissions as soon as possible and the action taken shall be reviewed promptly thereafter. 3.   Any measure adopted shall be immediately withdrawn or amended upon the economic operator's demonstrating that it has taken effective corrective action and that the device is in compliance with the requirements of this Regulation. 4.   Where a measure adopted pursuant to Articles 95 to 98 concerns a device for which a notified body has been involved in the conformity assessment, the competent authorities shall by means of the electronic system referred to in Article 100 inform the relevant notified body and the authority responsible for the notified body of the measure taken. Article 100 Electronic system on market surveillance 1.   The Commission, in collaboration with the Member States, shall set up and manage an electronic system to collate and process the following information: (a) summaries of the results of the surveillance activities referred to in Article 93(4); (b) the final inspection report referred to in Article 93(7); (c) information in relation to devices presenting an unacceptable risk to health and safety as referred to in Article 95(2), (4) and (6); (d) information in relation to non-compliance of products as referred to in Article 97(2); (e) information in relation to the preventive health protection measures referred to in Article 98(2); (f) summaries of the results of the reviews and assessments of the market surveillance activities of the Member States referred to in 93(8). 2.   The information referred to in paragraph 1 of this Article shall be immediately transmitted through the electronic system to all competent authorities concerned and, where applicable, to the notified body that issued a certificate in accordance with Article 56 for the device concerned and be accessible to the Member States and to the Commission. 3.   Information exchanged between Member States shall not be made public where to do so might impair market surveillance activities and co-operation between Member States. CHAPTER VIII COOPERATION BETWEEN MEMBER STATES, MEDICAL DEVICE COORDINATION GROUP, EXPERT LABORATORIES, EXPERT PANELS AND DEVICE REGISTERS Article 101 Competent authorities The Member States shall designate the competent authority or authorities responsible for the implementation of this Regulation. They shall entrust their authorities with the powers, resources, equipment and knowledge necessary for the proper performance of their tasks pursuant to this Regulation. The Member States shall communicate the names and contact details of the competent authorities to the Commission which shall publish a list of competent authorities. Article 102 Cooperation 1.   The competent authorities of the Member States shall cooperate with each other and with the Commission. The Commission shall provide for the organisation of exchanges of information necessary to enable this Regulation to be applied uniformly. 2.   Member States shall, with the support of the Commission, participate, where appropriate, in initiatives developed at international level with the aim of ensuring cooperation between regulatory authorities in the field of medical devices. Article 103 Medical Device Coordination Group 1.   A Medical Device Coordination Group (‘MDCG’) is hereby established. 2.   Each Member State shall appoint to the MDCG, for a three-year term which may be renewed, one member and one alternate each with expertise in the field of medical devices, and one member and one alternate with expertise in the field of in vitro diagnostic medical devices. A Member State may choose to appoint only one member and one alternate, each with expertise in both fields. The members of the MDCG shall be chosen for their competence and experience in the field of medical devices and in vitro diagnostic medical devices. They shall represent the competent authorities of the Member States. The names and affiliation of members shall be made public by the Commission. The alternates shall represent and vote for the members in their absence. 3.   The MDCG shall meet at regular intervals and, where the situation requires, upon request by the Commission or a Member State. The meetings shall be attended either by the members appointed for their role and expertise in the field of medical devices, or by the members appointed for their expertise in the field of in vitro diagnostic medical devices, or by the members appointed for their expertise in both fields, or their alternates, as appropriate. 4.   The MDCG shall use its best endeavours to reach consensus. If such consensus cannot be reached, the MDCG shall decide by a majority of its members. Members with diverging positions may request that their positions and the grounds on which they are based be recorded in the MDCG's position. 5.   The MDCG shall be chaired by a representative of the Commission. The chair shall not take part in votes of the MDCG. 6.   The MDCG may invite, on a case-by-case basis, experts and other third parties to attend meetings or provide written contributions. 7.   The MDCG may establish standing or temporary sub-groups. Where appropriate, organisations representing the interests of the medical device industry, healthcare professionals, laboratories, patients and consumers at Union level shall be invited to such sub-groups in the capacity of observers. 8.   The MDCG shall establish its rules of procedure which shall, in particular, lay down procedures for the following: — the adoption of opinions or recommendations or other positions, including in cases of urgency; — the delegation of tasks to reporting and co-reporting members; — the implementation of Article 107 regarding conflict of interests; — the functioning of sub-groups. 9.   The MDCG shall have the tasks laid down in Article 105 of this Regulation and Article 99 of Regulation (EU) 2017/746. Article 104 Support by the Commission The Commission shall support the functioning of the cooperation between national competent authorities. It shall, in particular, provide for the organisation of exchanges of experience between the competent authorities and provide technical, scientific and logistic support to the MDCG and its sub-groups. It shall organise the meetings of the MDCG and its sub-groups, participate in those meetings and ensure the appropriate follow-up. Article 105 Tasks of the MDCG Under this Regulation, the MDCG shall have the following tasks: (a) to contribute to the assessment of applicant conformity assessment bodies and notified bodies pursuant to the provisions set out in Chapter IV; (b) to advise the Commission, at its request, in matters concerning the coordination group of notified bodies as established pursuant to Article 49; (c) to contribute to the development of guidance aimed at ensuring effective and harmonised implementation of this Regulation, in particular regarding the designation and monitoring of notified bodies, application of the general safety and performance requirements and conduct of clinical evaluations and investigations by manufacturers, assessment by notified bodies and vigilance activities; (d) to contribute to the continuous monitoring of technical progress and assessment of whether the general safety and performance requirements laid down in this Regulation and Regulation (EU) 2017/746 are adequate to ensure safety and performance of devices, and thereby contribute to identifying whether there is a need to amend Annex I to this Regulation; (e) to contribute to the development of device standards, of CS and of scientific guidelines, including product specific guidelines, on clinical investigation of certain devices in particular implantable devices and class III devices; (f) to assist the competent authorities of the Member States in their coordination activities in particular in the fields of classification and the determination of the regulatory status of devices, clinical investigations, vigilance and market surveillance including the development and maintenance of a framework for a European market surveillance programme with the objective of achieving efficiency and harmonisation of market surveillance in the Union, in accordance with Article 93; (g) to provide advice, either on its own initiative or at request of the Commission, in the assessment of any issue related to the implementation of this Regulation; (h) to contribute to harmonised administrative practice with regard to devices in the Member States. Article 106 Provision of scientific, technical and clinical opinions and advice 1.   The Commission shall, by means of implementing acts and in consultation with the MDCG, make provision for expert panels to be designated for the assessment of the clinical evaluation in relevant medical fields as referred to in paragraph 9 of this Article and to provide views in accordance with Article 48(6) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices and, where necessary, for categories or groups of devices, or for specific hazards relating to categories or groups of devices, observing the principles of highest scientific competence, impartiality, independence and transparency. The same principles shall apply where the Commission decides to appoint expert laboratories in accordance with paragraph 7 of this Article. 2.   Expert panels and expert laboratories may be designated in areas where the Commission, in consultation with the MDCG, has identified a need for the provision of consistent scientific, technical and/or clinical advice or laboratory expertise in relation to the implementation of this Regulation. Expert panels and expert laboratories may be appointed on a standing or temporary basis. 3.   Expert panels shall consist of advisors appointed by the Commission on the basis of up-to-date clinical, scientific or technical expertise in the field and with a geographical distribution that reflects the diversity of scientific and clinical approaches in the Union. The Commission shall determine the number of members of each panel in accordance with the requisite needs. The members of expert panels shall perform their tasks with impartiality and objectivity. They shall neither seek nor take instructions from notified bodies or manufacturers. Each member shall draw up a declaration of interests, which shall be made publicly available. The Commission shall establish systems and procedures to actively manage and prevent potential conflicts of interest. 4.   Expert panels shall take into account relevant information provided by stakeholders including patients' organisations and healthcare professionals when preparing their scientific opinions. 5.   The Commission, following consultation with the MDCG, may appoint advisors to expert panels following publication in the Official Journal of the European Union and on the Commission website following a call for expressions of interest. Depending on the type of task and the need for specific expertise, advisors may be appointed to the expert panels for a maximum period of three years and their appointment may be renewed. 6.   The Commission, following consultation with the MDCG, may include advisors on a central list of available experts who, whilst not being formally appointed to a panel, are available to provide advice and to support the work of the expert panel as needed. That list shall be published on the Commission website. 7.   The Commission may, by means of implementing acts and following consultation with the MDCG, designate expert laboratories, on the basis of their expertise in: — physico-chemical characterisation, or — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical biological and toxicological testing of specific devices, categories or groups of devices. The Commission shall only designate expert laboratories for which a Member State or the Joint Research Centre has submitted an application for designation. 8.   Expert laboratories shall satisfy the following criteria: (a) have adequate and appropriately qualified staff with adequate knowledge and experience in the field of the devices for which they are designated; (b) possess the necessary equipment to carry out the tasks assigned to them; (c) have the necessary knowledge of international standards and best practices; (d) have an appropriate administrative organisation and structure; (e) ensure that their staff observe the confidentiality of information and data obtained in carrying out their tasks. 9.   Expert panels appointed for clinical evaluation in relevant medical fields shall fulfil the tasks provided for in Article 54(1) and Article 61(2) and Section 5.1 of Annex IX or Section 6 of Annex X, as applicable. 10.   Expert panels and expert laboratories may have the following tasks, depending on the requisite needs: (a) to provide scientific, technical and clinical assistance to the Commission and the MDCG in relation to the implementation of this Regulation; (b) to contribute to the development and maintenance of appropriate guidance and CS for: — clinical investigations, — clinical evaluation and PMCF, — performance studies, — performance evaluation and post-market performance follow-up, — physico-chemical characterisation, and — microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing for specific devices, or a category or group of devices, or for specific hazards related to a category or group of devices; (c) to develop and review clinical evaluation guidance and performance evaluation guidance for performance of conformity assessment in line with the state of the art with regard to clinical evaluation, performance evaluation, physico-chemical characterisation, and microbiological, biocompatibility, mechanical, electrical, electronic or non-clinical toxicological testing; (d) to contribute to the development of standards at international level, ensuring that such standards reflect the state of the art; (e) to provide opinions in response to consultations by manufacturers in accordance with Article 61(2), notified bodies and Member States in accordance with paragraphs 11 to 13 of this Article. (f) to contribute to identification of concerns and emerging issues on the safety and performance of medical devices; (g) to provide views in accordance with Article 48(4) of Regulation (EU) 2017/746 on the performance evaluation of certain in vitro diagnostic medical devices. 11.   The Commission, shall facilitate the access of Member States and notified bodies and manufacturers to advice provided by expert panels and expert laboratories concerning, inter alia, the criteria for an appropriate data set for assessment of the conformity of a device, in particular with regard to the clinical data required for clinical evaluation, with regard to physico-chemical characterisation, and with regard to microbiological, biocompatibility, mechanical, electrical, electronic and non-clinical toxicological testing. 12.   When adopting its scientific opinion in accordance with paragraph 9, the members of the expert panels shall use their best endeavours to reach consensus. If consensus cannot be reached, the expert panels shall decide by a majority of their members, and the scientific opinion shall mention the divergent positions and the grounds on which they are based. The Commission shall publish the scientific opinion and advice delivered in accordance with paragraphs 9 and 11 of this Article, ensuring consideration of aspects of confidentiality as set out in Article 109. The clinical evaluation guidance referred to in point (c) of paragraph 10 shall be published following consultation with the MDCG. 13.   The Commission may require manufacturers and notified bodies to pay fees for the advice provided by expert panels and expert laboratories. The structure and the level of fees as well as the scale and structure of recoverable costs shall be adopted by the Commission by means of implementing acts, taking into account the objectives of the adequate implementation of this Regulation, protection of health and safety, support of innovation and cost-effectiveness and the necessity to achieve active participation in the expert panels. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). 14.   The fees payable to the Commission in accordance with the procedure under paragraph 13 of this Article shall be set in a transparent manner and on the basis of the costs for the services provided. The fees payable shall be reduced in the case of a clinical evaluation consultation procedure initiated in accordance with point (c) of Section 5.1 of Annex IX involving a manufacturer who is a micro, small or medium-sized enterprise within the meaning of Recommendation 2003/361/EC. 15.   The Commission is empowered to adopt delegated acts in accordance with Article 115 to amend the tasks of expert panels and expert laboratories referred to in paragraph 10 of this Article. Article 107 Conflict of interests 1.   Members of the MDCG, its sub-groups, and members of expert panels and expert laboratories shall not have financial or other interests in the medical device industry which could affect their impartiality. They shall undertake to act in the public interest and in an independent manner. They shall declare any direct or indirect interests they may have in the medical device industry and update that declaration whenever a relevant change occurs. The declaration of interests shall be made publicly available on the Commission website. This Article shall not apply to the representatives of stakeholder organisations participating in the sub-groups of the MDCG. 2.   Experts and other third parties invited by the MDCG on a case-by-case basis shall declare any interests they may have in the issue in question. Article 108 Device registers and databanks The Commission and the Member States shall take all appropriate measures to encourage the establishment of registers and databanks for specific types of devices setting common principles to collect comparable information. Such registers and databanks shall contribute to the independent evaluation of the long-term safety and performance of devices, or the traceability of implantable devices, or all of such characteristics. CHAPTER IX CONFIDENTIALITY, DATA PROTECTION, FUNDING AND PENALTIES Article 109 Confidentiality 1.   Unless otherwise provided for in this Regulation and without prejudice to existing national provisions and practices in the Member States on confidentiality, all parties involved in the application of this Regulation shall respect the confidentiality of information and data obtained in carrying out their tasks in order to protect the following: (a) personal data, in accordance with Article 110; (b) commercially confidential information and trade secrets of a natural or legal person, including intellectual property rights; unless disclosure is in the public interest; (c) the effective implementation of this Regulation, in particular for the purpose of inspections, investigations or audits. 2.   Without prejudice to paragraph 1, information exchanged on a confidential basis between competent authorities and between competent authorities and the Commission shall not be disclosed without the prior agreement of the originating authority. 3.   Paragraphs 1 and 2 shall not affect the rights and obligations of the Commission, Member States and notified bodies with regard to exchange of information and the dissemination of warnings, nor the obligations of the persons concerned to provide information under criminal law. 4.   The Commission and Member States may exchange confidential information with regulatory authorities of third countries with which they have concluded bilateral or multilateral confidentiality arrangements. Article 110 Data protection 1.   Member States shall apply Directive 95/46/EC to the processing of personal data carried out in the Member States pursuant to this Regulation. 2.   Regulation (EC) No 45/2001 shall apply to the processing of personal data carried out by the Commission pursuant to this Regulation. Article 111 Levying of fees 1.   This Regulation shall be without prejudice to the possibility for Member States to levy fees for the activities set out in this Regulation, provided that the level of the fees is set in a transparent manner and on the basis of cost-recovery principles. 2.   Member States shall inform the Commission and the other Member States at least three months before the structure and level of fees is to be adopted. The structure and level of fees shall be made publicly available on request. Article 112 Funding of activities related to designation and monitoring of notified bodies The costs associated with joint assessment activities shall be covered by the Commission. The Commission shall, by means of implementing acts, lay down the scale and structure of recoverable costs and other necessary implementing rules. Those implementing acts shall be adopted in accordance with the examination procedure referred to in Article 114(3). Article 113 Penalties The Member States shall lay down the rules on penalties applicable for infringement of the provisions of this Regulation and shall take all measures necessary to ensure that they are implemented. The penalties provided for shall be effective, proportionate, and dissuasive. The Member States shall notify the Commission of those rules and of those measures by 25 February 2020 and shall notify it, without delay, of any subsequent amendment affecting them. CHAPTER X FINAL PROVISIONS Article 114 Committee procedure 1.   The Commission shall be assisted by a Committee on Medical Devices. That Committee shall be a committee within the meaning of Regulation (EU) No 182/2011. 2.   Where reference is made to this paragraph, Article 4 of Regulation (EU) No 182/2011 shall apply. 3.   Where reference is made to this paragraph, Article 5 of Regulation (EU) No 182/2011 shall apply. Where the committee delivers no opinion, the Commission shall not adopt the draft implementing act and the third subparagraph of Article 5(4) of Regulation (EU) No 182/2011 shall apply. 4.   Where reference is made to this paragraph, Article 8 of Regulation (EU) No 182/2011, in conjunction with Article 4 or 5 thereof, as appropriate, shall apply. Article 115 Exercise of the delegation 1.   The power to adopt delegated acts is conferred on the Commission subject to the conditions laid down in this Article. 2.   The power to adopt delegated acts referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall be conferred on the Commission for a period of five years from 25 May 2017. The Commission shall draw up a report in respect of the delegation of power not later than nine months before the end of the five-year period. The delegation of power shall be tacitly extended for periods of an identical duration, unless the European Parliament or the Council opposes such extension not later than three months before the end of each period. 3.   The delegation of power referred to in Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) may be revoked at any time by the European Parliament or by the Council. A decision to revoke shall put an end to the delegation of the power specified in that decision. It shall take effect the day following the publication of the decision in the Official Journal of the European Union or at a later date specified therein. It shall not affect the validity of any delegated acts already in force. 4.   Before adopting a delegated act, the Commission shall consult experts designated by each Member State in accordance with the principles laid down in the Interinstitutional Agreement of 13 April 2016 on Better Law-Making. 5.   As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament and to the Council. 6.   A delegated act adopted pursuant to Articles 1(5), 3, 10(4), 18(3), 19(4), 27(10), 44(11), 52(5), 56(6), 61(8), 70(8) and 106(15) shall enter into force only if no objection has been expressed either by the European Parliament or by the Council within a period of three months of notification of that act to the European Parliament and the Council or if, before the expiry of that period, the European Parliament and the Council have both informed the Commission that they will not object. That period shall be extended by three months at the initiative of the European Parliament or of the Council. Article 116 Separate delegated acts for different delegated powers The Commission shall adopt a separate delegated act in respect of each power delegated to it pursuant to this Regulation. Article 117 Amendment to Directive 2001/83/EC In Annex I to Directive 2001/83/EC, point 12 of Section 3.2. is replaced by the following: ‘(12) Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*1), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device. If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question. Article 118 Amendment to Regulation (EC) No 178/2002 In the third paragraph of Article 2 of Regulation (EC) No 178/2002, the following point is added: ‘(i) medical devices within the meaning of Regulation (EU) 2017/745 of the European Parliament and of the Council (*2). Article 119 Amendment to Regulation (EC) No 1223/2009 In Article 2 of Regulation (EC) No 1223/2009, the following paragraph is added: ‘4.   The Commission may, at the request of a Member State or on its own initiative, adopt the necessary measures to determine whether or not a specific product or group of products falls within the definition ‘cosmetic product’. Those measures shall be adopted in accordance with the regulatory procedure referred to in Article 32(2).’. Article 120 Transitional provisions 1.   From 26 May 2020, any publication of a notification in respect of a notified body in accordance with Directives 90/385/EEC and 93/42/EEC shall become void. 2.   Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC prior to 25 May 2017 shall remain valid until the end of the period indicated on the certificate, except for certificates issued in accordance with Annex 4 to Directive 90/385/EEC or Annex IV to Directive 93/42/EEC which shall become void at the latest on 27 May 2022. Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC from 25 May 2017 shall remain valid until the end of the period indicated on the certificate, which shall not exceed five years from its issuance. They shall however become void at the latest on 27 May 2024. 3.   By way of derogation from Article 5 of this Regulation, a device with a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC and which is valid by virtue of paragraph 2 of this Article may only be placed on the market or put into service provided that from the date of application of this Regulation it continues to comply with either of those Directives, and provided there are no significant changes in the design and intended purpose. However, the requirements of this Regulation relating to post-market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply in place of the corresponding requirements in those Directives. Without prejudice to Chapter IV and paragraph 1 of this Article, the notified body that issued the certificate referred to in the first subparagraph shall continue to be responsible for the appropriate surveillance in respect of all of the applicable requirements relating to the devices it has certified. 4.   Devices lawfully placed on the market pursuant to Directives 90/385/EEC and 93/42/EEC prior to 26 May 2020, and devices placed on the market from 26 May 2020 by virtue of a certificate as referred to in paragraph 2 of this Article, may continue to be made available on the market or put into service until 27 May 2025. 5.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, devices which comply with this Regulation may be placed on the market prior to 26 May 2020. 6.   By way of derogation from Directives 90/385/EEC and 93/42/EEC, conformity assessment bodies which comply with this Regulation may be designated and notified prior 26 May 2020. Notified bodies which are designated and notified in accordance with this Regulation may carry out the conformity assessment procedures laid down in this Regulation and issue certificates in accordance with this Regulation prior to 26 May 2020. 7.   As regards devices subject to the consultation procedure laid down in Article 54, paragraph 5 of this Article shall apply provided that the necessary appointments to the MDCG and expert panels have been made. 8.   By way of derogation from Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC and Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, manufacturers, authorised representatives, importers and notified bodies which, during the period starting on the later of the dates referred to point (d) of Article 123(3) and ending 18 months later, comply with Article 29(4) and Article 56(5) of this Regulation shall be considered to comply with the laws and regulations adopted by Member States in accordance with, respectively, Article 10a of Directive 90/385/EEC or Article 14(1) and (2) of Directive 93/42/EEC and with, respectively, point (a) of Article 10b(1) of Directive 90/385/EEC or points (a) and (b) of Article 14a(1) of Directive 93/42/EEC as specified in Decision 2010/227/EU. 9.   Authorisations granted by the competent authorities of the Member States in accordance with Article 9(9) of Directive 90/385/EEC or Article 11(13) of Directive 93/42/EEC shall keep the validity indicated in the authorisation. 10.   Devices falling within the scope of this Regulation in accordance with points (f) and (g) of Article 1(6) which have been legally placed on the market or put into service in accordance with the rules in force in the Member States prior to 26 May 2020 may continue to be placed on the market and put into service in the Member States concerned. 11.   Clinical investigations which have started to be conducted in accordance with Article 10 of Directive 90/385/EEC or Article 15 of Directive 93/42/EEC prior to 26 May 2020 may continue to be conducted. As of 26 May 2020, however, the reporting of serious adverse events and device deficiencies shall be carried out in accordance with this Regulation. 12.   Until the Commission has designated, pursuant to Article 27(2), issuing entities, GS1, HIBCC and ICCBBA shall be considered to be designated issuing entities. Article 121 Evaluation By 27 May 2027, the Commission shall assess the application of this Regulation and produce an evaluation report on the progress towards achievement of the objectives contained herein including an assessment of the resources required to implement this Regulation. Special attention shall be given to the traceability of medical devices through the storage, pursuant to Article 27, of the UDI by economic operators, health institutions and health professionals. Article 122 Repeal Without prejudice to Articles 120(3) and (4) of this Regulation, and without prejudice to the obligations of the Member States and manufacturers as regards vigilance and to the obligations of manufacturers as regards the making available of documentation, under Directives 90/385/EEC and 93/42/EEC, those Directives are repealed with effect from 26 May 2020, with the exception of: — Articles 8 and 10, points (b) and (c) of Article 10b(1), Article 10b(2) and Article 10b(3) of Directive 90/385/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10a and point (a) of Article 10b(1) of Directive 90/385/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation; — Article 10, points (c) and (d) of Article 14a(1), Article 14a(2), Article 14a(3) and Article 15 of Directive 93/42/EEC, and the obligations relating to vigilance and clinical investigations provided for in the corresponding Annexes, which are repealed with effect from the later of the dates referred to in point (d) of Article 123(3) of this Regulation; and — Article 14(1) and (2) and points (a) and (b) of Article 14a(1) of Directive 93/42/EEC, and the obligations relating to registration of devices and economic operators, and to certificate notifications, provided for in the corresponding Annexes, which are repealed with effect from 18 months after the later of the dates referred to in point (d) of Article 123(3) of this Regulation. As regards the devices referred to in Article 120 (3) and (4) of this Regulation, the Directives referred to in the first paragraph shall continue to apply until 27 May 2025 to the extent necessary for the application of those paragraphs. Notwithstanding the first paragraph, Regulations (EU) No 207/2012 and (EU) No 722/2012 shall remain in force and continue to apply unless and until repealed by implementing acts adopted by the Commission pursuant to this Regulation. References to the repealed Directives shall be understood as references to this Regulation and shall be read in accordance with the correlation table laid down in Annex XVII to this Regulation. Article 123 Entry into force and date of application 1.   This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union. 2.   It shall apply from 26 May 2020. 3.   By way of derogation from paragraph 2: (a) Articles 35 to 50 shall apply from 26 November 2017. However, from that date until 26 May 2020, the obligations on notified bodies pursuant to Articles 35 to 50 shall apply only to those bodies which submit an application for designation in accordance with Article 38; (b) Articles 101 and 103 shall apply from 26 November 2017; (c) Article 102 shall apply from 26 May 2018; (d) without prejudice to the obligations on the Commission pursuant to Article 34, where, due to circumstances that could not reasonably have been foreseen when drafting the plan referred to in Article 34(1), Eudamed is not fully functional on 26 May 2020, the obligations and requirements that relate to Eudamed shall apply from the date corresponding to six months after the date of publication of the notice referred to in Article 34(3). The provisions referred to in the preceding sentence are: — Article 29, — Article 31, — Article 32, — Article 33(4), — the second sentence of Article 40(2), — Article 42(10), — Article 43(2), — the second subparagraph of Article 44(12), — points (d) and (e) of Article 46(7), — Article 53(2), — Article 54(3), — Article 55(1), — Articles 70 to 77, — paragraphs 1 to 13 of Article 78, — Articles 79 to 82, — Article 86(2), — Articles 87 and 88, — Article 89(5) and (7), and the third subparagraph of Article 89(8), — Article 90, — Article 93(4), (7) and (8), — Article 95(2) and (4), — the last sentence of Article 97(2), — Article 99(4), — the second sentence of the first subparagraph of Article 120(3). Until Eudamed is fully functional, the corresponding provisions of Directives 90/385/EEC and 93/42/EEC shall continue to apply for the purpose of meeting the obligations laid down in the provisions listed in the first paragraph of this point regarding exchange of information including, and in particular, information regarding vigilance reporting, clinical investigations, registration of devices and economic operators, and certificate notifications. (e) Article 29(4) and Article 56(5) shall apply from 18 months after the later of the dates referred to in point (d); (f) for implantable devices and for class III devices Article 27(4) shall apply from 26 May 2021. For class IIa and class IIb devices Article 27(4) shall apply from 26 May 2023. For class I devices Article 27(4) shall apply from 26 May 2025; (g) for reusable devices that shall bear the UDI carrier on the device itself, Article 27(4) shall apply from two years after the date referred to in point (f) of this paragraph for the respective class of devices in that point; (h) The procedure set out in Article 78 shall apply from 26 May 2027, without prejudice to Article 78(14); (i) Article 120(12) shall apply from 26 May 2019. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Strasbourg, 5 April 2017. For the European Parliament The President A. TAJANI For the Council The President I. BORG (1)  Opinion of 14 February 2013 (OJ C 133, 9.5.2013, p. 52). (2)  Position of the European Parliament of 2 April 2014 (not yet published in the Official Journal) and position of the Council at first reading of 7 March 2017 (not yet published in the Official Journal). (3)  Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (OJ L 189, 20.7.1990, p. 17). (4)  Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ L 169, 12.7.1993, p. 1). (5)  Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety (OJ L 31, 1.2.2002, p. 1). (6)  Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products (OJ L 342, 22.12.2009, p. 59). (7)  Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67). (8)  Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (OJ L 324, 10.12.2007, p. 121). (9)  Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (OJ L 102, 7.4.2004, p. 48). (10)  Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components (OJ L 33, 8.2.2003, p. 30). (11)  Commission Recommendation 2011/696/EU of 18 October 2011 on the definition of nanomaterial (OJ L 275, 20.10.2011, p. 38). (12)  Directive 2014/30/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to electromagnetic compatibility (OJ L 96, 29.3.2014. p. 79). (13)  Council Directive 2013/59/Euratom of 5 December 2013 laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation, and repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom (OJ L 13, 17.1.2014, p. 1). (14)  Directive (EU) 2015/1535 of the European Parliament and of the Council of 9 September 2015 laying down a procedure for the provision of information in the field of technical regulations and of rules on Information Society services (OJ L 241, 17.9.2015, p. 1). (15)  Regulation (EU) No 1025/2012 of the European Parliament and of the Council of 25 October 2012 on European standardisation, amending Council Directives 89/686/EEC and 93/15/EEC and Directives 94/9/EC, 94/25/EC, 95/16/EC, 97/23/EC, 98/34/EC, 2004/22/EC, 2007/23/EC, 2009/23/EC and 2009/105/EC of the European Parliament and of the Council and repealing Council Decision 87/95/EEC and Decision No 1673/2006/EC of the European Parliament and of the Council (OJ L 316, 14.11.2012, p. 12). (16)  Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (OJ L 331, 7.12.1998, p. 1). (17)  Regulation (EC) No 765/2008 of the European Parliament and of the Council of 9 July 2008 setting out the requirements for accreditation and market surveillance relating to the marketing of products and repealing Regulation (EEC) No 339/93 (OJ L 218, 13.8.2008, p. 30). (18)  Decision No 768/2008/EC of the European Parliament and of the Council of 9 July 2008 on a common framework for the marketing of products, and repealing Council Decision 93/465/EEC (OJ L 218, 13.8.2008, p. 82). (19)  Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of the Member States concerning liability for defective products (OJ L 210, 7.8.1985, p. 29). (20)  Judgment of 28 July 2011 in Orifarm and Paranova, joined cases C-400/09 and C-207/10, ECLI:EU:C:2011:519. (21)  Commission Decision 2010/227/EU of 19 April 2010 on the European Databank for Medical Devices (OJ L 102, 23.4.2010, p. 45). (22)  Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data (OJ L 281, 23.11.1995, p. 31). (23)  Regulation (EC) No 45/2001 of the European Parliament and of the Council of 18 December 2000 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data (OJ L 8, 12.1.2001, p. 1). (24)  Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes (OJ L 276, 20.10.2010, p. 33). (25)  Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU (see page 176 of this Official Journal). (26)   OJ L 123, 12.5.2016, p. 1. (27)  Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February 2011 laying down the rules and general principles concerning mechanisms for control by Member States of the Commission's exercise of implementing powers (OJ L 55, 28.2.2011, p. 13). (28)  Commission Regulation (EU) No 207/2012 of 9 March 2012 on electronic instructions for use of medical devices (OJ L 72, 10.3.2012, p. 28). (29)  Commission Regulation (EU) No 722/2012 of 8 August 2012 concerning particular requirements as regards the requirements laid down in Council Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and medical devices manufactured utilising tissues of animal origin (OJ L 212, 9.8.2012, p. 3). (30)  Commission Directive 2003/12/EC of 3 February 2003 on the reclassification of breast implants in the framework of Directive 93/42/EEC concerning medical devices (OJ L 28, 4.2.2003, p. 43). (31)  Commission Directive 2005/50/EC of 11 August 2005 on the reclassification of hip, knee and shoulder joint replacements in the framework of Council Directive 93/42/EEC concerning medical devices (OJ L 210, 12.8.2005, p. 41). (32)  Commission Implementing Regulation (EU) No 920/2013 of 24 September 2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices (OJ L 253, 25.9.2013, p. 8). (33)   OJ C 358, 7.12.2013, p. 10. (34)  Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (OJ L 136, 30.4.2004, p. 1). (35)  Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24). (36)  Commission Recommendation 2003/361/ΕC of 6 May 2003 concerning the definition of micro, small and medium-sized enterprises (OJ L 124, 20.5.2003, p. 36). (37)  Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 27.5.2014, p. 1). ANNEXES I    General safety and performance requirements II    Technical documentation III    Technical documentation on post-market surveillance IV    EU declaration of conformity V    CE marking of conformity VI    Information to be submitted upon the registration of devices and economic operators in accordance with Articles 29(4) and 31; core data elements to be provided to the UDI database together with the UDI-DI in accordance with Articles 28 and 29;and the UDI system VII    Requirements to be met by notified bodies VIII    Classification rules IX    Conformity assessment based on a quality management system and assessment of the technical documentation X    Conformity assessment based on type examination XI    Conformity assessment based on product conformity verification XII    Certificates issued by a notified body XIII    Procedure for custom-made devices XIV    Clinical evaluation and post-market clinical follow-up XV    Clinical investigations XVI    List of groups of products without an intended medical purpose referred to in Article 1(2) XVII    Correlation table ANNEX I GENERAL SAFETY AND PERFORMANCE REQUIREMENTS CHAPTER I GENERAL REQUIREMENTS 1.   Devices shall achieve the performance intended by their manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose. They shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. 2.   The requirement in this Annex to reduce risks as far as possible means the reduction of risks as far as possible without adversely affecting the benefit-risk ratio. 3.   Manufacturers shall establish, implement, document and maintain a risk management system. Risk management shall be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. In carrying out risk management manufacturers shall: (a) establish and document a risk management plan for each device; (b) identify and analyse the known and foreseeable hazards associated with each device; (c) estimate and evaluate the risks associated with, and occurring during, the intended use and during reasonably foreseeable misuse; (d) eliminate or control the risks referred to in point (c) in accordance with the requirements of Section 4; (e) evaluate the impact of information from the production phase and, in particular, from the post-market surveillance system, on hazards and the frequency of occurrence thereof, on estimates of their associated risks, as well as on the overall risk, benefit-risk ratio and risk acceptability; and (f) based on the evaluation of the impact of the information referred to in point (e), if necessary amend control measures in line with the requirements of Section 4. 4.   Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art. To reduce risks, Manufacturers shall manage risks so that the residual risk associated with each hazard as well as the overall residual risk is judged acceptable. In selecting the most appropriate solutions, manufacturers shall, in the following order of priority: (a) eliminate or reduce risks as far as possible through safe design and manufacture; (b) where appropriate, take adequate protection measures, including alarms if necessary, in relation to risks that cannot be eliminated; and (c) provide information for safety (warnings/precautions/contra-indications) and, where appropriate, training to users. Manufacturers shall inform users of any residual risks. 5.   In eliminating or reducing risks related to use error, the manufacturer shall: (a) reduce as far as possible the risks related to the ergonomic features of the device and the environment in which the device is intended to be used (design for patient safety), and (b) give consideration to the technical knowledge, experience, education, training and use environment, where applicable, and the medical and physical conditions of intended users (design for lay, professional, disabled or other users). 6.   The characteristics and performance of a device shall not be adversely affected to such a degree that the health or safety of the patient or the user and, where applicable, of other persons are compromised during the lifetime of the device, as indicated by the manufacturer, when the device is subjected to the stresses which can occur during normal conditions of use and has been properly maintained in accordance with the manufacturer's instructions. 7.   Devices shall be designed, manufactured and packaged in such a way that their characteristics and performance during their intended use are not adversely affected during transport and storage, for example, through fluctuations of temperature and humidity, taking account of the instructions and information provided by the manufacturer. 8.   All known and foreseeable risks, and any undesirable side-effects, shall be minimised and be acceptable when weighed against the evaluated benefits to the patient and/or user arising from the achieved performance of the device during normal conditions of use. 9.   For the devices referred to in Annex XVI, the general safety requirements set out in Sections 1 and 8 shall be understood to mean that the device, when used under the conditions and for the purposes intended, does not present a risk at all or presents a risk that is no more than the maximum acceptable risk related to the product's use which is consistent with a high level of protection for the safety and health of persons. CHAPTER II REQUIREMENTS REGARDING DESIGN AND MANUFACTURE 10.   Chemical, physical and biological properties 10.1.   Devices shall be designed and manufactured in such a way as to ensure that the characteristics and performance requirements referred to in Chapter I are fulfilled. Particular attention shall be paid to: (a) the choice of materials and substances used, particularly as regards toxicity and, where relevant, flammability; (b) the compatibility between the materials and substances used and biological tissues, cells and body fluids, taking account of the intended purpose of the device and, where relevant, absorption, distribution, metabolism and excretion; (c) the compatibility between the different parts of a device which consists of more than one implantable part; (d) the impact of processes on material properties; (e) where appropriate, the results of biophysical or modelling research the validity of which has been demonstrated beforehand; (f) the mechanical properties of the materials used, reflecting, where appropriate, matters such as strength, ductility, fracture resistance, wear resistance and fatigue resistance; (g) surface properties; and (h) the confirmation that the device meets any defined chemical and/or physical specifications. 10.2.   Devices shall be designed, manufactured and packaged in such a way as to minimise the risk posed by contaminants and residues to patients, taking account of the intended purpose of the device, and to the persons involved in the transport, storage and use of the devices. Particular attention shall be paid to tissues exposed to those contaminants and residues and to the duration and frequency of exposure. 10.3.   Devices shall be designed and manufactured in such a way that they can be used safely with the materials and substances, including gases, with which they enter into contact during their intended use; if the devices are intended to administer medicinal products they shall be designed and manufactured in such a way as to be compatible with the medicinal products concerned in accordance with the provisions and restrictions governing those medicinal products and that the performance of both the medicinal products and of the devices is maintained in accordance with their respective indications and intended use. 10.4.   Substances 10.4.1.   Design and manufacture of devices Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by substances or particles, including wear debris, degradation products and processing residues, that may be released from the device. Devices, or those parts thereof or those materials used therein that: — are invasive and come into direct contact with the human body, — (re)administer medicines, body liquids or other substances, including gases, to/from the body, or — transport or store such medicines, body fluids or substances, including gases, to be (re)administered to the body, shall only contain the following substances in a concentration that is above 0,1 % weight by weight (w/w) where justified pursuant to Section 10.4.2: (a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the European Parliament and of the Council (1), or (b) substances having endocrine-disrupting properties for which there is scientific evidence of probable serious effects to human health and which are identified either in accordance with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council (2) or, once a delegated act has been adopted by the Commission pursuant to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European Parliament and the Council (3), in accordance with the criteria that are relevant to human health amongst the criteria established therein. 10.4.2.   Justification regarding the presence of CMR and/or endocrine-disrupting substances The justification for the presence of such substances shall be based upon: (a) an analysis and estimation of potential patient or user exposure to the substance; (b) an analysis of possible alternative substances, materials or designs, including, where available, information about independent research, peer-reviewed studies, scientific opinions from relevant scientific committees and an analysis of the availability of such alternatives; (c) argumentation as to why possible substance and/ or material substitutes, if available, or design changes, if feasible, are inappropriate in relation to maintaining the functionality, performance and the benefit-risk ratios of the product; including taking into account if the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials; and (d) where applicable and available, the latest relevant scientific committee guidelines in accordance with Sections 10.4.3. and 10.4.4. 10.4.3.   Guidelines on phthalates For the purposes of Section 10.4., the Commission shall, as soon as possible and by 26 May 2018, provide the relevant scientific committee with a mandate to prepare guidelines that shall be ready before 26 May 2020. The mandate for the committee shall encompass at least a benefit-risk assessment of the presence of phthalates which belong to either of the groups of substances referred to in points (a) and (b) of Section 10.4.1. The benefit-risk assessment shall take into account the intended purpose and context of the use of the device, as well as any available alternative substances and alternative materials, designs or medical treatments. When deemed appropriate on the basis of the latest scientific evidence, but at least every five years, the guidelines shall be updated. 10.4.4.   Guidelines on other CMR and endocrine-disrupting substances Subsequently, the Commission shall mandate the relevant scientific committee to prepare guidelines as referred to in Section 10.4.3. also for other substances referred to in points (a) and (b) of Section 10.4.1., where appropriate. 10.4.5.   Labelling Where devices, parts thereof or materials used therein as referred to in Section 10.4.1. contain substances referred to in points (a) or (b) of Section 10.4.1. in a concentration above 0,1 % weight by weight (w/w), the presence of those substances shall be labelled on the device itself and/or on the packaging for each unit or, where appropriate, on the sales packaging, with the list of such substances. If the intended use of such devices includes treatment of children or treatment of pregnant or breastfeeding women or treatment of other patient groups considered particularly vulnerable to such substances and/or materials, information on residual risks for those patient groups and, if applicable, on appropriate precautionary measures shall be given in the instructions for use. 10.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks posed by the unintentional ingress of substances into the device taking into account the device and the nature of the environment in which it is intended to be used. 10.6.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks linked to the size and the properties of particles which are or can be released into the patient's or user's body, unless they come into contact with intact skin only. Special attention shall be given to nanomaterials. 11.   Infection and microbial contamination 11.1.   Devices and their manufacturing processes shall be designed in such a way as to eliminate or to reduce as far as possible the risk of infection to patients, users and, where applicable, other persons. The design shall: (a) reduce as far as possible and appropriate the risks from unintended cuts and pricks, such as needle stick injuries, (b) allow easy and safe handling, (c) reduce as far as possible any microbial leakage from the device and/or microbial exposure during use, and (d) prevent microbial contamination of the device or its content such as specimens or fluids. 11.2.   Where necessary devices shall be designed to facilitate their safe cleaning, disinfection, and/or re-sterilisation. 11.3.   Devices labelled as having a specific microbial state shall be designed, manufactured and packaged to ensure that they remain in that state when placed on the market and remain so under the transport and storage conditions specified by the manufacturer. 11.4.   Devices delivered in a sterile state shall be designed, manufactured and packaged in accordance with appropriate procedures, to ensure that they are sterile when placed on the market and that, unless the packaging which is intended to maintain their sterile condition is damaged, they remain sterile, under the transport and storage conditions specified by the manufacturer, until that packaging is opened at the point of use. It shall be ensured that the integrity of that packaging is clearly evident to the final user. 11.5.   Devices labelled as sterile shall be processed, manufactured, packaged and, sterilised by means of appropriate, validated methods. 11.6.   Devices intended to be sterilised shall be manufactured and packaged in appropriate and controlled conditions and facilities. 11.7.   Packaging systems for non-sterile devices shall maintain the integrity and cleanliness of the product and, where the devices are to be sterilised prior to use, minimise the risk of microbial contamination; the packaging system shall be suitable taking account of the method of sterilisation indicated by the manufacturer. 11.8.   The labelling of the device shall distinguish between identical or similar devices placed on the market in both a sterile and a non-sterile condition additional to the symbol used to indicate that devices are sterile. 12.   Devices incorporating a substance considered to be a medicinal product and devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body. 12.1.   In the case of devices referred to in the first subparagraph of Article 1(8), the quality, safety and usefulness of the substance which, if used separately, would be considered to be a medicinal product within the meaning of point (2) of Article 1 of Directive 2001/83/EC, shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC, as required by the applicable conformity assessment procedure under this Regulation. 12.2.   Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation. 13.   Devices incorporating materials of biological origin 13.1.   For devices manufactured utilising derivatives of tissues or cells of human origin which are non-viable or are rendered non-viable covered by this Regulation in accordance with point (g) of Article 1(6), the following shall apply: (a) donation, procurement and testing of the tissues and cells shall be done in accordance with Directive 2004/23/EC; (b) processing, preservation and any other handling of those tissues and cells or their derivatives shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process; (c) the traceability system for those devices shall be complementary and compatible with the traceability and data protection requirements laid down in Directive 2004/23/EC and in Directive 2002/98/EC. 13.2.   For devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable the following shall apply: (a) where feasible taking into account the animal species, tissues and cells of animal origin, or their derivatives, shall originate from animals that have been subjected to veterinary controls that are adapted to the intended use of the tissues. Information on the geographical origin of the animals shall be retained by manufacturers; (b) sourcing, processing, preservation, testing and handling of tissues, cells and substances of animal origin, or their derivatives, shall be carried out so as to provide safety for patients, users and, where applicable, other persons. In particular safety with regard to viruses and other transmissible agents shall be addressed by implementation of validated methods of elimination or viral inactivation in the course of the manufacturing process, except when the use of such methods would lead to unacceptable degradation compromising the clinical benefit of the device; (c) in the case of devices manufactured utilising tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 the particular requirements laid down in that Regulation shall apply. 13.3.   For devices manufactured utilising non-viable biological substances other than those referred to in Sections 13.1 and 13.2, the processing, preservation, testing and handling of those substances shall be carried out so as to provide safety for patients, users and, where applicable, other persons, including in the waste disposal chain. In particular, safety with regard to viruses and other transmissible agents shall be addressed by appropriate methods of sourcing and by implementation of validated methods of elimination or inactivation in the course of the manufacturing process. 14.   Construction of devices and interaction with their environment 14.1.   If the device is intended for use in combination with other devices or equipment the whole combination, including the connection system shall be safe and shall not impair the specified performance of the devices. Any restrictions on use applying to such combinations shall be indicated on the label and/or in the instructions for use. Connections which the user has to handle, such as fluid, gas transfer, electrical or mechanical coupling, shall be designed and constructed in such a way as to minimise all possible risks, such as misconnection. 14.2.   Devices shall be designed and manufactured in such a way as to remove or reduce as far as possible: (a) the risk of injury, in connection with their physical features, including the volume/pressure ratio, dimensional and where appropriate ergonomic features; (b) risks connected with reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, temperature, variations in pressure and acceleration or radio signal interferences; (c) the risks associated with the use of the device when it comes into contact with materials, liquids, and substances, including gases, to which it is exposed during normal conditions of use; (d) the risks associated with the possible negative interaction between software and the IT environment within which it operates and interacts; (e) the risks of accidental ingress of substances into the device; (f) the risks of reciprocal interference with other devices normally used in the investigations or for the treatment given; and (g) risks arising where maintenance or calibration are not possible (as with implants), from ageing of materials used or loss of accuracy of any measuring or control mechanism. 14.3.   Devices shall be designed and manufactured in such a way as to minimise the risks of fire or explosion during normal use and in single fault condition. Particular attention shall be paid to devices the intended use of which includes exposure to or use in association with flammable or explosive substances or substances which could cause combustion. 14.4.   Devices shall be designed and manufactured in such a way that adjustment, calibration, and maintenance can be done safely and effectively. 14.5.   Devices that are intended to be operated together with other devices or products shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe. 14.6   Any measurement, monitoring or display scale shall be designed and manufactured in line with ergonomic principles, taking account of the intended purpose, users and the environmental conditions in which the devices are intended to be used. 14.7.   Devices shall be designed and manufactured in such a way as to facilitate their safe disposal and the safe disposal of related waste substances by the user, patient or other person. To that end, manufacturers shall identify and test procedures and measures as a result of which their devices can be safely disposed after use. Such procedures shall be described in the instructions for use. 15.   Devices with a diagnostic or measuring function 15.1.   Diagnostic devices and devices with a measuring function, shall be designed and manufactured in such a way as to provide sufficient accuracy, precision and stability for their intended purpose, based on appropriate scientific and technical methods. The limits of accuracy shall be indicated by the manufacturer. 15.2.   The measurements made by devices with a measuring function shall be expressed in legal units conforming to the provisions of Council Directive 80/181/EEC (4). 16.   Protection against radiation 16.1.   General (a) Devices shall be designed, manufactured and packaged in such a way that exposure of patients, users and other persons to radiation is reduced as far as possible, and in a manner that is compatible with the intended purpose, whilst not restricting the application of appropriate specified levels for therapeutic and diagnostic purposes. (b) The operating instructions for devices emitting hazardous or potentially hazardous radiation shall contain detailed information as to the nature of the emitted radiation, the means of protecting the patient and the user, and on ways of avoiding misuse and of reducing the risks inherent to installation as far as possible and appropriate. Information regarding the acceptance and performance testing, the acceptance criteria, and the maintenance procedure shall also be specified. 16.2.   Intended radiation (a) Where devices are designed to emit hazardous, or potentially hazardous, levels of ionizing and/or non-ionizing radiation necessary for a specific medical purpose the benefit of which is considered to outweigh the risks inherent to the emission, it shall be possible for the user to control the emissions. Such devices shall be designed and manufactured to ensure reproducibility of relevant variable parameters within an acceptable tolerance. (b) Where devices are intended to emit hazardous, or potentially hazardous, ionizing and/or non-ionizing radiation, they shall be fitted, where possible, with visual displays and/or audible warnings of such emissions. 16.3.   Devices shall be designed and manufactured in such a way that exposure of patients, users and other persons to the emission of unintended, stray or scattered radiation is reduced as far as possible. Where possible and appropriate, methods shall be selected which reduce the exposure to radiation of patients, users and other persons who may be affected. 16.4.   Ionising radiation (a) Devices intended to emit ionizing radiation shall be designed and manufactured taking into account the requirements of the Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionising radiation. (b) Devices intended to emit ionising radiation shall be designed and manufactured in such a way as to ensure that, where possible, taking into account the intended use, the quantity, geometry and quality of the radiation emitted can be varied and controlled, and, if possible, monitored during treatment. (c) Devices emitting ionising radiation intended for diagnostic radiology shall be designed and manufactured in such a way as to achieve an image and/or output quality that are appropriate to the intended medical purpose whilst minimising radiation exposure of the patient and user. (d) Devices that emit ionising radiation and are intended for therapeutic radiology shall be designed and manufactured in such a way as to enable reliable monitoring and control of the delivered dose, the beam type, energy and, where appropriate, the quality of radiation. 17.   Electronic programmable systems — devices that incorporate electronic programmable systems and software that are devices in themselves 17.1.   Devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, shall be designed to ensure repeatability, reliability and performance in line with their intended use. In the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks or impairment of performance. 17.2.   For devices that incorporate software or for software that are devices in themselves, the software shall be developed and manufactured in accordance with the state of the art taking into account the principles of development life cycle, risk management, including information security, verification and validation. 17.3.   Software referred to in this Section that is intended to be used in combination with mobile computing platforms shall be designed and manufactured taking into account the specific features of the mobile platform (e.g. size and contrast ratio of the screen) and the external factors related to their use (varying environment as regards level of light or noise). 17.4.   Manufacturers shall set out minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. 18.   Active devices and devices connected to them 18.1.   For non-implantable active devices, in the event of a single fault condition, appropriate means shall be adopted to eliminate or reduce as far as possible consequent risks. 18.2.   Devices where the safety of the patient depends on an internal power supply shall be equipped with a means of determining the state of the power supply and an appropriate warning or indication for when the capacity of the power supply becomes critical. If necessary, such warning or indication shall be given prior to the power supply becoming critical. 18.3.   Devices where the safety of the patient depends on an external power supply shall include an alarm system to signal any power failure. 18.4.   Devices intended to monitor one or more clinical parameters of a patient shall be equipped with appropriate alarm systems to alert the user of situations which could lead to death or severe deterioration of the patient's state of health. 18.5.   Devices shall be designed and manufactured in such a way as to reduce as far as possible the risks of creating electromagnetic interference which could impair the operation of the device in question or other devices or equipment in the intended environment. 18.6.   Devices shall be designed and manufactured in such a way as to provide a level of intrinsic immunity to electromagnetic interference such that is adequate to enable them to operate as intended. 18.7.   Devices shall be designed and manufactured in such a way as to avoid, as far as possible, the risk of accidental electric shocks to the patient, user or any other person, both during normal use of the device and in the event of a single fault condition in the device, provided the device is installed and maintained as indicated by the manufacturer. 18.8.   Devices shall be designed and manufactured in such a way as to protect, as far as possible, against unauthorised access that could hamper the device from functioning as intended. 19.   Particular requirements for active implantable devices 19.1.   Active implantable devices shall be designed and manufactured in such a way as to remove or minimize as far as possible: (a) risks connected with the use of energy sources with particular reference, where electricity is used, to insulation, leakage currents and overheating of the devices, (b) risks connected with medical treatment, in particular those resulting from the use of defibrillators or high-frequency surgical equipment, and (c) risks which may arise where maintenance and calibration are impossible, including: — excessive increase of leakage currents, — ageing of the materials used, — excess heat generated by the device, — decreased accuracy of any measuring or control mechanism. 19.2.   Active implantable devices shall be designed and manufactured in such a way as to ensure — if applicable, the compatibility of the devices with the substances they are intended to administer, and — the reliability of the source of energy. 19.3.   Active implantable devices and, if appropriate, their component parts shall be identifiable to allow any necessary measure to be taken following the discovery of a potential risk in connection with the devices or their component parts. 19.4.   Active implantable devices shall bear a code by which they and their manufacturer can be unequivocally identified (particularly with regard to the type of device and its year of manufacture); it shall be possible to read this code, if necessary, without the need for a surgical operation. 20.   Protection against mechanical and thermal risks 20.1.   Devices shall be designed and manufactured in such a way as to protect patients and users against mechanical risks connected with, for example, resistance to movement, instability and moving parts. 20.2.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from vibration generated by the devices, taking account of technical progress and of the means available for limiting vibrations, particularly at source, unless the vibrations are part of the specified performance. 20.3.   Devices shall be designed and manufactured in such a way as to reduce to the lowest possible level the risks arising from the noise emitted, taking account of technical progress and of the means available to reduce noise, particularly at source, unless the noise emitted is part of the specified performance. 20.4.   Terminals and connectors to the electricity, gas or hydraulic and pneumatic energy supplies which the user or other person has to handle, shall be designed and constructed in such a way as to minimise all possible risks. 20.5.   Errors likely to be made when fitting or refitting certain parts which could be a source of risk shall be made impossible by the design and construction of such parts or, failing this, by information given on the parts themselves and/or their housings. The same information shall be given on moving parts and/or their housings where the direction of movement needs to be known in order to avoid a risk. 20.6.   Accessible parts of devices (excluding the parts or areas intended to supply heat or reach given temperatures) and their surroundings shall not attain potentially dangerous temperatures under normal conditions of use. 21.   Protection against the risks posed to the patient or user by devices supplying energy or substances 21.1.   Devices for supplying the patient with energy or substances shall be designed and constructed in such a way that the amount to be delivered can be set and maintained accurately enough to ensure the safety of the patient and of the user. 21.2.   Devices shall be fitted with the means of preventing and/or indicating any inadequacies in the amount of energy delivered or substances delivered which could pose a danger. Devices shall incorporate suitable means to prevent, as far as possible, the accidental release of dangerous levels of energy or substances from an energy and/or substance source. 21.3.   The function of the controls and indicators shall be clearly specified on the devices. Where a device bears instructions required for its operation or indicates operating or adjustment parameters by means of a visual system, such information shall be understandable to the user and, as appropriate, the patient. 22.   Protection against the risks posed by medical devices intended by the manufacturer for use by lay persons 22.1.   Devices for use by lay persons shall be designed and manufactured in such a way that they perform appropriately for their intended purpose taking into account the skills and the means available to lay persons and the influence resulting from variation that can be reasonably anticipated in the lay person's technique and environment. The information and instructions provided by the manufacturer shall be easy for the lay person to understand and apply. 22.2.   Devices for use by lay persons shall be designed and manufactured in such a way as to: — ensure that the device can be used safely and accurately by the intended user at all stages of the procedure, if necessary after appropriate training and/or information, — reduce, as far as possible and appropriate, the risk from unintended cuts and pricks such as needle stick injuries, and — reduce as far as possible the risk of error by the intended user in the handling of the device and, if applicable, in the interpretation of the results. 22.3.   Devices for use by lay persons shall, where appropriate, include a procedure by which the lay person: — can verify that, at the time of use, the device will perform as intended by the manufacturer, and — if applicable, is warned if the device has failed to provide a valid result. CHAPTER III REQUIREMENTS REGARDING THE INFORMATION SUPPLIED WITH THE DEVICE 23.   Label and instructions for use 23.1.   General requirements regarding the information supplied by the manufacturer Each device shall be accompanied by the information needed to identify the device and its manufacturer, and by any safety and performance information relevant to the user, or any other person, as appropriate. Such information may appear on the device itself, on the packaging or in the instructions for use, and shall, if the manufacturer has a website, be made available and kept up to date on the website, taking into account the following: (a) The medium, format, content, legibility, and location of the label and instructions for use shall be appropriate to the particular device, its intended purpose and the technical knowledge, experience, education or training of the intended user(s). In particular, instructions for use shall be written in terms readily understood by the intended user and, where appropriate, supplemented with drawings and diagrams. (b) The information required on the label shall be provided on the device itself. If this is not practicable or appropriate, some or all of the information may appear on the packaging for each unit, and/or on the packaging of multiple devices. (c) Labels shall be provided in a human-readable format and may be supplemented by machine-readable information, such as radio-frequency identification (‘RFID’) or bar codes. (d) Instructions for use shall be provided together with devices. By way of exception, instructions for use shall not be required for class I and class IIa devices if such devices can be used safely without any such instructions and unless otherwise provided for elsewhere in this Section. (e) Where multiple devices are supplied to a single user and/or location, a single copy of the instructions for use may be provided if so agreed by the purchaser who in any case may request further copies to be provided free of charge. (f) Instructions for use may be provided to the user in non-paper format (e.g. electronic) to the extent, and only under the conditions, set out in Regulation (EU) No 207/2012 or in any subsequent implementing rules adopted pursuant to this Regulation. (g) Residual risks which are required to be communicated to the user and/or other person shall be included as limitations, contra-indications, precautions or warnings in the information supplied by the manufacturer. (h) Where appropriate, the information supplied by the manufacturer shall take the form of internationally recognised symbols. Any symbol or identification colour used shall conform to the harmonised standards or CS. In areas for which no harmonised standards or CS exist, the symbols and colours shall be described in the documentation supplied with the device. 23.2.   Information on the label The label shall bear all of the following particulars: (a) the name or trade name of the device; (b) the details strictly necessary for a user to identify the device, the contents of the packaging and, where it is not obvious for the user, the intended purpose of the device; (c) the name, registered trade name or registered trade mark of the manufacturer and the address of its registered place of business; (d) if the manufacturer has its registered place of business outside the Union, the name of the authorised representative and address of the registered place of business of the authorised representative; (e) where applicable, an indication that the device contains or incorporates: — a medicinal substance, including a human blood or plasma derivative, or — tissues or cells, or their derivatives, of human origin, or — tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012; (f) where applicable, information labelled in accordance with Section 10.4.5.; (g) the lot number or the serial number of the device preceded by the words LOT NUMBER or SERIAL NUMBER or an equivalent symbol, as appropriate; (h) the UDI carrier referred to in Article 27(4) and Part C of Annex VII; (i) an unambiguous indication of t the time limit for using or implanting the device safely, expressed at least in terms of year and month, where this is relevant; (j) where there is no indication of the date until when it may be used safely, the date of manufacture. This date of manufacture may be included as part of the lot number or serial number, provided the date is clearly identifiable; (k) an indication of any special storage and/or handling condition that applies; (l) if the device is supplied sterile, an indication of its sterile state and the sterilisation method; (m) warnings or precautions to be taken that need to be brought to the immediate attention of the user of the device, and to any other person. This information may be kept to a minimum in which case more detailed information shall appear in the instructions for use, taking into account the intended users; (n) if the device is intended for single use, an indication of that fact. A manufacturer's indication of single use shall be consistent across the Union; (o) if the device is a single-use device that has been reprocessed, an indication of that fact, the number of reprocessing cycles already performed, and any limitation as regards the number of reprocessing cycles; (p) if the device is custom-made, the words ‘custom-made device’; (q) an indication that the device is a medical device. If the device is intended for clinical investigation only, the words ‘exclusively for clinical investigation’; (r) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body, the overall qualitative composition of the device and quantitative information on the main constituent or constituents responsible for achieving the principal intended action; (s) for active implantable devices, the serial number, and for other implantable devices, the serial number or the lot number. 23.3.   Information on the packaging which maintains the sterile condition of a device (‘sterile packaging’) The following particulars shall appear on the sterile packaging: (a) an indication permitting the sterile packaging to be recognised as such, (b) a declaration that the device is in a sterile condition, (c) the method of sterilisation, (d) the name and address of the manufacturer, (e) a description of the device, (f) if the device is intended for clinical investigations, the words ‘exclusively for clinical investigations’, (g) if the device is custom-made, the words ‘custom-made device’, (h) the month and year of manufacture, (i) an unambiguous indication of the time limit for using or implanting the device safely expressed at least in terms of year and month, and (j) an instruction to check the instructions for use for what to do if the sterile packaging is damaged or unintentionally opened before use. 23.4.   Information in the instructions for use The instructions for use shall contain all of the following particulars: (a) the particulars referred to in points (a), (c), (e), (f), (k), (l), (n) and (r) of Section 23.2; (b) the device's intended purpose with a clear specification of indications, contra-indications, the patient target group or groups, and of the intended users, as appropriate; (c) where applicable, a specification of the clinical benefits to be expected. (d) where applicable, links to the summary of safety and clinical performance referred to in Article 32; (e) the performance characteristics of the device; (f) where applicable, information allowing the healthcare professional to verify if the device is suitable and select the corresponding software and accessories; (g) any residual risks, contra-indications and any undesirable side-effects, including information to be conveyed to the patient in this regard; (h) specifications the user requires to use the device appropriately, e.g. if the device has a measuring function, the degree of accuracy claimed for it; (i) details of any preparatory treatment or handling of the device before it is ready for use or during its use, such as sterilisation, final assembly, calibration, etc., including the levels of disinfection required to ensure patient safety and all available methods for achieving those levels of disinfection; (j) any requirements for special facilities, or special training, or particular qualifications of the device user and/or other persons; (k) the information needed to verify whether the device is properly installed and is ready to perform safely and as intended by the manufacturer, together with, where relevant: — details of the nature, and frequency, of preventive and regular maintenance, and of any preparatory cleaning or disinfection, — identification of any consumable components and how to replace them, — information on any necessary calibration to ensure that the device operates properly and safely during its intended lifetime, and — methods for eliminating the risks encountered by persons involved in installing, calibrating or servicing devices; (l) if the device is supplied sterile, instructions in the event of the sterile packaging being damaged or unintentionally opened before use; (m) if the device is supplied non-sterile with the intention that it is sterilised before use, the appropriate instructions for sterilisation; (n) if the device is reusable, information on the appropriate processes for allowing reuse, including cleaning, disinfection, packaging and, where appropriate, the validated method of re-sterilisation appropriate to the Member State or Member States in which the device has been placed on the market. Information shall be provided to identify when the device should no longer be reused, e.g. signs of material degradation or the maximum number of allowable reuses; (o) an indication, if appropriate, that a device can be reused only if it is reconditioned under the responsibility of the manufacturer to comply with the general safety and performance requirements; (p) if the device bears an indication that it is for single use, information on known characteristics and technical factors known to the manufacturer that could pose a risk if the device were to be re-used. This information shall be based on a specific section of the manufacturer's risk management documentation, where such characteristics and technical factors shall be addressed in detail. If in accordance with point (d) of Section 23.1. no instructions for use are required, this information shall be made available to the user upon request; (q) for devices intended for use together with other devices and/or general purpose equipment: — information to identify such devices or equipment, in order to obtain a safe combination, and/or — information on any known restrictions to combinations of devices and equipment; (r) if the device emits radiation for medical purposes: — detailed information as to the nature, type and where appropriate, the intensity and distribution of the emitted radiation, — the means of protecting the patient, user, or other person from unintended radiation during use of the device; (s) information that allows the user and/or patient to be informed of any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. That information shall, where relevant, allow the user to brief the patient about any warnings, precautions, contra-indications, measures to be taken and limitations of use regarding the device. The information shall cover, where appropriate: — warnings, precautions and/or measures to be taken in the event of malfunction of the device or changes in its performance that may affect safety, — warnings, precautions and/or measures to be taken as regards the exposure to reasonably foreseeable external influences or environmental conditions, such as magnetic fields, external electrical and electromagnetic effects, electrostatic discharge, radiation associated with diagnostic or therapeutic procedures, pressure, humidity, or temperature, — warnings, precautions and/or measures to be taken as regards the risks of interference posed by the reasonably foreseeable presence of the device during specific diagnostic investigations, evaluations, or therapeutic treatment or other procedures such as electromagnetic interference emitted by the device affecting other equipment, — if the device is intended to administer medicinal products, tissues or cells of human or animal origin, or their derivatives, or biological substances, any limitations or incompatibility in the choice of substances to be delivered, — warnings, precautions and/or limitations related to the medicinal substance or biological material that is incorporated into the device as an integral part of the device; and — precautions related to materials incorporated into the device that contain or consist of CMR substances or endocrine-disrupting substances, or that could result in sensitisation or an allergic reaction by the patient or user; (t) in the case of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, warnings and precautions, where appropriate, related to the general profile of interaction of the device and its products of metabolism with other devices, medicinal products and other substances as well as contra-indications, undesirable side-effects and risks relating to overdose; (u) in the case of implantable devices, the overall qualitative and quantitative information on the materials and substances to which patients can be exposed; (v) warnings or precautions to be taken in order to facilitate the safe disposal of the device, its accessories and the consumables used with it, if any. This information shall cover, where appropriate: — infection or microbial hazards such as explants, needles or surgical equipment contaminated with potentially infectious substances of human origin, and — physical hazards such as from sharps. If in accordance with the point (d) of Section 23.1 no instructions for use are required, this information shall be made available to the user upon request; (w) for devices intended for use by lay persons, the circumstances in which the user should consult a healthcare professional; (x) for the devices covered by this Regulation pursuant to Article 1(2), information regarding the absence of a clinical benefit and the risks related to use of the device; (y) date of issue of the instructions for use or, if they have been revised, date of issue and identifier of the latest revision of the instructions for use; (z) a notice to the user and/or patient that any serious incident that has occurred in relation to the device should be reported to the manufacturer and the competent authority of the Member State in which the user and/or patient is established; (aa) information to be supplied to the patient with an implanted device in accordance with Article 18; (ab) for devices that incorporate electronic programmable systems, including software, or software that are devices in themselves, minimum requirements concerning hardware, IT networks characteristics and IT security measures, including protection against unauthorised access, necessary to run the software as intended. (1)  Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 ( OJ L 353, 31.12.2008, p. 1). (2)  Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (OJ L 396, 30.12.2006, p. 1). (3)  Regulation (EU) No 528/2012 of the European Parliament and the Council of 22 May 2012 concerning the making available on the market of and use of biocidal products (OJ L 167, 27.6.2012, p. 1). (4)  Council Directive 80/181/EEC of 20 December 1979 on the approximation of the laws of the Member States relating to units of measurement and on the repeal of Directive 71/354/EEC (OJ L 39, 15.2.1980, p. 40). ANNEX II TECHNICAL DOCUMENTATION The technical documentation and, if applicable, the summary thereof to be drawn up by the manufacturer shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements listed in this Annex. 1.   DEVICE DESCRIPTION AND SPECIFICATION, INCLUDING VARIANTS AND ACCESSORIES 1.1.   Device description and specification (a) product or trade name and a general description of the device including its intended purpose and intended users; (b) the Basic UDI-DI as referred to in Part C of Annex VI assigned by the manufacturer to the device in question, as soon as identification of this device becomes based on a UDI system, or otherwise a clear identification by means of product code, catalogue number or other unambiguous reference allowing traceability; (c) the intended patient population and medical conditions to be diagnosed, treated and/or monitored and other considerations such as patient selection criteria, indications, contra-indications, warnings; (d) principles of operation of the device and its mode of action, scientifically demonstrated if necessary; (e) the rationale for the qualification of the product as a device; (f) the risk class of the device and the justification for the classification rule(s) applied in accordance with Annex VIII; (g) an explanation of any novel features; (h) a description of the accessories for a device, other devices and other products that are not devices, which are intended to be used in combination with it; (i) a description or complete list of the various configurations/variants of the device that are intended to be made available on the market; (j) a general description of the key functional elements, e.g. its parts/components (including software if appropriate), its formulation, its composition, its functionality and, where relevant, its qualitative and quantitative composition. Where appropriate, this shall include labelled pictorial representations (e.g. diagrams, photographs, and drawings), clearly indicating key parts/components, including sufficient explanation to understand the drawings and diagrams; (k) a description of the raw materials incorporated into key functional elements and those making either direct contact with the human body or indirect contact with the body, e.g., during extracorporeal circulation of body fluids; (l) technical specifications, such as features, dimensions and performance attributes, of the device and any variants/configurations and accessories that would typically appear in the product specification made available to the user, for example in brochures, catalogues and similar publications. 1.2.   Reference to previous and similar generations of the device (a) an overview of the previous generation or generations of the device produced by the manufacturer, where such devices exist; (b) an overview of identified similar devices available on the Union or international markets, where such devices exist. 2.   INFORMATION TO BE SUPPLIED BY THE MANUFACTURER A complete set of: — the label or labels on the device and on its packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions, in the languages accepted in the Member States where the device is envisaged to be sold; and — the instructions for use in the languages accepted in the Member States where the device is envisaged to be sold. 3.   DESIGN AND MANUFACTURING INFORMATION (a) information to allow the design stages applied to the device to be understood; (b) complete information and specifications, including the manufacturing processes and their validation, their adjuvants, the continuous monitoring and the final product testing. Data shall be fully included in the technical documentation; (c) identification of all sites, including suppliers and sub-contractors, where design and manufacturing activities are performed. 4.   GENERAL SAFETY AND PERFORMANCE REQUIREMENTS The documentation shall contain information for the demonstration of conformity with the general safety and performance requirements set out in Annex I that are applicable to the device taking into account its intended purpose, and shall include a justification, validation and verification of the solutions adopted to meet those requirements. The demonstration of conformity shall include: (a) the general safety and performance requirements that apply to the device and an explanation as to why others do not apply; (b) the method or methods used to demonstrate conformity with each applicable general safety and performance requirement; (c) the harmonised standards, CS or other solutions applied; and (d) the precise identity of the controlled documents offering evidence of conformity with each harmonised standard, CS or other method applied to demonstrate conformity with the general safety and performance requirements. The information referred to under this point shall incorporate a cross-reference to the location of such evidence within the full technical documentation and, if applicable, the summary technical documentation. 5.   BENEFIT-RISK ANALYSIS AND RISK MANAGEMENT The documentation shall contain information on: (a) the benefit-risk analysis referred to in Sections 1 and 8 of Annex I, and (b) the solutions adopted and the results of the risk management referred to in Section 3 of Annex I. 6.   PRODUCT VERIFICATION AND VALIDATION The documentation shall contain the results and critical analyses of all verifications and validation tests and/or studies undertaken to demonstrate conformity of the device with the requirements of this Regulation and in particular the applicable general safety and performance requirements. 6.1.   Pre-clinical and clinical data (a) results of tests, such as engineering, laboratory, simulated use and animal tests, and evaluation of published literature applicable to the device, taking into account its intended purpose, or to similar devices, regarding the pre-clinical safety of the device and its conformity with the specifications; (b) detailed information regarding test design, complete test or study protocols, methods of data analysis, in addition to data summaries and test conclusions regarding in particular: — the biocompatibility of the device including the identification of all materials in direct or indirect contact with the patient or user; — physical, chemical and microbiological characterisation; — electrical safety and electromagnetic compatibility; — software verification and validation (describing the software design and development process and evidence of the validation of the software, as used in the finished device. This information shall typically include the summary results of all verification, validation and testing performed both in-house and in a simulated or actual user environment prior to final release. It shall also address all of the different hardware configurations and, where applicable, operating systems identified in the information supplied by the manufacturer); — stability, including shelf life; and — performance and safety. Where applicable, conformity with the provisions of Directive 2004/10/EC of the European Parliament and of the Council (1) shall be demonstrated. Where no new testing has been undertaken, the documentation shall incorporate a rationale for that decision. An example of such a rationale would be that biocompatibility testing on identical materials was conducted when those materials were incorporated in a previous version of the device that has been legally placed on the market or put into service; (c) the clinical evaluation report and its updates and the clinical evaluation plan referred to in Article 61(12) and Part A of Annex XIV; (d) the PMCF plan and PMCF evaluation report referred to in Part B of Annex XIV or a justification why a PMCF is not applicable. 6.2.   Additional information required in specific cases (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as referred to in the first subparagraph of Article 1(8), a statement indicating this fact. In this case, the documentation shall identify the source of that substance and contain the data of the tests conducted to assess its safety, quality and usefulness, taking account of the intended purpose of the device. (b) Where a device is manufactured utilising tissues or cells of human or animal origin, or their derivatives, and is covered by this Regulation in accordance with points (f) and (g) of Article 1(6, and where a device incorporates, as an integral part, tissues or cells of human origin or their derivatives that have an action ancillary to that of the device and is covered by this Regulation in accordance with the first subparagraph of Article 1(10), a statement indicating this fact. In such a case, the documentation shall identify all materials of human or animal origin used and provide detailed information concerning the conformity with Sections 13.1. or 13.2., respectively, of Annex I. (c) In the case of devices that are composed of substances or combinations of substances that are intended to be introduced into the human body and that are absorbed by or locally dispersed in the human body, detailed information, including test design, complete test or study protocols, methods of data analysis, and data summaries and test conclusions, regarding studies in relation to: — absorption, distribution, metabolism and excretion; — possible interactions of those substances, or of their products of metabolism in the human body, with other devices, medicinal products or other substances, considering the target population, and its associated medical conditions; — local tolerance; and — toxicity, including single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental toxicity, as applicable depending on the level and nature of exposure to the device. In the absence of such studies, a justification shall be provided. (d) In the case of devices containing CMR or endocrine-disrupting substances referred to in Section 10.4.1 of Annex I, the justification referred to in Section 10.4.2 of that Annex. (e) In the case of devices placed on the market in a sterile or defined microbiological condition, a description of the environmental conditions for the relevant manufacturing steps. In the case of devices placed on the market in a sterile condition, a description of the methods used, including the validation reports, with respect to packaging, sterilisation and maintenance of sterility. The validation report shall address bioburden testing, pyrogen testing and, if applicable, testing for sterilant residues. (f) In the case of devices placed on the market with a measuring function, a description of the methods used in order to ensure the accuracy as given in the specifications. (g) If the device is to be connected to other device(s) in order to operate as intended, a description of this combination/configuration including proof that it conforms to the general safety and performance requirements when connected to any such device(s) having regard to the characteristics specified by the manufacturer. (1)  Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances (OJ L 50, 20.2.2004, p. 44). ANNEX III TECHNICAL DOCUMENTATION ON POST-MARKET SURVEILLANCE The technical documentation on post-market surveillance to be drawn up by the manufacturer in accordance with Articles 83 to 86 shall be presented in a clear, organised, readily searchable and unambiguous manner and shall include in particular the elements described in this Annex. 1.1.   The post-market surveillance plan drawn up in accordance with Article 84. The manufacturer shall prove in a post-market surveillance plan that it complies with the obligation referred to in Article 83. (a) The post-market surveillance plan shall address the collection and utilization of available information, in particular: — information concerning serious incidents, including information from PSURs, and field safety corrective actions; — records referring to non-serious incidents and data on any undesirable side-effects; — information from trend reporting; — relevant specialist or technical literature, databases and/or registers; — information, including feedbacks and complaints, provided by users, distributors and importers; and — publicly available information about similar medical devices. (b) The post-market surveillance plan shall cover at least: — a proactive and systematic process to collect any information referred to in point (a). The process shall allow a correct characterisation of the performance of the devices and shall also allow a comparison to be made between the device and similar products available on the market; — effective and appropriate methods and processes to assess the collected data; — suitable indicators and threshold values that shall be used in the continuous reassessment of the benefit-risk analysis and of the risk management as referred to in Section 3 of Annex I; — effective and appropriate methods and tools to investigate complaints and analyse market-related experience collected in the field; — methods and protocols to manage the events subject to the trend report as provided for in Article 88, including the methods and protocols to be used to establish any statistically significant increase in the frequency or severity of incidents as well as the observation period; — methods and protocols to communicate effectively with competent authorities, notified bodies, economic operators and users; — reference to procedures to fulfil the manufacturers obligations laid down in Articles 83, 84 and 86; — systematic procedures to identify and initiate appropriate measures including corrective actions; — effective tools to trace and identify devices for which corrective actions might be necessary; and — a PMCF plan as referred to in Part B of Annex XIV, or a justification as to why a PMCF is not applicable. 1.2.   The PSUR referred to in Article 86 and the post-market surveillance report referred to in Article 85. ANNEX IV EU DECLARATION OF CONFORMITY The EU declaration of conformity shall contain all of the following information: 1. Name, registered trade name or registered trade mark and, if already issued, SRN as referred to in Article 31 of the manufacturer, and, if applicable, its authorised representative, and the address of their registered place of business where they can be contacted and their location be established; 2. A statement that the EU declaration of conformity is issued under the sole responsibility of the manufacturer; 3. The Basic UDI-DI as referred to in Part C of Annex VI; 4. Product and trade name, product code, catalogue number or other unambiguous reference allowing identification and traceability of the device covered by the EU declaration of conformity, such as a photograph, where appropriate, as well as its intended purpose. Except for the product or trade name, the information allowing identification and traceability may be provided by the Basic UDI-DI referred to in point 3; 5. Risk class of the device in accordance with the rules set out in Annex VIII; 6. A statement that the device that is covered by the present declaration is in conformity with this Regulation and, if applicable, with any other relevant Union legislation that provides for the issuing of an EU declaration of conformity; 7. References to any CS used and in relation to which conformity is declared; 8. Where applicable, the name and identification number of the notified body, a description of the conformity assessment procedure performed and identification of the certificate or certificates issued; 9. Where applicable, additional information; 10. Place and date of issue of the declaration, name and function of the person who signed it as well as an indication for, and on behalf of whom, that person signed, signature. ANNEX V CE MARKING OF CONFORMITY 1. The CE marking shall consist of the initials ‘CE’ taking the following form: 2. If the CE marking is reduced or enlarged, the proportions given in the above graduated drawing shall be respected. 3. The various components of the CE marking shall have substantially the same vertical dimension, which may not be less than 5 mm. This minimum dimension may be waived for small-scale devices. ANNEX VI INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31, CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29, AND THE UDI SYSTEM PART A INFORMATION TO BE SUBMITTED UPON THE REGISTRATION OF DEVICES AND ECONOMIC OPERATORS IN ACCORDANCE WITH ARTICLES 29(4) AND 31 Manufacturers or, when applicable, authorised representatives, and, when applicable, importers shall submit the information referred to in Section 1 and shall ensure that the information on their devices referred to in Section 2 is complete, correct and updated by the relevant party. 1.   Information relating to the economic operator 1.1. type of economic operator(manufacturer, authorised representative, or importer), 1.2. name, address and contact details of the economic operator, 1.3. where submission of information is carried out by another person on behalf of any of the economic operators mentioned under Section 1.1, the name, address and contact details of that person, 1.4. name address and contact details of the person or persons responsible for regulatory compliance referred to in Article 15. 2.   Information relating to the device 2.1. Basic UDI-DI, 2.2. type, number and expiry date of the certificate issued by the notified body and the name or identification number of that notified body and the link to the information that appears on the certificate and was entered by the notified body in the electronic system on notified bodies and certificates, 2.3. Member State in which the device is to or has been placed on the market in the Union, 2.4. in the case of class IIa, class IIb or class III devices: Member States where the device is or is to be made available, 2.5. risk class of the device, 2.6. reprocessed single-use device (y/n), 2.7. presence of a substance which, if used separately, may be considered to be a medicinal product and name of that substance, 2.8. presence of a substance which, if used separately, may be considered to be a medicinal product derived from human blood or human plasma and name of this substance, 2.9. presence of tissues or cells of human origin, or their derivatives (y/n), 2.10. presence of tissues or cells of animal origin, or their derivatives, as referred to in Regulation (EU) No 722/2012 (y/n), 2.11. where applicable, the single identification number of the clinical investigation or investigations conducted in relation to the device or a link to the clinical investigation registration in the electronic system on clinical investigations, 2.12. in the case of devices listed in Annex XVI, specification as to whether the intended purpose of the device is other than a medical purpose, 2.13. in the case of devices designed and manufactured by another legal or natural person as referred in Article 10(15), the name, address and contact details of that legal or natural person, 2.14. in the case of class III or implantable devices, the summary of safety and clinical performance, 2.15. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART B CORE DATA ELEMENTS TO BE PROVIDED TO THE UDI DATABASE TOGETHER WITH THE UDI-DI IN ACCORDANCE WITH ARTICLES 28 AND 29 The manufacturer shall provide to the UDI database the UDI-DI and all of the following information relating to the manufacturer and the device: 1. quantity per package configuration, 2. the Basic UDI-DI as referred to in Article 29 and any additional UDI-DIs, 3. the manner in which production of the device is controlled (expiry date or manufacturing date, lot number, serial number), 4. if applicable, the unit of use UDI-DI (where a UDI is not labelled on the device at the level of its unit of use, a ‘unit of use’ DI shall be assigned so as to associate the use of a device with a patient), 5. name and address of the manufacturer (as indicated on the label), 6. the SRN issued in accordance with Article 31(2), 7. if applicable, name and address of the authorised representative (as indicated on the label), 8. the medical device nomenclature code as provided for in Article 26, 9. risk class of the device, 10. if applicable, name or trade name, 11. if applicable, device model, reference, or catalogue number, 12. if applicable, clinical size (including volume, length, gauge, diameter), 13. additional product description (optional), 14. if applicable, storage and/or handling conditions (as indicated on the label or in the instructions for use), 15. if applicable, additional trade names of the device, 16. labelled as a single-use device (y/n), 17. if applicable, the maximum number of reuses, 18. device labelled sterile (y/n), 19. need for sterilisation before use (y/n), 20. containing latex (y/n), 21. where applicable, information labelled in accordance with Section 10.4.5 of Annex I, 22. URL for additional information, such as electronic instructions for use (optional), 23. if applicable, critical warnings or contra-indications, 24. status of the device (on the market, no longer placed on the market, recalled, field safety corrective action initiated). PART C THE UDI SYSTEM 1.   Definitions Automatic identification and data capture (‘AIDC’) AIDC is a technology used to automatically capture data. AIDC technologies include bar codes, smart cards, biometrics and RFID. Basic UDI-DI The Basic UDI-DI is the primary identifier of a device model. It is the DI assigned at the level of the device unit of use. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity. Unit of Use DI The Unit of Use DI serves to associate the use of a device with a patient in instances in which a UDI is not labelled on the individual device at the level of its unit of use, for example in the event of several units of the same device being packaged together. Configurable device A configurable device is a device that consists of several components which can be assembled by the manufacturer in multiple configurations. Those individual components may be devices in themselves. Configurable devices include computed tomography (CT) systems, ultrasound systems, anaesthesia systems, physiological Monitoring systems, radiology information systems (RIS). Configuration Configuration is a combination of items of equipment, as specified by the manufacturer, that operate together as a device to achieve an intended purpose. The combination of items may be modified, adjusted or customized to meet specific needs. Configurations include inter alia: — gantries, tubes, tables, consoles and other items of equipment that can be configured/combined to deliver an intended function in computed tomography. — ventilators, breathing circuits, vaporizers combined to deliver an intended function in anaesthesia. UDI-DI The UDI-DI is a unique numeric or alphanumeric code specific to a model of device and that is also used as the ‘access key’ to information stored in a UDI database. Human Readable Interpretation (‘HRI’) HRI is a legible interpretation of the data characters encoded in the UDI carrier. Packaging levels Packaging levels means the various levels of device packaging that contain a defined quantity of devices, such as a carton or case. UDI-PI The UDI-PI is a numeric or alphanumeric code that identifies the unit of device production. The different types of UDI-PIs include serial number, lot number, software identification and manufacturing or expiry date or both types of date. Radio Frequency Identification RFID RFID is a technology that uses communication through the use of radio waves to exchange data between a reader and an electronic tag attached to an object, for the purpose of identification. Shipping containers A shipping container is a container in relation to which traceability is controlled by a process specific to logistics systems. Unique Device Identifier (‘UDI’) The UDI is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific device on the market. The UDI is comprised of the UDI-DI and the UDI-PI. The word ‘Unique’ does not imply serialisation of individual production units. UDI carrier The UDI carrier is the means of conveying the UDI by using AIDC and, if applicable, its HRI. UDI carriers include, inter alia, ID/linear bar code, 2D/Matrix bar code, RFID. 2.   General requirements 2.1.   The affixing of the UDI is an additional requirement — it does not replace any other marking or labelling requirements laid down in Annex I to this Regulation. 2.2.   The manufacturer shall assign and maintain unique UDIs for its devices. 2.3.   Only the manufacturer may place the UDI on the device or its packaging. 2.4.   Only coding standards provided by issuing entities designated by the Commission pursuant to Article 27(2) may be used. 3.   The UDI 3.1.   A UDI shall be assigned to the device itself or its packaging. Higher levels of packaging shall have their own UDI. 3.2.   Shipping containers shall be exempted from the requirement in Section 3.1. By way of example, a UDI shall not be required on a logistics unit; where a healthcare provider orders multiple devices using the UDI or model number of individual devices and the manufacturer places those devices in a container for shipping or to protect the individually packaged devices, the container (logistics unit) shall not be subject to UDI requirements. 3.3.   The UDI shall contain two parts: a UDI-DI and a UDI-PI. 3.4.   The UDI-DI shall be unique at each level of device packaging. 3.5.   If a lot number, serial number, software identification or expiry date appears on the label, it shall be part of the UDI-PI. If there is also a manufacturing date on the label, it does not need to be included in the UDI-PI. If there is only a manufacturing date on the label, this shall be used as the UDI-PI. 3.6.   Each component that is considered to be a device and is commercially available on its own shall be assigned a separate UDI unless the components are part of a configurable device that is marked with its own UDI. 3.7.   Systems and procedure packs as referred to in Article 22 shall be assigned and bear their own UDI. 3.8.   The manufacturer shall assign the UDI to a device following the relevant coding standard. 3.9.   A new UDI-DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability; in particular, any change of one of the following UDI database data elements shall require a new UDI-DI: (a) name or trade name, (b) device version or model, (c) labelled as single use, (d) packaged sterile, (e) need for sterilization before use, (f) quantity of devices provided in a package, (g) critical warnings or contra-indications: e.g. containing latex or DEHP. 3.10.   Manufacturers that repackage and/or relabel devices, with their own label shall retain a record of the original device manufacturer's UDI. 4.   UDI carrier 4.1.   The UDI carrier (AIDC and HRI representation of the UDI) shall be placed on the label or on the device itself and on all higher levels of device packaging. Higher levels do not include shipping containers. 4.2.   In the event of there being significant space constraints on the unit of use packaging, the UDI carrier may be placed on the next higher packaging level. 4.3.   For single-use devices of classes I and IIa packaged and labelled individually, the UDI carrier shall not be required to appear on the packaging but it shall appear on a higher level of packaging, e.g. a carton containing several individually packaged devices. However, when the healthcare provider is not expected to have access, in cases such as in home healthcare settings, to the higher level of device packaging, the UDI shall be placed on the packaging of the individual device. 4.4.   For devices exclusively intended for retail point of sale the UDI-PIs in AIDC shall not be required to appear on the point of sale packaging. 4.5.   When AIDC carriers other than the UDI carrier are part of the product labelling, the UDI carrier shall be readily identifiable. 4.6.   If linear bar codes are used, the UDI-DI and UDI-PI may be concatenated or non-concatenated in two or more bar codes. All parts and elements of the linear bar code shall be distinguishable and identifiable. 4.7.   If there are significant constraints limiting the use of both AIDC and HRI on the label, only the AIDC format shall be required to appear on the label. For devices intended to be used outside healthcare facilities, such as devices for home care, the HRI shall however appear on the label even if this results in there being no space for the AIDC. 4.8.   The HRI format shall follow the rules of the UDI code-issuing entity. 4.9.   If the manufacturer is using RFID technology, a linear or 2D bar code in line with the standard provided by the issuing entities shall also be provided on the label. 4.10.   Devices that are reusable shall bear a UDI carrier on the device itself. The UDI carrier for reusable devices that require cleaning, disinfection, sterilisation or refurbishing between patient uses shall be permanent and readable after each process performed to make the device ready for the subsequent use throughout the intended lifetime of the device. The requirement of this Section shall not apply to devices in the following circumstances: (a) any type of direct marking would interfere with the safety or performance of the device; (b) the device cannot be directly marked because it is not technologically feasible. 4.11.   The UDI carrier shall be readable during normal use and throughout the intended lifetime of the device. 4.12.   If the UDI carrier is readily readable or, in the case of AIDC, scannable, through the device's packaging, the placing of the UDI carrier on the packaging shall not be required. 4.13.   In the case of single finished devices made up of multiple parts that must be assembled before their first use, it shall be sufficient to place the UDI carrier on only one part of each device. 4.14.   The UDI carrier shall be placed in a manner such that the AIDC can be accessed during normal operation or storage. 4.15.   Bar code carriers that include both a UDI-DI and a UDI-PI may also include essential data for the device to operate or other data. 5.   General principles of the UDI database 5.1.   The UDI database shall support the use of all core UDI database data elements referred to in Part B of this Annex. 5.2.   Manufacturers shall be responsible for the initial submission and updates of the identifying information and other device data elements in the UDI database. 5.3.   Appropriate methods/procedures for validation of the data provided shall be implemented. 5.4.   Manufacturers shall periodically verify the correctness of all of the data relevant to devices they have placed on the market, except for devices that are no longer available on the market. 5.5.   The presence of the device UDI-DI in the UDI database shall not be assumed to mean that the device is in conformity with this Regulation. 5.6.   The database shall allow for the linking of all the packaging levels of the device. 5.7.   The data for new UDI-DIs shall be available at the time the device is placed on the market. 5.8.   Manufacturers shall update the relevant UDI database record within 30 days of a change being made to an element, which does not require a new UDI-DI. 5.9.   Internationally-accepted standards for data submission and updates shall, wherever possible, be used by the UDI database. 5.10.   The user interface of the UDI database shall be available in all official languages of the Union. The use of free-text fields shall, however, be minimized in order to reduce translations. 5.11.   Data relating to devices that are no longer available on the market shall be retained in the UDI database. 6.   Rules for specific device types 6.1.   Implantable devices: 6.1.1. Implantable devices shall, at their lowest level of packaging (‘unit packs’), be identified, or marked using AIDC, with a UDI (UDI-DI + UDI-PI); 6.1.2. The UDI-PI shall have at least the following characteristics: (a) the serial number for active implantable devices, (b) the serial number or lot number for other implantable devices. 6.1.3. The UDI of the implantable device shall be identifiable prior to implantation. 6.2.   Reusable devices requiring cleaning, disinfection, sterilisation or refurbishing between uses 6.2.1.   The UDI of such devices shall be placed on the device and be readable after each procedure to make the device ready for the next use. 6.2.2.   The UDI-PI characteristics such as the lot or serial number shall be defined by the manufacturer. 6.3.   Systems and procedure packs as referred to in Article 22 6.3.1.   The natural or legal person referred to in Article 22 shall be responsible for identifying the system or procedure pack with a UDI including both UDI-DI and UDI-PI. 6.3.2.   Device contents of system or procedure packs shall bear a UDI carrier on their packaging or on the device itself. Exemptions: (a) individual single-use disposable devices, the uses of which are generally known to the persons by whom they are intended to be used, which are contained within a system or procedure pack, and which are not intended for individual use outside the context of the system or procedure pack, shall not be required to bear their own UDI carrier; (b) devices that are exempted from bearing a UDI carrier on the relevant level of packaging shall not be required to bear a UDI carrier when included within a system or procedure pack. 6.3.3.   Placement of the UDI carrier on systems or procedure packs (a) The system or procedure pack UDI carrier shall as a general rule be affixed to the outside of the packaging. (b) The UDI carrier shall be readable, or, in the case of AIDC, scannable, whether placed on the outside of the packaging of the system or procedure pack or inside transparent packaging. 6.4.   Configurable devices: 6.4.1.   A UDI shall be assigned to the configurable device in its entirety and shall be called the configurable device UDI. 6.4.2.   The configurable device UDI-DI shall be assigned to groups of configurations, not per configuration within the group. A group of configurations is defined as the collection of possible configurations for a given device as described in the technical documentation. 6.4.3.   A configurable device UDI-PI shall be assigned to each individual configurable device. 6.4.4.   The carrier of the configurable device UDI shall be placed on the assembly that is most unlikely to be exchanged during the lifetime of the system and shall be identified as the configurable device UDI. 6.4.5.   Each component that is considered a device and is commercially available on its own shall be assigned a separate UDI. 6.5.   Device Software 6.5.1.   UDI assignment Criteria The UDI shall be assigned at the system level of the software. Only software which is commercially available on its own and software which constitutes a device in itself shall be subject to that requirement. The software identification shall be considered to be the manufacturing control mechanism and shall be displayed in the UDI-PI. 6.5.2.   A new UDI-DI shall be required whenever there is a modification that changes: (a) the original performance; (b) the safety or the intended use of the software; (c) interpretation of data. Such modifications include new or modified algorithms, database structures, operating platform, architecture or new user interfaces or new channels for interoperability. 6.5.3.   Minor software revisions shall require a new UDI-PI and not a new UDI-DI. Minor software revisions are generally associated with bug fixes, usability enhancements that are not for safety purposes, security patches or operating efficiency. Minor software revisions shall be identified by a manufacturer-specific form of identification. 6.5.4.   UDI placement criteria for software (a) where the software is delivered on a physical medium, e.g. CD or DVD, each packaging level shall bear the human readable and AIDC representation of the complete UDI. The UDI that is applied to the physical medium containing the software and its packaging shall be identical to the UDI assigned to the system level software; (b) the UDI shall be provided on a readily accessible screen for the user in an easily-readable plain-text format, such as an ‘about’ file, or included on the start-up screen; (c) software lacking a user interface such as middleware for image conversion, shall be capable of transmitting the UDI through an application programming interface (API); (d) only the human readable portion of the UDI shall be required in electronic displays of the software. The marking of UDI using AIDC shall not be required in the electronic displays, such as ‘about’ menu, splash screen etc.; (e) the human readable format of the UDI for the software shall include the Application Identifiers (AI) for the standard used by the issuing entities, so as to assist the user in identifying the UDI and determining which standard is being used to create the UDI. ANNEX VII REQUIREMENTS TO BE MET BY NOTIFIED BODIES 1.   ORGANISATIONAL AND GENERAL REQUIREMENTS 1.1.   Legal status and organisational structure 1.1.1.   Each notified body shall be established under the national law of a Member State, or under the law of a third country with which the Union has concluded an agreement in this respect. Its legal personality and status shall be fully documented. Such documentation shall include information about ownership and the legal or natural persons exercising control over the notified body. 1.1.2.   If the notified body is a legal entity that is part of a larger organisation, the activities of that organisation as well as its organisational structure and governance, and the relationship with the notified body shall be clearly documented. In such cases, the requirements of Section 1.2 are applicable to both the notified body and the organisation to which it belongs. 1.1.3.   If a notified body wholly or partly owns legal entities established in a Member State or in a third country or is owned by another legal entity, the activities and responsibilities of those entities, as well as their legal and operational relationships with the notified body, shall be clearly defined and documented. Personnel of those entities performing conformity assessment activities under this Regulation shall be subject to the applicable requirements of this Regulation. 1.1.4.   The organisational structure, allocation of responsibilities, reporting lines and operation of the notified body shall be such that they ensure that there is confidence in the performance by the notified body and in the results of the conformity assessment activities it conducts. 1.1.5.   The notified body shall clearly document its organisational structure and the functions, responsibilities and authority of its top-level management and of other personnel who may have an influence upon the performance by the notified body and upon the results of its conformity assessment activities. 1.1.6.   The notified body shall identify the persons in top-level management that have overall authority and responsibility for each of the following: — the provision of adequate resources for conformity assessment activities; — the development of procedures and policies for the operation of the notified body; — the supervision of implementation of the procedures, policies and quality management systems of the notified body; — the supervision of the notified body's finances; — the activities and decisions taken by the notified body, including contractual agreements; — the delegation of authority to personnel and/or committees, where necessary, for the performance of defined activities; — the interaction with the authority responsible for notified bodies and the obligations regarding communications with other competent authorities, the Commission and other notified bodies. 1.2.   Independence and impartiality 1.2.1.   The notified body shall be a third-party body that is independent of the manufacturer of the device in relation to which it performs conformity assessment activities. The notified body shall also be independent of any other economic operator having an interest in the device as well as of any competitors of the manufacturer. This does not preclude the notified body from carrying out conformity assessment activities for competing manufacturers. 1.2.2.   The notified body shall be organised and operated so as to safeguard the independence, objectivity and impartiality of its activities. The notified body shall document and implement a structure and procedures for safeguarding impartiality and for promoting and applying the principles of impartiality throughout its organisation, personnel and assessment activities. Such procedures shall provide for the identification, investigation and resolution of any case in which a conflict of interest may arise, including involvement in consultancy services in the field of devices prior to taking up employment with the notified body. The investigation, outcome and its resolution shall be documented. 1.2.3.   The notified body, its top-level management and the personnel responsible for carrying out the conformity assessment tasks shall not: (a) be the designer, manufacturer, supplier, installer, purchaser, owner or maintainer of devices which they assess, nor the authorised representative of any of those parties. Such restriction shall not preclude the purchase and use of assessed devices that are necessary for the operations of the notified body and the conduct of the conformity assessment, or the use of such devices for personal purposes; (b) be involved in the design, manufacture or construction, marketing, installation and use, or maintenance of the devices for which they are designated, nor represent the parties engaged in those activities; (c) engage in any activity that may conflict with their independence of judgement or integrity in relation to conformity assessment activities for which they are designated; (d) offer or provide any service which may jeopardise the confidence in their independence, impartiality or objectivity. In particular, they shall not offer or provide consultancy services to the manufacturer, its authorised representative, a supplier or a commercial competitor as regards the design, construction, marketing or maintenance of devices or processes under assessment, and (e) be linked to any organisation which itself provides consultancy services as referred to in point (d). Such restriction does not preclude general training activities that are not client specific and that relate to regulation of devices or to related standards. 1.2.4.   Involvement in consultancy services in the field of devices prior to taking up employment with a notified body shall be fully documented at the time of employment and potential conflicts of interest shall be monitored and resolved in accordance with this Annex. Personnel who were formerly employed by a specific client, or provided consultancy services in the field of devices to that specific client prior to taking up employment with a notified body, shall not be assigned for conformity assessment activities for that specific client or companies belonging to the same group for a period of three years. 1.2.5.   The impartiality of notified bodies, of their top-level management and of the assessment personnel shall be guaranteed. The level of the remuneration of the top-level management and assessment personnel of a notified body and subcontractors, involved in assessment activities shall not depend on the results of the assessments. Notified bodies shall make publicly available the declarations of interest of their top-level management. 1.2.6.   If a notified body is owned by a public entity or institution, independence and absence of any conflict of interest shall be ensured and documented between, on the one hand, the authority responsible for notified bodies and/or the competent authority and, on the other hand, the notified body. 1.2.7.   The notified body shall ensure and document that the activities of its subsidiaries or subcontractors, or of any associated body, including the activities of its owners do not affect its independence, impartiality or the objectivity of its conformity assessment activities. 1.2.8.   The notified body shall operate in accordance with a set of consistent, fair and reasonable terms and conditions, taking into account the interests of small and medium-sized enterprises as defined in Recommendation 2003/361/EC in relation to fees. 1.2.9.   The requirements laid down in this Section in no way preclude exchanges of technical information and regulatory guidance between a notified body and a manufacturer applying for conformity assessment. 1.3.   Confidentiality 1.3.1.   The notified body shall have documented procedures in place ensuring that its personnel, committees, subsidiaries, subcontractors, and any associated body or personnel of external bodies respect the confidentiality of the information which comes into its possession during the performance of conformity assessment activities, except when disclosure is required by law. 1.3.2.   The personnel of a notified body shall observe professional secrecy in carrying out their tasks under this Regulation or any provision of national law giving effect to it, except in relation to the authorities responsible for notified bodies, competent authorities for medical devices in the Member States or the Commission. Proprietary rights shall be protected. The notified body shall have documented procedures in place in respect of the requirements of this Section. 1.4.   Liability 1.4.1.   The notified body shall take out appropriate liability insurance for its conformity assessment activities, unless liability is assumed by the Member State in question in accordance with national law or that Member State is directly responsible for the conformity assessment. 1.4.2.   The scope and overall financial value of the liability insurance shall correspond to the level and geographic scope of activities of the notified body and be commensurate with the risk profile of the devices certified by the notified body. The liability insurance shall cover cases where the notified body may be obliged to withdraw, restrict or suspend certificates. 1.5.   Financial requirements The notified body shall have at its disposal the financial resources required to conduct its conformity assessment activities within its scope of designation and related business operations. It shall document and provide evidence of its financial capacity and its long-term economic viability, taking into account, where relevant, any specific circumstances during an initial start-up phase. 1.6.   Participation in coordination activities 1.6.1.   The notified body shall participate in, or ensure that its assessment personnel is informed of, any relevant standardisation activities and in the activities of the notified body coordination group referred to in Article 49 and that its assessment and decision-making personnel are informed of all relevant legislation, guidance and best practice documents adopted in the framework of this Regulation. 1.6.2.   The notified body shall take into consideration guidance and best practice documents. 2.   QUALITY MANAGEMENT REQUIREMENTS 2.1.   The notified body shall establish, document, implement, maintain and operate a quality management system that is appropriate to the nature, area and scale of its conformity assessment activities and is capable of supporting and demonstrating the consistent fulfilment of the requirements of this Regulation. 2.2.   The quality management system of the notified body shall address at least the following: — management system structure and documentation, including policies and objectives for its activities; — policies for assignment of activities and responsibilities to personnel; — assessment and decision-making processes in accordance with the tasks, responsibilities and role of the notified body's personnel and top-level management; — the planning, conduct, evaluation and, if necessary, adaptation of its conformity assessment procedures; — control of documents; — control of records; — management reviews; — internal audits; — corrective and preventive actions; — complaints and appeals; and — continuous training. Where documents are used in various languages, the notified body shall ensure and control that they have the same content. 2.3.   The top-level management of the notified body shall ensure that the quality management system is fully understood, implemented and maintained throughout the notified body organisation including subsidiaries and subcontractors involved in conformity assessment activities pursuant to this Regulation. 2.4.   The notified body shall require all personnel to formally commit themselves by a signature or equivalent to comply with the procedures defined by the notified body. That commitment shall cover aspects relating to confidentiality and to independence from commercial and other interests, and any existing or prior association with clients. The personnel shall be required to complete written statements indicating their compliance with confidentiality, independence and impartiality principles. 3.   RESOURCE REQUIREMENTS 3.1.   General 3.1.1.   Notified bodies shall be capable of carrying out all the tasks falling to them under this Regulation with the highest degree of professional integrity and the requisite competence in the specific field, whether those tasks are carried out by notified bodies themselves or on their behalf and under their responsibility. In particular, notified bodies shall have the necessary personnel and possess or have access to all equipment, facilities and competence needed to perform properly the technical, scientific and administrative tasks entailed in the conformity assessment activities in relation to which they have been designated. Such requirement presupposes at all times and for each conformity assessment procedure and each type of devices in relation to which they have been designated, that the notified body has permanent availability of sufficient administrative, technical and scientific personnel who possess experience and knowledge relating to the relevant devices and the corresponding technologies. Such personnel shall be in sufficient numbers to ensure that the notified body in question can perform the conformity assessment tasks, including the assessment of the medical functionality, clinical evaluations and the performance and safety of devices, for which it has been designated, having regard to the requirements of this Regulation, in particular, those set out in Annex I. A notified body's cumulative competences shall be such as to enable it to assess the types of devices for which it is designated. The notified body shall have sufficient internal competence to critically evaluate assessments conducted by external expertise. Tasks which a notified body is precluded from subcontracting are set out in Section 4.1. Personnel involved in the management of the operation of a notified body's conformity assessment activities for devices shall have appropriate knowledge to set up and operate a system for the selection of assessment and verification staff, for verification of their competence, for authorisation and allocation of their tasks, for organisation of their initial and ongoing training and for the assignment of their duties and the monitoring of those staff, in order to ensure that personnel who carry out and perform assessment and verification operations are competent to fulfil the tasks required of them. The notified body shall identify at least one individual within its top-level management as having overall responsibility for all conformity assessment activities in relation to devices. 3.1.2.   The notified body shall ensure that personnel involved in conformity assessment activities maintain their qualification and expertise by implementing a system for exchange of experience and a continuous training and education programme. 3.1.3.   The notified body shall clearly document the extent and limits of duties and responsibilities and the level of authorisation of the personnel, including any subcontractors and external experts, involved in conformity assessment activities and inform those personnel accordingly. 3.2.   Qualification criteria in relation to personnel 3.2.1.   The Notified Body shall establish and document qualification criteria and procedures for selection and authorisation of persons involved in conformity assessment activities, including as regards knowledge, experience and other competence required, and the required initial and ongoing training. The qualification criteria shall address the various functions within the conformity assessment process, such as auditing, product evaluation or testing, technical documentation review and decision-making, as well as the devices, technologies and areas, such as biocompatibility, sterilisation, tissues and cells of human and animal origin and clinical evaluation, covered by the scope of designation. 3.2.2.   The qualification criteria referred to in Section 3.2.1 shall refer to the scope of a notified body's designation in accordance with the scope description used by the Member State for the notification referred to in Article 42(3), providing a sufficient level of detail for the required qualification within the subdivisions of the scope description. Specific qualification criteria shall be defined at least for the assessment of: — the pre-clinical evaluation, — clinical evaluation, — tissues and cells of human and animal origin, — functional safety, — software, — packaging, — devices that incorporate as an integral part a medicinal product, — devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body and — the different types of sterilisation processes. 3.2.3.   The personnel responsible for establishing qualification criteria and for authorising other personnel to perform specific conformity assessment activities shall be employed by the notified body itself and shall not be external experts or subcontracted. They shall have proven knowledge and experience in all of the following: — Union devices legislation and relevant guidance documents; — the conformity assessment procedures provided for in this Regulation; — a broad base of knowledge of device technologies and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualification criteria; — training relevant to personnel involved in conformity assessment activities in relation to devices; — adequate experience in conformity assessments under this Regulation or previously applicable law within a notified body. 3.2.4.   The notified body shall have permanent availability of personnel with relevant clinical expertise and where possible such personnel shall be employed by the notified body itself. Such personnel shall be integrated throughout the notified body's assessment and decision-making process in order to: — identify when specialist input is required for the assessment of the clinical evaluation conducted by the manufacturer and identify appropriately qualified experts; — appropriately train external clinical experts in the relevant requirements of this Regulation, CS, guidance and harmonised standards and ensure that the external clinical experts are fully aware of the context and implications of their assessment and the advice they provide; — be able to review and scientifically challenge the clinical data contained within the clinical evaluation, and any associated clinical investigations, and appropriately guide external clinical experts in the assessment of the clinical evaluation presented by the manufacturer; — be able to scientifically evaluate and, if necessary, challenge the clinical evaluation presented, and the results of the external clinical experts' assessment of the manufacturer's clinical evaluation; — be able to ascertain the comparability and consistency of the assessments of clinical evaluations conducted by clinical experts; — be able to make an assessment of the manufacturer's clinical evaluation and a clinical judgement of the opinion provided by any external expert and make a recommendation to the notified body's decision maker; and — be able to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.5.   The personnel responsible for carrying out product-related reviews (product reviewers), such as technical documentation reviews or type examination, including aspects such as clinical evaluation, biological safety, sterilisation and software validation, shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, e.g. medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the design, manufacture, testing or use of the device or technology to be assessed or related to the scientific aspects to be assessed; — knowledge of device legislation, including the general safety and performance requirements set out in Annex I; — appropriate knowledge and experience of relevant harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge and experience of clinical evaluation; — appropriate knowledge of the devices which they are assessing; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those assessments; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.6.   The personnel responsible for carrying out audits of the manufacturer's quality management system (site auditors) shall have all of the following proven qualifications: — successful completion of a university or a technical college degree or equivalent qualification in relevant studies, such as medicine, pharmacy, engineering or other relevant sciences; — four years' professional experience in the field of healthcare products or related activities, such as in manufacturing, auditing or research, of which two years shall be in the area of quality management; — appropriate knowledge of devices legislation as well as related harmonised standards, CS and guidance documents; — appropriate knowledge and experience of risk management and related device standards and guidance documents; — appropriate knowledge of quality management systems and related standards and guidance documents; — appropriate knowledge and experience of the conformity assessment procedures laid down in Annexes IX to XI, in particular of the aspects of those procedures for which they are responsible, and adequate authorisation for carrying out those audits; — training in auditing techniques enabling them to challenge quality management systems; — the ability to draw up records and reports demonstrating that the relevant conformity assessment activities have been appropriately carried out. 3.2.7.   The personnel with overall responsibility for final reviews and decision-making on certification shall be employed by the notified body itself and shall not be external experts or be subcontracted. Those personnel shall, as a group, have proven knowledge and comprehensive experience of all of the following: — devices legislation and relevant guidance documents; — the device conformity assessments relevant to this Regulation; — the types of qualifications, experience and expertise relevant to device conformity assessment; — a broad base of knowledge of device technologies, including sufficient experience of conformity assessment of devices being reviewed for certification, the device industry and the design and manufacture of devices; — the notified body's quality management system, related procedures and the required qualifications for personnel involved; — the ability to draw up records and reports demonstrating that the conformity assessment activities have been appropriately carried out. 3.3.   Documentation of qualification, training and authorisation of personnel 3.3.1.   The notified body shall have a procedure in place to fully document the qualification of each member of personnel involved in conformity assessment activities and the satisfaction of the qualification criteria referred to in Section 3.2. Where in exceptional circumstances the fulfilment of the qualification criteria set out in Section 3.2. cannot be fully demonstrated, the notified body shall justify to the authority responsible for notified bodies the authorisation of those members of personnel to carry out specific conformity assessment activities. 3.3.2.   For all of its personnel referred to in Sections 3.2.3 to 3.2.7, the notified body shall establish and maintain up to date: — a matrix detailing the authorisations and responsibilities of the personnel in respect of conformity assessment activities; and — records attesting to the required knowledge and experience for the conformity assessment activity for which they are authorised. The records shall contain a rationale for defining the scope of the responsibilities for each of the assessment personnel and records of the conformity assessment activities carried out by each of them. 3.4.   Subcontractors and external experts 3.4.1.   Notified bodies may, without prejudice to Section 3.2, subcontract certain clearly defined component parts of a conformity assessment activity. The subcontracting of the auditing of quality management systems or of product related reviews as a whole shall not be permitted; nevertheless parts of those activities may be conducted by subcontractors and external auditors and experts working on behalf of the notified body. The notified body in question shall retain full responsibility for being able to produce appropriate evidence of the competence of subcontractors and experts to fulfil their specific tasks, for making a decision based on a subcontractor's assessment and for the work conducted by subcontractors and experts on its behalf. The following activities may not be subcontracted by notified bodies: — review of the qualifications and monitoring of the performance of external experts; — auditing and certification activities where the subcontracting in question is to auditing or certification organisations; — allocation of work to external experts for specific conformity assessment activities; and — final review and decision making functions. 3.4.2.   Where a notified body subcontracts certain conformity assessment activities either to an organisation or an individual, it shall have a policy describing the conditions under which subcontracting may take place, and shall ensure that: — the subcontractor meets the relevant requirements of this Annex; — subcontractors and external experts do not further subcontract work to organisations or personnel; and — the natural or legal person that applied for conformity assessment has been informed of the requirements referred to in the first and second indent. Any subcontracting or consultation of external personnel shall be properly documented, shall not involve any intermediaries and shall be subject to a written agreement covering, among other things, confidentiality and conflicts of interest. The notified body in question shall take full responsibility for the tasks performed by subcontractors. 3.4.3.   Where subcontractors or external experts are used in the context of a conformity assessment, in particular regarding novel, invasive and implantable devices or technologies, the notified body in question shall have internal competence in each product area for which it is designated that is adequate for the purpose of leading the overall conformity assessment, verifying the appropriateness and validity of expert opinions and making decisions on certification. 3.5.   Monitoring of competences, training and exchange of experience 3.5.1.   The notified body shall establish procedures for the initial evaluation and on-going monitoring of the competence, conformity assessment activities and performance of all internal and external personnel, and subcontractors, involved in conformity assessment activities. 3.5.2.   Notified bodies shall review at regular intervals, the competence of their personnel, identify training needs and draw up a training plan to maintain the required level of qualification and knowledge of individual personnel. That review shall at a minimum, verify that personnel: — are aware of Union and national law in force on devices, relevant harmonised standards, CS, guidance documents and the results of the coordination activities referred to in Section 1.6; and — take part in the internal exchange of experience and the continuous training and education programme referred to in Section 3.1.2. 4.   PROCESS REQUIREMENTS 4.1.   General The notified body shall have in place documented processes and sufficiently detailed procedures for the conduct of each conformity assessment activity for which it is designated, comprising the individual steps from pre-application activities up to decision making and surveillance and taking into account, when necessary, the respective specificities of the devices. The requirements laid down in Sections 4.3, 4.4, 4.7 and 4.8 shall be fulfilled as part of the internal activities of notified bodies and shall not be subcontracted. 4.2.   Notified body quotations and pre-application activities The notified body shall: (a) publish a publicly available description of the application procedure by which manufacturers can obtain certification from it. That description shall include which languages are acceptable for submission of documentation and for any related correspondence; (b) have documented procedures relating to, and documented details about, fees charged for specific conformity assessment activities and any other financial conditions relating to notified bodies' assessment activities for devices; (c) have documented procedures in relation to advertising of their conformity assessment services. Those procedures shall ensure that advertising or promotional activities in no way imply or are capable of leading to an inference that their conformity assessment will offer manufacturers earlier market access or be quicker, easier or less stringent than that of other notified bodies; (d) have documented procedures requiring the review of pre-application information, including the preliminary verification that the product is covered by this Regulation and its classification, prior to issuing any quotation to the manufacturer relating to a specific conformity assessment; and (e) ensure that all contracts relating to the conformity assessment activities covered by this Regulation are concluded directly between the manufacturer and the notified body and not with any other organisation. 4.3.   Application review and contract The notified body shall require a formal application signed by a manufacturer or an authorised representative containing all of the information and the manufacturer's declarations required by the relevant conformity assessment as referred to in Annexes IX to XI. The contract between a notified body and a manufacturer shall take the form of a written agreement signed by both parties. It shall be kept by the notified body. This contract shall have clear terms and conditions and contain obligations that enable the notified body to act as required under this Regulation, including an obligation on the manufacturer to inform the notified body of vigilance reports, the right of the notified body to suspend, restrict or withdraw certificates issued and the duty of the notified body to fulfil its information obligations. The notified body shall have documented procedures to review applications, addressing: (a) the completeness of those applications with respect to the requirements of the relevant conformity assessment procedure, as referred to in the corresponding Annex, under which approval has been sought, (b) the verification of the qualification of products covered by those applications as devices and their respective classifications, (c) whether the conformity assessment procedures chosen by the applicant are applicable to the device in question under this Regulation, (d) the ability of the notified body to assess the application based on its designation, and (e) the availability of sufficient and appropriate resources. The outcome of each review of an application shall be documented. Refusals or withdrawals of applications shall be notified to the electronic system referred to in Article 57 and shall be accessible to other notified bodies. 4.4.   Allocation of resources The notified body shall have documented procedures to ensure that all conformity assessment activities are conducted by appropriately authorised and qualified personnel who are sufficiently experienced in the evaluation of the devices, systems and processes and related documentation that are subject to conformity assessment. For each application, the notified body shall determine the resources needed and identify one individual responsible for ensuring that the assessment of that application is conducted in accordance with the relevant procedures and for ensuring that the appropriate resources including personnel are utilised for each of the tasks of the assessment. The allocation of tasks required to be carried out as part of the conformity assessment and any changes subsequently made to this allocation shall be documented. 4.5.   Conformity assessment activities 4.5.1.   General The notified body and its personnel shall carry out the conformity assessment activities with the highest degree of professional integrity and the requisite technical and scientific competence in the specific fields. The notified body shall have expertise, facilities and documented procedures that are sufficient to effectively conduct the conformity assessment activities for which the notified body in question is designated, taking account of the relevant requirements set out in Annexes IX to XI, and in particular all of the following requirements: — appropriately plan the conduct of each individual project, — ensure that the composition of the assessment teams is such that there is sufficient experience in relation to the technology concerned, and that there is continuous objectivity and independence, and to provide for rotation of the members of the assessment team at appropriate intervals, — specify the rationale for fixing time limits for completion of conformity assessment activities, — assess the manufacturer's technical documentation and the solutions adopted to meet the requirements laid down in Annex I, — review the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects, — review the manufacturer's procedures and documentation relating to clinical evaluation, — address the interface between the manufacturer's risk management process and its appraisal and analysis of the pre-clinical and clinical evaluation and to evaluate their relevance for the demonstration of conformity with the relevant requirements in Annex I, — carry out the specific procedures referred to in Sections 5.2 to 5.4 of Annex IX, — in the case of class IIa or class IIb devices, assess the technical documentation of devices selected on a representative basis, — plan and periodically carry out appropriate surveillance audits and assessments, carry out or request certain tests to verify the proper functioning of the quality management system and to perform unannounced on site audits, — relating to the sampling of devices, verify that the manufactured device is in conformity with the technical documentation; such requirements shall define the relevant sampling criteria and testing procedure prior to sampling, — evaluate and verify a manufacturer's compliance with relevant Annexes. The notified body shall, where relevant, take into consideration available CS, guidance and best practice documents and harmonised standards, even if the manufacturer does not claim to be in compliance. 4.5.2.   Quality management system auditing (a) As part of the assessment of the quality management system, a notified body shall prior to an audit and in accordance with its documented procedures: — assess the documentation submitted in accordance with the relevant conformity assessment Annex, and draw up an audit programme which clearly identifies the number and sequence of activities required to demonstrate complete coverage of a manufacturer's quality management system and to determine whether it meets the requirements of this Regulation, — identify links between, and allocation of responsibilities among, the various manufacturing sites, and identify relevant suppliers and/or subcontractors of the manufacturer, and consider the need to specifically audit any of those suppliers or subcontractors or both, — clearly define, for each audit identified in the audit programme, the objectives, criteria and scope of the audit, and draw up an audit plan that adequately addresses and takes account of the specific requirements for the devices, technologies and processes involved, — draw up and keep up to date, for class IIa and class IIb devices, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III covering the range of such devices covered by the manufacturer's application. That plan shall ensure that all devices covered by the certificate are sampled over the period of validity of the certificate, and — select and assign appropriately qualified and authorised personnel for conducting the individual audits. The respective roles, responsibilities and authorities of the team members shall be clearly defined and documented. (b) Based on the audit programme it has drawn up, the notified body shall, in accordance with its documented procedures: — audit the manufacturer's quality management system, in order to verify that the quality management system ensures that the devices covered conform to the relevant provisions of this Regulation which apply to devices at every stage, from design through final quality control to ongoing surveillance, and shall determine whether the requirements of this Regulation are met, — based on relevant technical documentation and in order to determine whether the manufacturer meets the requirements referred to in the relevant conformity assessment Annex, review and audit the manufacturer's processes and subsystems, in particular for: — design and development, — production and process controls, — product documentation, — purchasing controls including verification of purchased devices, — corrective and preventive actions, including for post-market surveillance, and — PMCF, and review and audit requirements and provisions adopted by the manufacturer, including those in relation to fulfilling the general safety and performance requirements set out in Annex I. The documentation shall be sampled in such a manner as to reflect the risks associated with the intended use of the device, the complexity of the manufacturing technologies, the range and classes of devices produced and any available post-market surveillance information, — if not already covered by the audit programme, audit the control of processes on the premises of the manufacturer's suppliers, when the conformity of finished devices is significantly influenced by the activity of suppliers and, in particular when the manufacturer cannot demonstrate sufficient control over its suppliers, — conduct assessments of the technical documentation based on its sampling plan and taking account of Sections 4.5.4. and 4.5.5. for pre-clinical and clinical evaluations, and — the notified body shall ensure that audit findings are appropriately and consistently classified in accordance with the requirements of this Regulation and with relevant standards, or with best practice documents developed or adopted by the MDCG. 4.5.3.   Product verification Assessment of the technical documentation For assessment of the technical documentation conducted in accordance with Chapter II of Annex IX, notified bodies shall have sufficient expertise, facilities and documented procedures for: — the allocation of appropriately qualified and authorised personnel for the examination of individual aspects such as use of the device, biocompatibility, clinical evaluation, risk management, and sterilisation, and — the assessment of conformity of the design with this Regulation, and for taking account of Sections 4.5.4. to 4.5.6. That assessment shall include examination of the implementation by manufacturers of incoming, in-process and final checks and the results thereof. If further tests or other evidence is required for the assessment of conformity with the requirements of this Regulation, the notified body in question shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. Type-examinations The notified body shall have documented procedures, sufficient expertise and facilities for the type-examination of devices in accordance with Annex X including the capacity to: — examine and assess the technical documentation taking account of Sections 4.5.4. to 4.5.6., and verify that the type has been manufactured in conformity with that documentation; — establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility; — document its rationale for the selection of those parameters; — carry out the appropriate examinations and tests in order to verify that the solutions adopted by the manufacturer meet the general safety and performance requirements set out in Annex I. Such examinations and tests shall include all tests necessary to verify that the manufacturer has in fact applied the relevant standards it has opted to use; — agree with the applicant as to where the necessary tests will be performed if they are not to be carried out directly by the notified body; and — assume full responsibility for test results. Test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. Verification by examination and testing of every product The notified body shall: (a) have documented procedures, sufficient expertise and facilities for the verification by examination and testing of every product in accordance with Part B of Annex XI; (b) establish a test plan identifying all relevant and critical parameters which need to be tested by the notified body or under its responsibility in order to: — verify, for class IIb devices, the conformity of the device with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to those devices, — confirm, for class IIa devices, the conformity with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to those devices; (c) document its rationale for the selection of the parameters referred to in point (b); (d) have documented procedures to carry out the appropriate assessments and tests in order to verify the conformity of the device with the requirements of this Regulation by examining and testing every product as specified in Section 15 of Annex XI; (e) have documented procedures providing for the reaching of an agreement with the applicant concerning when and where necessary tests that are not to be carried out by the notified body itself are to be performed; and (f) assume full responsibility for test results in accordance with documented procedures; test reports submitted by the manufacturer shall only be taken into account if they have been issued by conformity assessment bodies which are competent and independent of the manufacturer. 4.5.4.   Pre-clinical evaluation assessment The notified body shall have documented procedures in place for the review of the manufacturer's procedures and documentation relating to the evaluation of pre-clinical aspects. The notified body shall examine, validate and verify that the manufacturer's procedures and documentation adequately address: (a) the planning, conduct, assessment, reporting and, where appropriate, updating of the pre-clinical evaluation, in particular of — the scientific pre-clinical literature search, and — the pre-clinical testing, for example laboratory testing, simulated use testing, computer modelling, the use of animal models, (b) the nature and duration of body contact and the specific associated biological risks, (c) the interface with the risk management process, and (d) the appraisal and analysis of the available pre-clinical data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I. The notified body's assessment of pre-clinical evaluation procedures and documentation shall address the results of literature searches and all validation, verification and testing performed and conclusions drawn, and shall typically include considering the use of alternative materials and substances and take account of the packaging, stability, including shelf life, of the finished device. Where no new testing has been undertaken by a manufacturer or where there are deviations from procedures, the notified body in question shall critically examine the justification presented by the manufacturer. 4.5.5.   Clinical evaluation assessment The notified body shall have documented procedures in place relating to the assessment of a manufacturer's procedures and documentation relating to clinical evaluation both for initial conformity assessment and on an ongoing basis. The notified body shall examine, validate and verify that manufacturers' procedures and documentation adequately address: — the planning, conduct, assessment, reporting and updating of the clinical evaluation as referred to in Annex XIV, — post-market surveillance and PMCF, — the interface with the risk management process, — the appraisal and analysis of the available data and its relevance with regard to demonstrating conformity with the relevant requirements in Annex I, and — the conclusions drawn with regard to the clinical evidence and drawing up of the clinical evaluation report. These procedures referred to in the first paragraph shall take into consideration available CS, guidance and best practice documents. The notified body's assessment of clinical evaluations as referred to in Annex XIV shall cover: — the intended use specified by the manufacturer and claims for the device defined by it, — the planning of the clinical evaluation, — the methodology for the literature search, — relevant documentation from the literature search, — the clinical investigation, — validity of equivalence claimed in relation to other devices, the demonstration of equivalence, the suitability and conclusions data from equivalent and similar devices, — post-market surveillance and PMCF, — the clinical evaluation report, and — justifications in relation to non-performance of clinical investigations or PMCF. In relation to clinical data from clinical investigations included within the clinical evaluation, the notified body in question shall ensure that the conclusions drawn by the manufacturer are valid in the light of the approved clinical investigation plan. The notified body shall ensure that the clinical evaluation adequately addresses the relevant safety and performance requirements provided for in Annex I, that it is appropriately aligned with the risk management requirements, that it is conducted in accordance with Annex XIV and that it is appropriately reflected in the information provided relating to the device. 4.5.6.   Specific Procedures The notified body shall have documented procedures, sufficient expertise and facilities for the procedures referred to in Sections 5 and 6 of Annex IX, Section 6 of Annex X and Section 16 of Annex XI, for which they are designated. In the case of devices manufactured utilising tissues or cells of animal origin or their derivatives, such as from TSE susceptible species, as referred to in Regulation (EU) No 722/2012, the notified body shall have documented procedures in place that fulfil the requirements laid down in that Regulation, including for the preparation of a summary evaluation report for the relevant competent authority. 4.6.   Reporting The notified body shall: — ensure that all steps of the conformity assessment are documented so that the conclusions of the assessment are clear and demonstrate compliance with the requirements of this Regulation and can represent objective evidence of such compliance to persons that are not themselves involved in the assessment, for example personnel in designating authorities, — ensure that records that are sufficient to provide a discernible audit trail are available for quality management system audits, — clearly document the conclusions of its assessment of clinical evaluation in a clinical evaluation assessment report, and — for each specific project, provide a detailed report which shall be based on a standard format containing a minimum set of elements determined by the MDCG. The report of the notified body shall: — clearly document the outcome of its assessment and draw clear conclusions from the verification of the manufacturer's conformity with the requirements of this Regulation, — make a recommendation for a final review and for a final decision to be taken by the notified body; this recommendation shall be signed off by the member of personnel responsible in the notified body, and — be provided to the manufacturer in question. 4.7.   Final review The notified body shall prior to making a final decision: — ensure that the personnel assigned for the final review and decision-making on specific projects are appropriately authorised and are different from the personnel who have conducted the assessments, — verify that the report or reports and supporting documentation needed for decision making, including concerning resolution of non-conformities noted during assessment, are complete and sufficient with respect to the scope of the application, and — verify whether there are any unresolved non-conformities preventing issuance of a certificate. 4.8.   Decisions and Certifications The notified body shall have documented procedures for decision-making including as regards the allocation of responsibilities for the issuance, suspension, restriction and withdrawal of certificates. Those procedures shall include the notification requirements laid down in Chapter V of this Regulation. The procedures shall allow the notified body in question to: — decide, based on the assessment documentation and additional information available, whether the requirements of this Regulation are fulfilled, — decide, based on the results of its assessment of the clinical evaluation and risk management, whether the post-market surveillance plan, including the PMCF plan, is adequate, — decide on specific milestones for further review by the notified body of the up to date clinical evaluation, — decide whether specific conditions or provisions need to be defined for the certification, — decide, based on the novelty, risk classification, clinical evaluation and conclusions from the risk analysis of the device, on a period of certification not exceeding five years, — clearly document decision making and approval steps including approval by signature of the members of personnel responsible, — clearly document responsibilities and mechanisms for communication of decisions, in particular, where the final signatory of a certificate differs from the decision maker or decision makers or does not fulfil the requirements laid down in Section 3.2.7, — issue a certificate or certificates in accordance with the minimum requirements laid down in Annex XII for a period of validity not exceeding five years and shall indicate whether there are specific conditions or limitations associated with the certification, — issue a certificate or certificates for the applicant alone and shall not issue certificates covering multiple entities, and — ensure that the manufacturer is notified of the outcome of the assessment and the resultant decision and that they are entered into the electronic system referred to in Article 57. 4.9.   Changes and modifications The notified body shall have documented procedures and contractual arrangements with manufacturers in place relating to the manufacturers' information obligations and the assessment of changes to: — the approved quality management system or systems or to the product-range covered, — the approved design of a device, — the intended use of or claims made for the device, — the approved type of a device, and — any substance incorporated in or utilised for the manufacturing of a device and being subject to the specific procedures in accordance with Section 4.5.6. The procedures and contractual arrangements referred to in the first paragraph shall include measures for checking the significance of the changes referred to in the first paragraph. In accordance with its documented procedures, the notified body in question shall: — ensure that manufacturers submit for prior approval plans for changes as referred to in the first paragraph and relevant information relating to such changes, — assess the changes proposed and verify whether, after these changes, the quality management system, or the design of a device or type of a device, still meets the requirements of this Regulation, and — notify the manufacturer of its decision and provide a report or as applicable a supplementary report, which shall contain the justified conclusions of its assessment. 4.10.   Surveillance activities and post-certification monitoring The notified body shall have documented procedures: — defining how and when surveillance activities of manufacturers are to be conducted. Those procedures shall include arrangements for unannounced on-site audits of manufacturers and, where applicable, subcontractors and suppliers carrying out product tests and the monitoring of compliance with any conditions binding manufacturers and associated with certification decisions, such as updates to clinical data at defined intervals, — for screening relevant sources of scientific and clinical data and post-market information relating to the scope of their designation. Such information shall be taken into account in the planning and conduct of surveillance activities, and — to review vigilance data to which they have access under Article 92(2) in order to estimate its impact, if any, on the validity of existing certificates. The results of the evaluation and any decisions taken shall be thoroughly documented. The notified body in question shall, upon receipt of information about vigilance cases from a manufacturer or competent authorities, decide which of the following options to apply: — not to take action on the basis that the vigilance case is clearly not related to the certification granted, — observe the manufacturer's and competent authority's activities and the results of the manufacturer's investigation so as to determine whether the certification granted is at risk or whether adequate corrective action has been taken, — perform extraordinary surveillance measures, such as document reviews, short-notice or unannounced audits and product testing, where it is likely that the certification granted is at risk, — increase the frequency of surveillance audits, — review specific products or processes on the occasion of the next audit of the manufacturer, or — take any other relevant measure. In relation to surveillance audits of manufacturers, the notified body shall have documented procedures to: — conduct surveillance audits of the manufacturer on at least an annual basis which shall be planned and conducted in line with the relevant requirements in Section 4.5, — ensure adequate assessment of the manufacturer's documentation on, and application of the provisions on, vigilance, the post-market surveillance, and PMCF, — sample and test devices and technical documentation, during audits, according to pre-defined sampling criteria and testing procedures to ensure that the manufacturer continuously applies the approved quality management system, — ensure that the manufacturer complies with the documentation and information obligations laid down in the relevant Annexes and that its procedures take into account best practices in the implementation of quality management systems, — ensure that the manufacturer does not use quality management system or device approvals in a misleading manner, — gather sufficient information to determine if the quality management system continues to comply with the requirements of this Regulation, — ask the manufacturer, if non-conformities are detected, for corrections, corrective actions and, where applicable, preventive actions, and — where necessary, impose specific restrictions on the relevant certificate, or suspend or withdraw it. The notified body shall, if listed as part of the conditions for certification: — conduct an in-depth review of the clinical evaluation as most recently updated by the manufacturer based on the manufacturer's post-market surveillance, on its PMCF and on clinical literature relevant to the condition being treated with the device or on clinical literature relevant to similar devices, — clearly document the outcome of the in-depth review and address any specific concerns to the manufacturer or impose any specific conditions on it, and — ensure that the clinical evaluation as most recently updated, is appropriately reflected in the instructions for use and, where applicable, the summary of safety and performance. 4.11.   Re-certification The notified body shall have documented procedures in place relating to the re-certification reviews and the renewal of certificates. Re-certification of approved quality management systems or EU technical documentation assessment certificates or EU type-examination certificates shall occur at least every five years. The notified body shall have documented procedures relating to renewals of EU technical documentation assessment certificates and EU type-examination certificates and those procedures shall require the manufacturer in question to submit a summary of changes and scientific findings for the device, including: (a) all changes to the originally approved device, including changes not yet notified, (b) experience gained from post-market surveillance, (c) experience from risk management, (d) experience from updating the proof of compliance with the general safety and performance requirements set out in Annex I, (e) experience from reviews of the clinical evaluation, including the results of any clinical investigations and PMCF, (f) changes to the requirements, to components of the device or to the scientific or regulatory environment, (g) changes to applied or new harmonised standards, CS or equivalent documents, and (h) changes in medical, scientific and technical knowledge, such as: — new treatments, — changes in test methods, — new scientific findings on materials and components, including findings on their biocompatibility, — experience from studies on comparable devices, — data from registers and registries, — experience from clinical investigations with comparable devices. The notified body shall have documented procedures to assess the information referred to in the second paragraph and shall pay particular attention to clinical data from post-market surveillance and PMCF activities undertaken since the previous certification or re-certification, including appropriate updates to manufacturers' clinical evaluation reports. For the decision on re-certification, the notified body in question shall use the same methods and principles as for the initial certification decision. If necessary, separate forms shall be established for re-certification taking into account the steps taken for certification such as application and application review. ANNEX VIII CLASSIFICATION RULES CHAPTER I DEFINITIONS SPECIFIC TO CLASSIFICATION RULES 1.   DURATION OF USE 1.1.    ‘Transient’ means normally intended for continuous use for less than 60 minutes. 1.2.    ‘Short term’ means normally intended for continuous use for between 60 minutes and 30 days. 1.3.    ‘Long term’ means normally intended for continuous use for more than 30 days. 2.   INVASIVE AND ACTIVE DEVICES 2.1.    ‘Body orifice’ means any natural opening in the body, as well as the external surface of the eyeball, or any permanent artificial opening, such as a stoma. 2.2.    ‘Surgically invasive device’ means: (a) an invasive device which penetrates inside the body through the surface of the body, including through mucous membranes of body orifices with the aid or in the context of a surgical operation; and (b) a device which produces penetration other than through a body orifice. 2.3.    ‘Reusable surgical instrument’ means an instrument intended for surgical use in cutting, drilling, sawing, scratching, scraping, clamping, retracting, clipping or similar procedures, without a connection to an active device and which is intended by the manufacturer to be reused after appropriate procedures such as cleaning, disinfection and sterilisation have been carried out. 2.4.    ‘Active therapeutic device’ means any active device used, whether alone or in combination with other devices, to support, modify, replace or restore biological functions or structures with a view to treatment or alleviation of an illness, injury or disability. 2.5.    ‘Active device intended for diagnosis and monitoring’ means any active device used, whether alone or in combination with other devices, to supply information for detecting, diagnosing, monitoring or treating physiological conditions, states of health, illnesses or congenital deformities. 2.6.    ‘Central circulatory system’ means the following blood vessels: arteriae pulmonales, aorta ascendens, arcus aortae, aorta descendens to the bifurcatio aortae, arteriae coronariae, arteria carotis communis, arteria carotis externa, arteria carotis interna, arteriae cerebrales, truncus brachiocephalicus, venae cordis, venae pulmonales, vena cava superior and vena cava inferior. 2.7.    ‘Central nervous system’ means the brain, meninges and spinal cord. 2.8.    ‘Injured skin or mucous membrane’ means an area of skin or a mucous membrane presenting a pathological change or change following disease or a wound. CHAPTER II IMPLEMENTING RULES 3.1.   Application of the classification rules shall be governed by the intended purpose of the devices. 3.2.   If the device in question is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. Accessories for a medical device and for a product listed in Annex XVI shall be classified in their own right separately from the device with which they are used. 3.3.   Software, which drives a device or influences the use of a device, shall fall within the same class as the device. If the software is independent of any other device, it shall be classified in its own right. 3.4.   If the device is not intended to be used solely or principally in a specific part of the body, it shall be considered and classified on the basis of the most critical specified use. 3.5.   If several rules, or if, within the same rule, several sub-rules, apply to the same device based on the device's intended purpose, the strictest rule and sub-rule resulting in the higher classification shall apply. 3.6.   In calculating the duration referred to in Section 1, continuous use shall mean: (a) the entire duration of use of the same device without regard to temporary interruption of use during a procedure or temporary removal for purposes such as cleaning or disinfection of the device. Whether the interruption of use or the removal is temporary shall be established in relation to the duration of the use prior to and after the period when the use is interrupted or the device removed; and (b) the accumulated use of a device that is intended by the manufacturer to be replaced immediately with another of the same type. 3.7.   A device is considered to allow direct diagnosis when it provides the diagnosis of the disease or condition in question by itself or when it provides decisive information for the diagnosis. CHAPTER III CLASSIFICATION RULES 4.   NON-INVASIVE DEVICES 4.1.   Rule 1 All non-invasive devices are classified as class I, unless one of the rules set out hereinafter applies. 4.2.   Rule 2 All non-invasive devices intended for channelling or storing blood, body liquids, cells or tissues, liquids or gases for the purpose of eventual infusion, administration or introduction into the body are classified as class IIa: — if they may be connected to a class IIa, class IIb or class III active device; or — if they are intended for use for channelling or storing blood or other body liquids or for storing organs, parts of organs or body cells and tissues, except for blood bags; blood bags are classified as class IIb. In all other cases, such devices are classified as class I. 4.3.   Rule 3 All non-invasive devices intended for modifying the biological or chemical composition of human tissues or cells, blood, other body liquids or other liquids intended for implantation or administration into the body are classified as class IIb, unless the treatment for which the device is used consists of filtration, centrifugation or exchanges of gas, heat, in which case they are classified as class IIa. All non-invasive devices consisting of a substance or a mixture of substances intended to be used in vitro in direct contact with human cells, tissues or organs taken from the human body or used in vitro with human embryos before their implantation or administration into the body are classified as class III. 4.4.   Rule 4 All non-invasive devices which come into contact with injured skin or mucous membrane are classified as: — class I if they are intended to be used as a mechanical barrier, for compression or for absorption of exudates; — class IIb if they are intended to be used principally for injuries to skin which have breached the dermis or mucous membrane and can only heal by secondary intent; — class IIa if they are principally intended to manage the micro-environment of injured skin or mucous membrane; and — class IIa in all other cases. This rule applies also to the invasive devices that come into contact with injured mucous membrane. 5.   INVASIVE DEVICES 5.1.   Rule 5 All invasive devices with respect to body orifices, other than surgically invasive devices, which are not intended for connection to an active device or which are intended for connection to a class I active device are classified as: — class I if they are intended for transient use; — class IIa if they are intended for short-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity, in which case they are classified as class I; and — class IIb if they are intended for long-term use, except if they are used in the oral cavity as far as the pharynx, in an ear canal up to the ear drum or in the nasal cavity and are not liable to be absorbed by the mucous membrane, in which case they are classified as class IIa. All invasive devices with respect to body orifices, other than surgically invasive devices, intended for connection to a class IIa, class IIb or class III active device, are classified as class IIa. 5.2.   Rule 6 All surgically invasive devices intended for transient use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are reusable surgical instruments, in which case they are classified as class I; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionising radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class IIb; or — are intended to administer medicinal products by means of a delivery system, if such administration of a medicinal product is done in a manner that is potentially hazardous taking account of the mode of application, in which case they are classified as class IIb. 5.3.   Rule 7 All surgically invasive devices intended for short-term use are classified as class IIa unless they: — are intended specifically to control, diagnose, monitor or correct a defect of the heart or of the central circulatory system through direct contact with those parts of the body, in which case they are classified as class III; — are intended specifically for use in direct contact with the heart or central circulatory system or the central nervous system, in which case they are classified as class III; — are intended to supply energy in the form of ionizing radiation in which case they are classified as class IIb; — have a biological effect or are wholly or mainly absorbed in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class IIb, except if the devices are placed in the teeth; or — are intended to administer medicines, in which case they are classified as class IIb. 5.4.   Rule 8 All implantable devices and long-term surgically invasive devices are classified as class IIb unless they: — are intended to be placed in the teeth, in which case they are classified as class IIa; — are intended to be used in direct contact with the heart, the central circulatory system or the central nervous system, in which case they are classified as class III; — have a biological effect or are wholly or mainly absorbed, in which case they are classified as class III; — are intended to undergo chemical change in the body in which case they are classified as class III, except if the devices are placed in the teeth; — are intended to administer medicinal products, in which case they are classified as class III; — are active implantable devices or their accessories, in which cases they are classified as class III; — are breast implants or surgical meshes, in which cases they are classified as class III; — are total or partial joint replacements, in which case they are classified as class III, with the exception of ancillary components such as screws, wedges, plates and instruments; or — are spinal disc replacement implants or are implantable devices that come into contact with the spinal column, in which case they are classified as class III with the exception of components such as screws, wedges, plates and instruments. 6.   ACTIVE DEVICES 6.1.   Rule 9 All active therapeutic devices intended to administer or exchange energy are classified as class IIa unless their characteristics are such that they may administer energy to or exchange energy with the human body in a potentially hazardous way, taking account of the nature, the density and site of application of the energy, in which case they are classified as class IIb. All active devices intended to control or monitor the performance of active therapeutic class IIb devices, or intended directly to influence the performance of such devices are classified as class IIb. All active devices intended to emit ionizing radiation for therapeutic purposes, including devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. All active devices that are intended for controlling, monitoring or directly influencing the performance of active implantable devices are classified as class III. 6.2.   Rule 10 Active devices intended for diagnosis and monitoring are classified as class IIa: — if they are intended to supply energy which will be absorbed by the human body, except for devices intended to illuminate the patient's body, in the visible spectrum, in which case they are classified as class I; — if they are intended to image in vivo distribution of radiopharmaceuticals; or — if they are intended to allow direct diagnosis or monitoring of vital physiological processes, unless they are specifically intended for monitoring of vital physiological parameters and the nature of variations of those parameters is such that it could result in immediate danger to the patient, for instance variations in cardiac performance, respiration, activity of the central nervous system, or they are intended for diagnosis in clinical situations where the patient is in immediate danger, in which cases they are classified as class IIb. Active devices intended to emit ionizing radiation and intended for diagnostic or therapeutic radiology, including interventional radiology devices and devices which control or monitor such devices, or which directly influence their performance, are classified as class IIb. 6.3.   Rule 11 Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: — death or an irreversible deterioration of a person's state of health, in which case it is in class III; or — a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. 6.4.   Rule 12 All active devices intended to administer and/or remove medicinal products, body liquids or other substances to or from the body are classified as class IIa, unless this is done in a manner that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the mode of application in which case they are classified as class IIb. 6.5.   Rule 13 All other active devices are classified as class I. 7.   SPECIAL RULES 7.1.   Rule 14 All devices incorporating, as an integral part, a substance which, if used separately, can be considered to be a medicinal product, as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma, as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the devices, are classified as class III. 7.2.   Rule 15 All devices used for contraception or prevention of the transmission of sexually transmitted diseases are classified as class IIb, unless they are implantable or long term invasive devices, in which case they are classified as class III. 7.3.   Rule 16 All devices intended specifically to be used for disinfecting, cleaning, rinsing or, where appropriate, hydrating contact lenses are classified as class IIb. All devices intended specifically to be used for disinfecting or sterilising medical devices are classified as class IIa, unless they are disinfecting solutions or washer-disinfectors intended specifically to be used for disinfecting invasive devices, as the end point of processing, in which case they are classified as class IIb. This rule does not apply to devices that are intended to clean devices other than contact lenses by means of physical action only. 7.4.   Rule 17 Devices specifically intended for recording of diagnostic images generated by X-ray radiation are classified as class IIa. 7.5.   Rule 18 All devices manufactured utilising tissues or cells of human or animal origin, or their derivatives, which are non-viable or rendered non-viable, are classified as class III, unless such devices are manufactured utilising tissues or cells of animal origin, or their derivatives, which are non-viable or rendered non-viable and are devices intended to come into contact with intact skin only. 7.6.   Rule 19 All devices incorporating or consisting of nanomaterial are classified as: — class III if they present a high or medium potential for internal exposure; — class IIb if they present a low potential for internal exposure; and — class IIa if they present a negligible potential for internal exposure. 7.7.   Rule 20 All invasive devices with respect to body orifices, other than surgically invasive devices, which are intended to administer medicinal products by inhalation are classified as class IIa, unless their mode of action has an essential impact on the efficacy and safety of the administered medicinal product or they are intended to treat life-threatening conditions, in which case they are classified as class IIb. 7.8.   Rule 21 Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as: — class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose; — class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body; — class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities; and — class IIb in all other cases. 7.9.   Rule 22 Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. ANNEX IX CONFORMITY ASSESSMENT BASED ON A QUALITY MANAGEMENT SYSTEM AND ON ASSESSMENT OF TECHNICAL DOCUMENTATION CHAPTER I QUALITY MANAGEMENT SYSTEM 1.   The manufacturer shall establish, document and implement a quality management system as described in Article 10(9) and maintain its effectiveness throughout the life cycle of the devices concerned. The manufacturer shall ensure the application of the quality management system as specified in Section 2 and shall be subject to audit, as laid down in Sections 2.3 and 2.4, and to surveillance as specified in Section 3. 2.   Quality management system assessment 2.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — the name of the manufacturer and address of its registered place of business and any additional manufacturing site covered by the quality management system, and, if the manufacturer's application is lodged by its authorised representative, the name of the authorised representative and the address of the authorised representative's registered place of business, — all relevant information on the device or group of devices covered by the quality management system, — a written declaration that no application has been lodged with any other notified body for the same device-related quality management system, or information about any previous application for the same device-related quality management system, — a draft of an EU declaration of conformity in accordance with Article 19 and Annex IV for the device model covered by the conformity assessment procedure, — the documentation on the manufacturer's quality management system, — a documented description of the procedures in place to fulfil the obligations arising from the quality management system and required under this Regulation and the undertaking by the manufacturer in question to apply those procedures, — a description of the procedures in place to ensure that the quality management system remains adequate and effective, and the undertaking by the manufacturer to apply those procedures, — the documentation on the manufacturer's post-market surveillance system and, where applicable, on the PMCF plan, and the procedures put in place to ensure compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, — a description of the procedures in place to keep up to date the post-market surveillance system, and, where applicable, the PMCF plan, and the procedures ensuring compliance with the obligations resulting from the provisions on vigilance set out in Articles 87 to 92, as well as the undertaking by the manufacturer to apply those procedures, — documentation on the clinical evaluation plan, and — a description of the procedures in place to keep up to date the clinical evaluation plan, taking into account the state of the art. 2.2.   Implementation of the quality management system shall ensure compliance with this Regulation. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures such as quality programmes, quality plans and quality records. Moreover, the documentation to be submitted for the assessment of the quality management system shall include an adequate description of, in particular: (a) the manufacturer's quality objectives; (b) the organisation of the business and in particular: — the organisational structures with the assignment of staff responsibilities in relation to critical procedures, the responsibilities of the managerial staff and their organisational authority, — the methods of monitoring whether the operation of the quality management system is efficient and in particular the ability of that system to achieve the desired design and device quality, including control of devices which fail to conform, — where the design, manufacture and/or final verification and testing of the devices, or parts of any of those processes, is carried out by another party, the methods of monitoring the efficient operation of the quality management system and in particular the type and extent of control applied to the other party, and — where the manufacturer does not have a registered place of business in a Member State, the draft mandate for the designation of an authorised representative and a letter of intention from the authorised representative to accept the mandate; (c) the procedures and techniques for monitoring, verifying, validating and controlling the design of the devices and the corresponding documentation as well as the data and records arising from those procedures and techniques. Those procedures and techniques shall specifically cover: — the strategy for regulatory compliance, including processes for identification of relevant legal requirements, qualification, classification, handling of equivalence, choice of and compliance with conformity assessment procedures, — identification of applicable general safety and performance requirements and solutions to fulfil those requirements, taking applicable CS and, where opted for, harmonised standards or other adequate solutions into account, — risk management as referred to in Section 3 of Annex I, — the clinical evaluation, pursuant to Article 61 and Annex XIV, including post-market clinical follow-up, — solutions for fulfilling the applicable specific requirements regarding design and construction, including appropriate pre-clinical evaluation, in particular the requirements of Chapter II of Annex I, — solutions for fulfilling the applicable specific requirements regarding the information to be supplied with the device, in particular the requirements of Chapter III of Annex I, — the device identification procedures drawn up and kept up to date from drawings, specifications or other relevant documents at every stage of manufacture, and — management of design or quality management system changes; and (d) the verification and quality assurance techniques at the manufacturing stage and in particular the processes and procedures which are to be used, particularly as regards sterilisation and the relevant documents; and (e) the appropriate tests and trials which are to be carried out before, during and after manufacture, the frequency with which they are to take place, and the test equipment to be used; it shall be possible to trace back adequately the calibration of that test equipment. In addition, the manufacturer shall grant the notified body access to the technical documentation referred to in Annexes II and III. 2.3.   Audit The notified body shall audit the quality management system to determine whether it meets the requirements referred to in Section 2.2. Where the manufacturer uses a harmonised standard or CS related to a quality management system, the notified body shall assess conformity with those standards or CS. The notified body shall assume that a quality management system which satisfies the relevant harmonised standards or CS conforms to the requirements covered by those standards or CS, unless it duly substantiates not doing so. The audit team of the notified body shall include at least one member with past experience of assessments of the technology concerned in accordance with Sections 4.3. to 4.5. of Annex VII. In circumstances where such experience is not immediately obvious or applicable, the notified body shall provide a documented rationale for the composition of that team. The assessment procedure shall include an audit on the manufacturer's premises and, if appropriate, on the premises of the manufacturer's suppliers and/or subcontractors to verify the manufacturing and other relevant processes. Moreover, in the case of class IIa and class IIb devices, the quality management system assessment shall be accompanied by the assessment of technical documentation for devices selected on a representative basis in accordance with Sections 4.4 to 4.8. In choosing representative samples, the notified body shall take into account the published guidance developed by the MDCG pursuant to Article 105 and in particular the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended purpose and the results of any previous relevant assessments such as with regard to physical, chemical, biological or clinical properties, that have been carried out in accordance with this Regulation. The notified body in question shall document its rationale for the samples taken. If the quality management system conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality management system certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. The decision shall contain the conclusions of the audit and a reasoned report. 2.4.   The manufacturer in question shall inform the notified body which approved the quality management system of any plan for substantial changes to the quality management system, or the device-range covered. The notified body shall assess the changes proposed, determine the need for additional audits and verify whether after those changes the quality management system still meets the requirements referred to in Section 2.2. It shall notify the manufacturer of its decision which shall contain the conclusions of the assessment, and where applicable, conclusions of additional audits. The approval of any substantial change to the quality management system or the device-range covered shall take the form of a supplement to the EU quality management system certificate. 3.   Surveillance assessment applicable to class IIa, class IIb and class III devices 3.1.   The aim of surveillance is to ensure that the manufacturer duly fulfils the obligations arising from the approved quality management system. 3.2.   The manufacturer shall give authorisation to the notified body to carry out all the necessary audits, including on-site audits, and supply it with all relevant information, in particular: — the documentation on its quality management system, — documentation on any findings and conclusions resulting from the application of the post-market surveillance plan, including the PMCF plan, for a representative sample of devices, and of the provisions on vigilance set out in Articles 87 to 92, — the data stipulated in the part of the quality management system relating to design, such as the results of analyses, calculations, tests and the solutions adopted regarding the risk-management as referred to in Section 4 of Annex I, and — the data stipulated in the part of the quality management system relating to manufacture, such as quality control reports and test data, calibration data, and records on the qualifications of the personnel concerned. 3.3.   Notified bodies shall periodically, at least once every 12 months, carry out appropriate audits and assessments to make sure that the manufacturer in question applies the approved quality management system and the post-market surveillance plan. Those audits and assessments shall include audits on the premises of the manufacturer and, if appropriate, of the manufacturer's suppliers and/or subcontractors. At the time of such on-site audits, the notified body shall, where necessary, carry out or ask for tests in order to check that the quality management system is working properly. It shall provide the manufacturer with a surveillance audit report and, if a test has been carried out, with a test report. 3.4.   The notified body shall randomly perform at least once every five years unannounced audits on the site of the manufacturer and, where appropriate, of the manufacturer's suppliers and/or subcontractors, which may be combined with the periodic surveillance assessment referred to in Section 3.3. or be performed in addition to that surveillance assessment. The notified body shall establish a plan for such unannounced on-site audits but shall not disclose it to the manufacturer. Within the context of such unannounced on-site audits, the notified body shall test an adequate sample of the devices produced or an adequate sample from the manufacturing process to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to unannounced on-site audits, the notified body shall specify the relevant sampling criteria and testing procedure. Instead of, or in addition to, sampling referred to in the second paragraph, the notified body shall take samples of devices from the market to verify that the manufactured device is in conformity with the technical documentation, with the exception of the devices referred to in the second subparagraph of Article 52(8). Prior to the sampling, the notified body in question shall specify the relevant sampling criteria and testing procedure. The notified body shall provide the manufacturer in question with an on-site audit report which shall include, if applicable, the result of the sample test. 3.5.   In the case of class IIa and class IIb devices, the surveillance assessment shall also include an assessment of the technical documentation as referred to in Sections 4.4 to 4.8 for the device or devices concerned on the basis of further representative samples chosen in accordance with the rationale documented by the notified body in accordance with the second paragraph of Section 2.3. In the case of class III devices, the surveillance assessment shall also include a test of the approved parts and/or materials that are essential for the integrity of the device, including, where appropriate, a check that the quantities of produced or purchased parts and/or materials correspond to the quantities of finished devices. 3.6.   The notified body shall ensure that the composition of the assessment team is such that there is sufficient experience with the evaluation of the devices, systems and processes concerned, continuous objectivity and neutrality; this shall include a rotation of the members of the assessment team at appropriate intervals. As a general rule, a lead auditor shall neither lead nor attend audits for more than three consecutive years in respect of the same manufacturer. 3.7.   If the notified body finds a divergence between the sample taken from the devices produced or from the market and the specifications laid down in the technical documentation or the approved design, it shall suspend or withdraw the relevant certificate or impose restrictions on it. CHAPTER II ASSESSMENT OF THE TECHNICAL DOCUMENTATION 4.   Assessment of the technical documentation applicable to class III devices and to the class IIb devices referred to in the second subparagraph of Article 52(4) 4.1.   In addition to the obligations laid down in Section 2, the manufacturer shall lodge with the notified body an application for assessment of the technical documentation relating to the device which it plans to place on the market or put into service and which is covered by the quality management system referred to in Section 2. 4.2.   The application shall describe the design, manufacture and performance of the device in question. It shall include the technical documentation as referred to in Annexes II and III. 4.3.   The notified body shall examine the application by using staff, employed by it, with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of the Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests. 4.4.   The notified body shall review the clinical evidence presented by the manufacturer in the clinical evaluation report and the related clinical evaluation that was conducted. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or the clinical condition in which it is utilised, for the purposes of that review. 4.5.   The notified body shall, in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity. For any characteristic of the device claimed as innovative by the manufacturer or for new indications, the notified body shall assess to what extent specific claims are supported by specific pre-clinical and clinical data and risk analysis. 4.6.   The notified body shall verify that the clinical evidence and the clinical evaluation are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. That verification shall include consideration of the adequacy of the benefit-risk determination, the risk management, the instructions for use, the user training and the manufacturer's post-market surveillance plan, and include a review of the need for, and the adequacy of, the PMCF plan proposed, where applicable. 4.7.   Based on its assessment of the clinical evidence, the notified body shall consider the clinical evaluation and the benefit-risk determination, and whether specific milestones need to be defined to allow the notified body to review updates to the clinical evidence that result from post-market surveillance and PMCF data. 4.8.   The notified body shall clearly document the outcome of its assessment in the clinical evaluation assessment report. 4.9.   The notified body shall provide the manufacturer with a report on the technical documentation assessment, including a clinical evaluation assessment report. If the device conforms to the relevant provisions of this Regulation, the notified body shall issue an EU technical documentation assessment certificate. The certificate shall contain the conclusions of the technical documentation assessment, the conditions of the certificate's validity, the data needed for identification of the approved design, and, where appropriate, a description of the intended purpose of the device. 4.10.   Changes to the approved device shall require approval from the notified body which issued the EU technical documentation assessment certificate where such changes could affect the safety and performance of the device or the conditions prescribed for use of the device. Where the manufacturer plans to introduce any of the above-mentioned changes it shall inform the notified body which issued the EU technical documentation assessment certificate thereof. The notified body shall assess the planned changes and decide whether the planned changes require a new conformity assessment in accordance with Article 52 or whether they could be addressed by means of a supplement to the EU technical documentation assessment certificate. In the latter case, the notified body shall assess the changes, notify the manufacturer of its decision and, where the changes are approved, provide it with a supplement to the EU technical documentation assessment certificate. 5.   Specific additional procedures 5.1.   Assessment procedure for certain class III and class IIb devices (a) For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product as referred to in Section 6.4. of Annex VIII (Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer referred to in Article 61(12), prepare a clinical evaluation assessment report which sets out its conclusions concerning the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication or indications and the PMCF plan referred to in Article 10(3) and Part B of Annex XIV. The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer's clinical evaluation documentation, referred to in points (c) and (d) of Section 6.1 of Annex II, to the Commission. The Commission shall immediately transmit those documents to the relevant expert panel referred to in Article 106. (b) The notified body may be requested to present its conclusions as referred to in point (a) to the expert panel concerned. (c) The expert panel shall decide, under the supervision of the Commission, on the basis of all of the following criteria: (i) the novelty of the device or of the related clinical procedure involved, and the possible major clinical or health impact thereof; (ii) a significantly adverse change in the benefit-risk profile of a specific category or group of devices due to scientifically valid health concerns in respect of components or source material or in respect of the impact on health in the case of failure of the device; (iii) a significantly increased rate of serious incidents reported in accordance with Article 87 in respect of a specific category or group of devices, whether to provide a scientific opinion on the clinical evaluation assessment report of the notified body based on the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the medical indication or indications and the PMCF plan. That scientific opinion shall be provided within a period of 60 days, starting on the day of receipt of the documents from the Commission as referred to in point (a). The reasons for the decision to provide a scientific opinion on the basis of the criteria in points (i), (ii) and (iii) shall be included in the scientific opinion. Where the information submitted is not sufficient for the expert panel to reach a conclusion, this shall be stated in the scientific opinion. (d) The expert panel may decide, under the supervision of the Commission, on the basis of the criteria laid down in point (c) not to provide a scientific opinion, in which case it shall inform the notified body as soon as possible and in any event within 21 days of receipt of the documents as referred to in point (a) from the Commission. The expert panel shall within that time limit provide the notified body and the Commission with the reasons for its decision, whereupon the notified body may proceed with the certification procedure of that device. (e) The expert panel shall within 21 days of receipt of the documents from the Commission notify the Commission, through Eudamed whether it intends to provide a scientific opinion, pursuant to point (c), or whether it intends not to provide a scientific opinion, pursuant to point (d). (f) Where no opinion has been delivered within a period of 60 days, the notified body may proceed with the certification procedure of the device in question. (g) The notified body shall give due consideration to the views expressed in the scientific opinion of the expert panel. Where the expert panel finds that the level of clinical evidence is not sufficient or otherwise gives rise to serious concerns about the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication(s), and with the PMCF plan, the notified body shall, if necessary, advise the manufacturer to restrict the intended purpose of the device to certain groups of patients or certain medical indications and/or to impose a limit on the duration of validity of the certificate, to undertake specific PMCF studies, to adapt the instructions for use or the summary of safety and performance, or to impose other restrictions in its conformity assessment report, as appropriate. The notified body shall provide a full justification where it has not followed the advice of the expert panel in its conformity assessment report and the Commission shall without prejudice to Article 109 make both the scientific opinion of the expert panel and the written justification provided by the notified body publicly available via Eudamed. (h) The Commission, after consultation with the Member States and relevant scientific experts shall provide guidance for expert panels for consistent interpretation of the criteria in point (c) before 26 May 2020. 5.2.   Procedure in the case of devices incorporating a medicinal substance (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (b) Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device. Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA. (c) When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body. (d) The medicinal products authority consulted shall provide its opinion to the notified body within 210 days of receipt of all the necessary documentation. (e) The scientific opinion of the medicinal products authority consulted, and any possible update of that opinion, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision. The notified body shall not deliver the certificate if the scientific opinion is unfavourable and shall convey its final decision to the medicinal products authority consulted. (f) Before any change is made with respect to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the manufacturer shall inform the notified body of the changes. That notified body shall seek the opinion of the medicinal products authority consulted, in order to confirm that the quality and safety of the ancillary substance remain unchanged. The medicinal products authority consulted shall take into account the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The medicinal products authority consulted shall provide its opinion within 60 days after receipt of all the necessary documentation regarding the changes. The notified body shall not deliver the supplement to the EU technical documentation assessment certificate if the scientific opinion provided by the medicinal products authority consulted is unfavourable. The notified body shall convey its final decision to the medicinal products authority consulted. (g) Where the medicinal products authority consulted obtains information on the ancillary substance, which could have an impact on the risk or benefit previously established concerning the incorporation of the substance into the device, it shall advise the notified body as to whether this information has an impact on the risk or benefit previously established concerning the incorporation of the substance into the device. The notified body shall take that advice into account in reconsidering its assessment of the conformity assessment procedure. 5.3.   Procedure in the case of devices manufactured utilising, or incorporating, tissues or cells of human or animal origin, or their derivatives, that are non-viable or rendered non-viable 5.3.1.   Tissues or cells of human origin or their derivatives (a) For devices manufactured utilising derivatives of tissues or cells of human origin that are covered by this Regulation in accordance with point (g) of Article 1(6) and for devices that incorporate, as an integral part, tissues or cells of human origin, or their derivatives, covered by Directive 2004/23/EC, that have an action ancillary to that of the device, the notified body shall, prior to issuing an EU technical documentation assessment certificate, seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2004/23/EC (‘human tissues and cells competent authority’) on the aspects relating to the donation, procurement and testing of tissues or cells of human origin or their derivatives. The notified body shall submit a summary of the preliminary conformity assessment which provides, among other things, information about the non-viability of the human tissues or cells in question, their donation, procurement and testing and the risk or benefit of the incorporation of the tissues or cells of human origin or their derivatives into the device. (b) Within 120 days of receipt of all the necessary documentation, the human tissues and cells competent authority shall provide to the notified body its opinion. (c) The scientific opinion of the human tissues and cells competent authority, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion of the human tissues and cells competent authority when making its decision. The notified body shall not deliver the certificate if that scientific opinion is unfavourable. It shall convey its final decision to the human tissues and cells competent authority concerned. (d) Before any change is made with respect to non-viable tissues or cells of human origin or their derivatives incorporated in a device, in particular relating to their donation, testing or procurement, the manufacturer shall inform the notified body of the intended changes. The notified body shall consult the authority that was involved in the initial consultation, in order to confirm that the quality and safety of the tissues or cells of human origin or their derivatives incorporated in the device are maintained. The human tissues and cells competent authority concerned shall take into account the data relating to the usefulness of incorporation of the tissues or cells of human origin or their derivatives into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit-risk ratio of the addition of the tissues or cells of human origin or their derivatives in the device. It shall provide its opinion within 60 days of receipt of all the necessary documentation regarding the intended changes. The notified body shall not deliver a supplement to the EU technical documentation assessment certificate if the scientific opinion is unfavourable and shall convey its final decision to the human tissues and cells competent authority concerned. 5.3.2.   Tissues or cells of animal origin or their derivatives In the case of devices manufactured utilising animal tissue which is rendered non-viable or utilising non-viable products derived from animal tissue, as referred to in Regulation (EU) No 722/2012, the notified body shall apply the relevant requirements laid down in that Regulation. 5.4.   Procedure in the case of devices that are composed of substances or of combinations of substances that are absorbed by or locally dispersed in the human body (a) The quality and safety of devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by, or locally dispersed in, the human body, shall be verified where applicable and only in respect of the requirements not covered by this Regulation, in accordance with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. (b) In addition, for devices, or their products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, the notified body shall seek a scientific opinion from one of the competent authorities designated by the Member States in accordance with Directive 2001/83/EC or from the EMA, either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the compliance of the device with the relevant requirements laid down in Annex I to Directive 2001/83/EC. (c) The opinion of the medicinal products authority consulted shall be drawn up within 150 days of receipt of all the necessary documentation. (d) The scientific opinion of the medicinal products authority consulted, and any possible update, shall be included in the documentation of the notified body concerning the device. The notified body shall give due consideration to the views expressed in the scientific opinion when making its decision and shall convey its final decision to the medicinal products authority consulted. 6.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in Article 1(8) Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma as referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. CHAPTER III ADMINISTRATIVE PROVISIONS 7.   The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 and in particular the data and records arising from the procedures referred to in point (c) of the second paragraph of Section 2.2, — information on the changes referred to in Section 2.4, — the documentation referred to in Section 4.2, and — the decisions and reports from the notified body as referred to in this Annex. 8.   Each Member State shall require that the documentation referred to in Section 7 is kept at the disposal of competent authorities for the period indicated in that Section in case a manufacturer, or its authorised representative, established within its territory goes bankrupt or ceases its business activity prior to the end of that period. ANNEX X CONFORMITY ASSESSMENT BASED ON TYPE-EXAMINATION 1.   EU type-examination is the procedure whereby a notified body ascertains and certifies that a device, including its technical documentation and relevant life cycle processes and a corresponding representative sample of the device production envisaged, fulfils the relevant provisions of this Regulation. 2.   Application The manufacturer shall lodge an application for assessment with a notified body. The application shall include: — the name of the manufacturer and address of the registered place of business of the manufacturer and, if the application is lodged by the authorised representative, the name of the authorised representative and the address of its registered place of business, — the technical documentation referred to in Annexes II and III. The applicant shall make a representative sample of the device production envisaged (‘type’) available to the notified body. The notified body may request other samples as necessary, and — a written declaration that no application has been lodged with any other notified body for the same type, or information about any previous application for the same type that was refused by another notified body or was withdrawn by the manufacturer or its authorised representative before that other notified body made its final assessment. 3.   Assessment The notified body shall: (a) examine the application by using staff with proven knowledge and experience regarding the technology concerned and its clinical application. The notified body may require the application to be completed by having further tests carried out or requesting further evidence to be provided to allow assessment of conformity with the relevant requirements of this Regulation. The notified body shall carry out adequate physical or laboratory tests in relation to the device or request the manufacturer to carry out such tests; (b) examine and assess the technical documentation for conformity with the requirements of this Regulation that are applicable to the device and verify that the type has been manufactured in conformity with that documentation; it shall also record the items designed in conformity with the applicable standards referred to in Article 8 or with applicable CS, and record the items not designed on the basis of the relevant standards referred to in Article 8 or of the relevant CS; (c) review the clinical evidence presented by the manufacturer in the clinical evaluation report in accordance with Section 4 of Annex XIV. The notified body shall employ device reviewers with sufficient clinical expertise and, if necessary, use external clinical experts with direct and current experience relating to the device in question or to the clinical condition in which it is utilised, for the purposes of that review; (d) in circumstances in which the clinical evidence is based partly or totally on data from devices which are claimed to be similar or equivalent to the device under assessment, assess the suitability of using such data, taking into account factors such as new indications and innovation. The notified body shall clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity; (e) clearly document the outcome of its assessment in a pre-clinical and clinical evaluation assessment report as part of the EU type examination report referred to in point (i); (f) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether the solutions adopted by the manufacturer meet the general safety and performance requirements laid down in this Regulation, in the event that the standards referred to in Article 8 or the CS have not been applied. Where the device has to be connected to another device or devices in order to operate as intended, proof shall be provided that it conforms to the general safety and performance requirements when connected to any such device or devices having the characteristics specified by the manufacturer; (g) carry out or arrange for the appropriate assessments and the physical or laboratory tests necessary to verify whether, in the event that the manufacturer has chosen to apply the relevant harmonised standards, those standards have actually been applied; (h) agree with the applicant on the place where the necessary assessments and tests are to be carried out; and (i) draw up an EU type-examination report on the results of the assessments and tests carried out under points (a) to (g). 4.   Certificate If the type conforms to this Regulation, the notified body shall issue an EU type-examination certificate. The certificate shall contain the name and address of the manufacturer, the conclusions of the type examination assessment, the conditions of the certificate's validity and the data needed for identification of the type approved. The certificate shall be drawn up in accordance with Annex XII. The relevant parts of the documentation shall be annexed to the certificate and a copy kept by the notified body. 5.   Changes to the type 5.1.   The applicant shall inform the notified body which issued the EU type-examination certificate of any planned change to the approved type or of its intended purpose and conditions of use. 5.2.   Changes to the approved device including limitations of its intended purpose and conditions of use shall require approval from the notified body which issued the EU type-examination certificate where such changes may affect conformity with the general safety and performance requirements or with the conditions prescribed for use of the product. The notified body shall examine the planned changes, notify the manufacturer of its decision and provide him with a supplement to the EU type-examination report. The approval of any change to the approved type shall take the form of a supplement to the EU type-examination certificate. 5.3.   Changes to the intended purpose and conditions of use of the approved device, with the exception of limitations of the intended purpose and conditions of use, shall necessitate a new application for a conformity assessment. 6.   Specific additional procedures Section 5 of Annex IX shall apply with the proviso that any reference to an EU technical documentation assessment certificate shall be understood as a reference to an EU type-examination certificate. 7.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the documentation referred to in the second indent of Section 2, — information on the changes referred to in Section 5, and — copies of EU type-examination certificates, scientific opinions and reports and their additions/supplements. Section 8 of Annex IX shall apply. ANNEX XI CONFORMITY ASSESSMENT BASED ON PRODUCT CONFORMITY VERIFICATION 1.   The objective of the conformity assessment based on product conformity verification is to ensure that devices conform to the type for which an EU type-examination certificate has been issued, and that they meet the provisions of this Regulation which apply to them. 2.   Where an EU type-examination certificate has been issued in accordance with Annex X, the manufacturer may either apply the procedure set out in Part A (production quality assurance) or the procedure set out in Part B (product verification) of this Annex. 3.   By way of derogation from Sections 1 and 2 above, the procedures in this Annex coupled with the drawing up of technical documentation as set out in Annexes II and III may also be applied by manufacturers of class IIa devices. PART A PRODUCTION QUALITY ASSURANCE 4.   The manufacturer shall ensure that the quality management system approved for the manufacture of the devices concerned is implemented, shall carry out a final verification, as specified in Section 6, and shall be subject to the surveillance referred to in Section 7. 5.   When the manufacturer fulfils the obligations laid down in Section 4, it shall draw up and keep an EU declaration of conformity in accordance with Article 19 and Annex IV for the device covered by the conformity assessment procedure. By issuing an EU declaration of conformity, the manufacturer shall be deemed to ensure and to declare that the device concerned conforms to the type described in the EU type-examination certificate and meets the requirements of this Regulation which apply to the device. 6.   Quality management system 6.1.   The manufacturer shall lodge an application for assessment of its quality management system with a notified body. The application shall include: — all elements listed in Section 2.1 of Annex IX, — the technical documentation referred to in Annexes II and III for the types approved, and — a copy of the EU type-examination certificates referred to in Section 4 of Annex X; if the EU type-examination certificates have been issued by the same notified body with which the application is lodged, a reference to the technical documentation and its updates and the certificates issued shall also be included in the application. 6.2.   Implementation of the quality management system shall be such as to ensure that there is compliance with the type described in the EU type-examination certificate and with the provisions of this Regulation which apply to the devices at each stage. All the elements, requirements and provisions adopted by the manufacturer for its quality management system shall be documented in a systematic and orderly manner in the form of a quality manual and written policies and procedures, such as quality programmes, quality plans and quality records. That documentation shall, in particular, include an adequate description of all elements listed in points (a), (b), (d) and (e) of Section 2.2 of Annex IX. 6.3.   The first and second paragraph of Section 2.3 of Annex IX shall apply. If the quality management system is such that it ensures that the devices conform to the type described in the EU type-examination certificate and that it conforms to the relevant provisions of this Regulation, the notified body shall issue an EU quality assurance certificate. The notified body shall notify the manufacturer of its decision to issue the certificate. That decision shall contain the conclusions of the notified body's audit and a reasoned assessment. 6.4.   Section 2.4 of Annex IX shall apply. 7.   Surveillance Section 3.1, the first, second and fourth indents of Section 3.2, Sections 3.3, 3.4, 3.6 and 3.7 of Annex IX shall apply. In the case of class III devices, surveillance shall also include a check that the quantities of produced or purchased raw material or crucial components approved for the type and correspond to the quantities of finished devices. 8.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 9.   Administrative provisions The manufacturer or, where the manufacturer does not have a registered place of business in a Member State, its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in the fifth indent of Section 2.1 of Annex IX, — the documentation referred to in the eighth indent of Section 2.1 of Annex IX, including the EU type-examination certificate referred to in Annex X, — information on the changes referred to in Section 2.4 of Annex IX, and — the decisions and reports from the notified body as referred to in Sections 2.3, 3.3 and 3.4 of Annex IX. Section 8 of Annex IX shall apply. 10.   Application to class IIa devices 10.1.   By way of derogation from Section 5, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 10.2.   For class IIa devices the notified body shall assess, as part of the assessment referred to in Section 6.3, whether the technical documentation as referred to in Annexes II and III for the devices selected on a representative basis is compliant with this Regulation. In choosing a representative sample or samples of devices, the notified body shall take into account the novelty of the technology, similarities in design, technology, manufacturing and sterilisation methods, the intended use and the results of any previous relevant assessments (e.g. with regard to physical, chemical, biological or clinical properties) that have been carried out in accordance with this Regulation. The notified body shall document its rationale for the sample or samples of devices taken. 10.3.   Where the assessment under Section 10.2. confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 10.4.   Samples additional to those taken for the initial conformity assessment of devices shall be assessed by the notified body as part of the surveillance assessment referred to in Section 7. 10.5.   By way of derogation from Section 6, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 10.3. Section 8 of Annex IX shall apply. PART B PRODUCT VERIFICATION 11.   Product verification shall be understood to be the procedure whereby after examination of every manufactured device, the manufacturer, by issuing an EU declaration of conformity in accordance with Article 19 and Annex IV, shall be deemed to ensure and to declare that the devices which have been subject to the procedure set out in Sections 14 and 15 conform to the type described in the EU type-examination certificate and meet the requirements of this Regulation which apply to them. 12.   The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which conform to the type described in the EU type-examination certificate and to the requirements of the Regulation which apply to them. Prior to the start of manufacture, the manufacturer shall prepare documents defining the manufacturing process, in particular as regards sterilisation where necessary, together with all routine, pre-established procedures to be implemented to ensure homogeneous production and, where appropriate, conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. In addition, for devices placed on the market in a sterile condition, and only for those aspects of the manufacturing process designed to secure and maintain sterility, the manufacturer shall apply the provisions of Sections 6 and 7. 13.   The manufacturer shall undertake to institute and keep up to date a post-market surveillance plan, including a PMCF plan, and the procedures ensuring compliance with the obligations of the manufacturer resulting from the provisions on vigilance and post-market surveillance system set out in Chapter VII. 14.   The notified body shall carry out the appropriate examinations and tests in order to verify the conformity of the device with the requirements of the Regulation by examining and testing every product as specified in Section 15. The examinations and tests referred to in the first paragraph of this Section shall not apply to aspects of the manufacturing process designed to secure sterility. 15.   Verification by examination and testing of every product 15.1.   Every device shall be examined individually and the appropriate physical or laboratory tests as defined in the relevant standard or standards referred to in Article 8, or equivalent tests and assessments, shall be carried out in order to verify, where appropriate, the conformity of the devices with the type described in the EU type-examination certificate and with the requirements of this Regulation which apply to them. 15.2.   The notified body shall affix, or have affixed, its identification number to each approved device and shall draw up an EU product verification certificate relating to the tests and assessments carried out. 16.   Batch verification in the case of devices incorporating, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in Article 1(8). Upon completing the manufacture of each batch of devices that incorporate, as an integral part, a medicinal substance which, if used separately, would be considered to be a medicinal product derived from human blood or human plasma referred to in the first subparagraph of Article 1(8), the manufacturer shall inform the notified body of the release of the batch of devices and send it the official certificate concerning the release of the batch of human blood or plasma derivative used in the device, issued by a Member State laboratory or a laboratory designated for that purpose by a Member State in accordance with Article 114(2) of Directive 2001/83/EC. 17.   Administrative provisions The manufacturer or its authorised representative shall, for a period ending no sooner than 10 years, and in the case of implantable devices no sooner than 15 years, after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the documentation referred to in Section 12, — the certificate referred to in Section 15.2, and — the EU type-examination certificate referred to in Annex X. Section 8 of Annex IX shall apply. 18.   Application to class IIa devices 18.1.   By way of derogation from Section 11, by virtue of the EU declaration of conformity the manufacturer shall be deemed to ensure and to declare that the class IIa devices in question are manufactured in conformity with the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them. 18.2.   The verification conducted by the notified body in accordance with Section 14 is intended to confirm the conformity of the class IIa devices in question with the technical documentation referred to in Annexes II and III and with the requirements of this Regulation which apply to them. 18.3.   If the verification referred to in Section 18.2 confirms that the class IIa devices in question conform to the technical documentation referred to in Annexes II and III and meet the requirements of this Regulation which apply to them, the notified body shall issue a certificate pursuant to this Part of this Annex. 18.4.   By way of derogation from Section 17, the manufacturer or its authorised representative shall, for a period ending no sooner than 10 years after the last device has been placed on the market, keep at the disposal of the competent authorities: — the EU declaration of conformity, — the technical documentation referred to in Annexes II and III, and — the certificate referred to in Section 18.3. Section 8 of Annex IX shall apply. ANNEX XII CERTIFICATES ISSUED BY A NOTIFIED BODY CHAPTER I GENERAL REQUIREMENTS 1. Certificates shall be drawn up in one of the official languages of the Union. 2. Each certificate shall refer to only one conformity assessment procedure. 3. Certificates shall only be issued to one manufacturer. The name and address of the manufacturer included in the certificate shall be the same as that registered in the electronic system referred to in Article 30. 4. The scope of the certificates shall unambiguously identify the device or devices covered: (a) EU technical documentation assessment certificates, EU type-examination certificates and EU product verification certificates shall include a clear identification, including the name, model and type, of the device or devices, the intended purpose, as included by the manufacturer in the instructions for use and in relation to which the device has been assessed in the conformity assessment procedure, risk classification and the Basic UDI-DI as referred to in Article 27(6); (b) EU quality management system certificates and EU quality assurance certificates shall include the identification of the devices or groups of devices, the risk classification, and, for class IIb devices, the intended purpose. 5. The notified body shall be able to demonstrate on request, which (individual) devices are covered by the certificate. The notified body shall set up a system that enables the determination of the devices, including their classification, covered by the certificate. 6. Certificates shall contain, if applicable, a note that, for the placing on the market of the device or devices it covers, another certificate issued in accordance with this Regulation is required. 7. EU quality management system certificates and EU quality assurance certificates for class I devices for which the involvement of a notified body is required pursuant to Article 52(7) shall include a statement that the audit by the notified body of the quality management system was limited to the aspects required under that paragraph. 8. Where a certificate is supplemented, modified or re-issued, the new certificate shall contain a reference to the preceding certificate and its date of issue with identification of the changes. CHAPTER II MINIMUM CONTENT OF THE CERTIFICATES 1. name, address and identification number of the notified body; 2. name and address of the manufacturer and, if applicable, of the authorised representative; 3. unique number identifying the certificate; 4. if already issued, the SRN of the manufacturer referred to in to Article 31(2); 5. date of issue; 6. date of expiry; 7. data needed for the unambiguous identification of the device or devices where applicable as specified in Section 4 of Part I; 8. if applicable, reference to any previous certificate as specified in Section 8 of Chapter I; 9. reference to this Regulation and the relevant Annex in accordance with which the conformity assessment has been carried out; 10. examinations and tests performed, e.g. reference to relevant CS, harmonised standards, test reports and audit report(s); 11. if applicable, reference to the relevant parts of the technical documentation or other certificates required for the placing on the market of the device or devices covered; 12. if applicable, information about the surveillance by the notified body; 13. conclusions of the notified body's conformity assessment with regard to the relevant Annex; 14. conditions for or limitations to the validity of the certificate; 15. legally binding signature of the notified body in accordance with the applicable national law. ANNEX XIII PROCEDURE FOR CUSTOM-MADE DEVICES 1. For custom-made devices, the manufacturer or its authorised representative shall draw up a statement containing all of the following information: — the name and address of the manufacturer, and of all manufacturing sites, — if applicable, the name and address of the authorised representative, — data allowing identification of the device in question, — a statement that the device is intended for exclusive use by a particular patient or user, identified by name, an acronym or a numerical code, — the name of the person who made out the prescription and who is authorised by national law by virtue of their professional qualifications to do so, and, where applicable, the name of the health institution concerned, — the specific characteristics of the product as indicated by the prescription, — a statement that the device in question conforms to the general safety and performance requirements set out in Annex I and, where applicable, indicating which general safety and performance requirements have not been fully met, together with the grounds, — where applicable, an indication that the device contains or incorporates a medicinal substance, including a human blood or plasma derivative, or tissues or cells of human origin, or of animal origin as referred to in Regulation (EU) No 722/2012. 2. The manufacturer shall undertake to keep available for the competent national authorities documentation that indicates its manufacturing site or sites and allows an understanding to be formed of the design, manufacture and performance of the device, including the expected performance, so as to allow assessment of conformity with the requirements of this Regulation. 3. The manufacturer shall take all the measures necessary to ensure that the manufacturing process produces devices which are manufactured in accordance with the documentation referred to in Section 2. 4. The statement referred to in the introductory part of Section 1 shall be kept for a period of at least 10 years after the device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Section 8 of Annex IX shall apply. 5. The manufacturer shall review and document experience gained in the post-production phase, including from PMCF as referred to in Part B of Annex XIV, and implement appropriate means to apply any necessary corrective action, In that context, it shall report in accordance with Article 87(1) to the competent authorities any serious incidents or field safety corrective actions or both as soon as it learns of them. ANNEX XIV CLINICAL EVALUATION AND POST-MARKET CLINICAL FOLLOW-UP PART A CLINICAL EVALUATION 1.   To plan, continuously conduct and document a clinical evaluation, manufacturers shall: (a) establish and update a clinical evaluation plan, which shall include at least: — an identification of the general safety and performance requirements that require support from relevant clinical data; — a specification of the intended purpose of the device; — a clear specification of intended target groups with clear indications and contra-indications; — a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters; — a specification of methods to be used for examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of residual risks and side-effects; — an indicative list and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device; — an indication how benefit-risk issues relating to specific components such as use of pharmaceutical, non-viable animal or human tissues, are to be addressed; and — a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF as referred to in Part B of this Annex with an indication of milestones and a description of potential acceptance criteria; (b) identify available clinical data relevant to the device and its intended purpose and any gaps in clinical evidence through a systematic scientific literature review; (c) appraise all relevant clinical data by evaluating their suitability for establishing the safety and performance of the device; (d) generate, through properly designed clinical investigations in accordance with the clinical development plan, any new or additional clinical data necessary to address outstanding issues; and (e) analyse all relevant clinical data in order to reach conclusions about the safety and clinical performance of the device including its clinical benefits. 2.   The clinical evaluation shall be thorough and objective, and take into account both favourable and unfavourable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer's claims in respect of the device. 3.   A clinical evaluation may be based on clinical data relating to a device for which equivalence to the device in question can be demonstrated. The following technical, biological and clinical characteristics shall be taken into consideration for the demonstration of equivalence: — Technical: the device is of similar design; is used under similar conditions of use; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements; — Biological: the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables; — Clinical: the device is used for the same clinical condition or purpose, including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification. It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence. 4.   The results of the clinical evaluation and the clinical evidence on which it is based shall be documented in a clinical evaluation report which shall support the assessment of the conformity of the device. The clinical evidence together with non-clinical data generated from non-clinical testing methods and other relevant documentation shall allow the manufacturer to demonstrate conformity with the general safety and performance requirements and shall be part of the technical documentation for the device in question. Both favourable and unfavourable data considered in the clinical evaluation shall be included in the technical documentation. PART B POST-MARKET CLINICAL FOLLOW-UP 5.   PMCF shall be understood to be a continuous process that updates the clinical evaluation referred to in Article 61 and Part A of this Annex and shall be addressed in the manufacturer's post-market surveillance plan. When conducting PMCF, the manufacturer shall proactively collect and evaluate clinical data from the use in or on humans of a device which bears the CE marking and is placed on the market or put into service within its intended purpose as referred to in the relevant conformity assessment procedure, with the aim of confirming the safety and performance throughout the expected lifetime of the device, of ensuring the continued acceptability of identified risks and of detecting emerging risks on the basis of factual evidence. 6.   PMCF shall be performed pursuant to a documented method laid down in a PMCF plan. 6.1.   The PMCF plan shall specify the methods and procedures for proactively collecting and evaluating clinical data with the aim of: (a) confirming the safety and performance of the device throughout its expected lifetime, (b) identifying previously unknown side-effects and monitoring the identified side-effects and contraindications, (c) identifying and analysing emergent risks on the basis of factual evidence, (d) ensuring the continued acceptability of the benefit-risk ratio referred to in Sections 1 and 9 of Annex I, and (e) identifying possible systematic misuse or off-label use of the device, with a view to verifying that the intended purpose is correct. 6.2.   The PMCF plan shall include at least: (a) the general methods and procedures of the PMCF to be applied, such as gathering of clinical experience gained, feedback from users, screening of scientific literature and of other sources of clinical data; (b) the specific methods and procedures of PMCF to be applied, such as evaluation of suitable registers or PMCF studies; (c) a rationale for the appropriateness of the methods and procedures referred to in points (a) and (b); (d) a reference to the relevant parts of the clinical evaluation report referred to in Section 4 and to the risk management referred to in Section 3 of Annex I; (e) the specific objectives to be addressed by the PMCF; (f) an evaluation of the clinical data relating to equivalent or similar devices; (g) reference to any relevant CS, harmonised standards when used by the manufacturer, and relevant guidance on PMCF; and (h) a detailed and adequately justified time schedule for PMCF activities (e.g. analysis of PMCF data and reporting) to be undertaken by the manufacturer. 7.   The manufacturer shall analyse the findings of the PMCF and document the results in a PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation. 8.   The conclusions of the PMCF evaluation report shall be taken into account for the clinical evaluation referred to in Article 61 and Part A of this Annex and in the risk management referred to in Section 3 of Annex I. If, through the PMCF, the need for preventive and/or corrective measures has been identified, the manufacturer shall implement them. ANNEX XV CLINICAL INVESTIGATIONS CHAPTER I GENERAL REQUIREMENTS 1.   Ethical principles Each step in the clinical investigation, from the initial consideration of the need for and justification of the study to the publication of the results, shall be carried out in accordance with recognised ethical principles. 2.   Methods 2.1.   Clinical investigations shall be performed on the basis of an appropriate plan of investigation reflecting the latest scientific and technical knowledge and defined in such a way as to confirm or refute the manufacturer's claims regarding the safety, performance and aspects relating to benefit-risk of devices as referred to in Article 62(1); the clinical investigations shall include an adequate number of observations to guarantee the scientific validity of the conclusions. The rationale for the design and chosen statistical methodology shall be presented as further described in Section 3.6 of Chapter II of this Annex. 2.2.   The procedures used to perform the clinical investigation shall be appropriate to the device under investigation. 2.3.   The research methodologies used to perform the clinical investigation shall be appropriate to the device under investigation. 2.4.   Clinical investigations shall be performed in accordance with the clinical investigation plan by a sufficient number of intended users and in a clinical environment that is representative of the intended normal conditions of use of the device in the target patient population. Clinical investigations shall be in line with the clinical evaluation plan as referred to in Part A of Annex XIV. 2.5.   All the appropriate technical and functional features of the device, in particular those involving safety and performance, and their expected clinical outcomes shall be appropriately addressed in the investigational design. A list of the technical and functional features of the device and the related expected clinical outcomes shall be provided. 2.6.   The endpoints of the clinical investigation shall address the intended purpose, clinical benefits, performance and safety of the device. The endpoints shall be determined and assessed using scientifically valid methodologies. The primary endpoint shall be appropriate to the device and clinically relevant. 2.7.   Investigators shall have access to the technical and clinical data regarding the device. Personnel involved in the conduct of an investigation shall be adequately instructed and trained in the proper use of the investigational device, and as regards the clinical investigation plan and good clinical practice. This training shall be verified and where necessary arranged by the sponsor and documented appropriately. 2.8.   The clinical investigation report, signed by the investigator, shall contain a critical evaluation of all the data collected during the clinical investigation, and shall include any negative findings. CHAPTER II DOCUMENTATION REGARDING THE APPLICATION FOR CLINICAL INVESTIGATION For investigational devices covered by Article 62, the sponsor shall draw up and submit the application in accordance with Article 70 accompanied by the following documents: 1.   Application form The application form shall be duly filled in, containing information regarding: 1.1. name, address and contact details of the sponsor and, if applicable, name, address and contact details of its contact person or legal representative in accordance with Article 62(2) established in the Union; 1.2. if different from those in Section 1.1, name, address and contact details of the manufacturer of the device intended for clinical investigation and, if applicable, of its authorised representative; 1.3. title of the clinical investigation; 1.4. status of the clinical investigation application (i.e. first submission, resubmission, significant amendment); 1.5. details and/or reference to the clinical evaluation plan; 1.6. If the application is a resubmission with regard to a device for which an application has been already submitted, the date or dates and reference number or numbers of the earlier application or in the case of significant amendment, reference to the original application. The sponsor shall identify all of the changes from the previous application together with a rationale for those changes, in particular, whether any changes have been made to address conclusions of previous competent authority or ethics committee reviews; 1.7. if the application is submitted in parallel with an application for a clinical trial in accordance with Regulation (EU) No 536/2014, reference to the official registration number of the clinical trial; 1.8. identification of the Member States and third countries in which the clinical investigation is to be conducted as part of a multicentre or multinational study at the time of application; 1.9. a brief description of the investigational device, its classification and other information necessary for the identification of the device and device type; 1.10. information as to whether the device incorporates a medicinal substance, including a human blood or plasma derivative or whether it is manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives; 1.11. summary of the clinical investigation plan including the objective or objectives of the clinical investigation, the number and gender of subjects, criteria for subject selection, whether there are subjects under 18 years of age, design of the investigation such as controlled and/or randomised studies, planned dates of commencement and of completion of the clinical investigation; 1.12. if applicable, information regarding a comparator device, its classification and other information necessary for the identification of the comparator device; 1.13. evidence from the sponsor that the clinical investigator and the investigational site are capable of conducting the clinical investigation in accordance with the clinical investigation plan; 1.14. details of the anticipated start date and duration of the investigation; 1.15. details to identify the notified body, if already involved at the stage of application for a clinical investigation; 1.16. confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application; and 1.17. the statement referred to in Section 4.1. 2.   Investigator's Brochure The investigator's brochure (IB) shall contain the clinical and non-clinical information on the investigational device that is relevant for the investigation and available at the time of application. Any updates to the IB or other relevant information that is newly available shall be brought to the attention of the investigators in a timely manner. The IB shall be clearly identified and contain in particular the following information: 2.1. Identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule pursuant to Annex VIII, design and manufacturing of the device and reference to previous and similar generations of the device. 2.2. Manufacturer's instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements, as well as, to the extent that such information is available, information to be placed on the label, and instructions for use to be provided with the device when placed on the market. In addition, information relating to any relevant training required. 2.3. Pre-clinical evaluation based on relevant pre-clinical testing and experimental data, in particular regarding in-design calculations, in vitro tests, ex vivo tests, animal tests, mechanical or electrical tests, reliability tests, sterilisation validation, software verification and validation, performance tests, evaluation of biocompatibility and biological safety, as applicable. 2.4. Existing clinical data, in particular: — from relevant scientific literature available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of the device and/or of equivalent or similar devices; — other relevant clinical data available relating to the safety, performance, clinical benefits to patients, design characteristics and intended purpose of equivalent or similar devices of the same manufacturer, including length of time on the market and a review of performance, clinical benefit and safety-related issues and any corrective actions taken. 2.5. Summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks, any undesirable effects, contraindications and warnings. 2.6. In the case of devices that incorporate a medicinal substance, including a human blood or plasma derivative or devices manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives, detailed information on the medicinal substance or on the tissues, cells or their derivatives, and on the compliance with the relevant general safety and performance requirements and the specific risk management in relation to the substance or tissues, cells or their derivatives, as well as evidence for the added value of incorporation of such constituents in relation to the clinical benefit and/or safety of the device. 2.7. A list detailing the fulfilment of the relevant general safety and performance requirements set out in Annex I, including the standards and CS applied, in full or in part, as well as a description of the solutions for fulfilling the relevant general safety and performance requirements, in so far as those standards and CS have not or have only been partly fulfilled or are lacking. 2.8. A detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation and in particular information on any deviation from normal clinical practice. 3.   Clinical Investigation Plan The clinical investigation plan (CIP) shall set out the rationale, objectives, design methodology, monitoring, conduct, record-keeping and the method of analysis for the clinical investigation. It shall contain in particular the information as laid down in this Annex. If part of this information is submitted in a separate document, it shall be referenced in the CIP. 3.1.   General 3.1.1.   Single identification number of the clinical investigation, as referred to in Article 70(1). 3.1.2.   Identification of the sponsor — name, address and contact details of the sponsor and, where applicable, the name, address and contact details of the sponsor's contact person or legal representative in accordance with Article 62(2) established in the Union. 3.1.3.   Information on the principal investigator at each investigational site, the coordinating investigator for the investigation, the address details for each investigational site and the emergency contact details for the principal investigator at each site. The roles, responsibilities and qualifications of the various kinds of investigators shall be specified in the CIP. 3.1.4.   A brief description of how the clinical investigation is financed and a brief description of the agreement between the sponsor and the site. 3.1.5.   Overall synopsis of the clinical investigation, in an official Union language determined by the Member State concerned. 3.2.   Identification and description of the device, including its intended purpose, its manufacturer, its traceability, the target population, materials coming into contact with the human body, the medical or surgical procedures involved in its use and the necessary training and experience for its use, background literature review, the current state of the art in clinical care in the relevant field of application and the proposed benefits of the new device. 3.3.   Risks and clinical benefits of the device to be examined, with justification of the corresponding expected clinical outcomes in the clinical investigation plan. 3.4.   Description of the relevance of the clinical investigation in the context of the state of the art of clinical practice. 3.5.   Objectives and hypotheses of the clinical investigation. 3.6.   Design of the clinical investigation with evidence of its scientific robustness and validity. 3.6.1.   General information such as type of investigation with rationale for choosing it, for its endpoints and for its variables as set out in the clinical evaluation plan. 3.6.2.   Information on the investigational device, on any comparator and on any other device or medication to be used in the clinical investigation. 3.6.3.   Information on subjects, selection criteria, size of investigation population, representativeness of investigation population in relation to target population and, if applicable, information on vulnerable subjects involved such as children, pregnant women, immuno-compromised or, elderly subjects. 3.6.4.   Details of measures to be taken to minimise bias, such as randomisation, and management of potential confounding factors. 3.6.5.   Description of the clinical procedures and diagnostic methods relating to the clinical investigation and in particular highlighting any deviation from normal clinical practice. 3.6.6.   Monitoring plan. 3.7.   Statistical considerations, with justification, including a power calculation for the sample size, if applicable. 3.8.   Data management. 3.9.   Information about any amendments to the CIP. 3.10.   Policy regarding follow-up and management of any deviations from the CIP at the investigational site and clear prohibition of use of waivers from the CIP. 3.11.   Accountability regarding the device, in particular control of access to the device, follow-up in relation to the device used in the clinical investigation and the return of unused, expired or malfunctioning devices. 3.12.   Statement of compliance with the recognised ethical principles for medical research involving humans, and the principles of good clinical practice in the field of clinical investigations of devices, as well as with the applicable regulatory requirements. 3.13.   Description of the Informed consent process. 3.14.   Safety reporting, including definitions of adverse events and serious adverse events, device deficiencies, procedures and timelines for reporting. 3.15.   Criteria and procedures for follow-up of subjects following the end, temporary halt or early termination of an investigation, for follow-up of subjects who have withdrawn their consent and procedures for subjects lost to follow-up. Such procedures shall for implantable devices, cover as a minimum traceability. 3.16.   A description of the arrangements for taking care of the subjects after their participation in the clinical investigation has ended, where such additional care is necessary because of the subjects' participation in the clinical investigation and where it differs from that normally expected for the medical condition in question. 3.17.   Policy as regards the establishment of the clinical investigation report and publication of results in accordance with the legal requirements and the ethical principles referred to in Section 1 of Chapter I. 3.18.   List of the technical and functional features of the device, with specific mention of those covered by the investigation. 3.19.   Bibliography. 4.   Other information 4.1.   A signed statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject. 4.2.   Where applicable according to national law, copy of the opinion or opinions of the ethics committee or committees concerned. Where according to national law the opinion or opinions of the ethics committee or committees is not required at the time of the submission of the application, a copy of the opinion or opinions shall be submitted as soon as available. 4.3.   Proof of insurance cover or indemnification of subjects in case of injury, pursuant to Article 69 and the corresponding national law. 4.4.   Documents to be used to obtain informed consent, including the patient information sheet and the informed consent document. 4.5.   Description of the arrangements to comply with the applicable rules on the protection and confidentiality of personal data, in particular: — organisational and technical arrangements that will be implemented to avoid unauthorised access, disclosure, dissemination, alteration or loss of information and personal data processed; — a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects; and — a description of measures that will be implemented in case of a data security breach in order to mitigate the possible adverse effects. 4.6.   Full details of the available technical documentation, for example detailed risk analysis/management documentation or specific test reports, shall, upon request, be submitted to the competent authority reviewing an application. CHAPTER III OTHER OBLIGATIONS OF THE SPONSOR 1.   The sponsor shall undertake to keep available for the competent national authorities any documentation necessary to provide evidence for the documentation referred to in Chapter II of this Annex. If the sponsor is not the natural or legal person responsible for the manufacture of the investigational device, that obligation may be fulfilled by that person on behalf of the sponsor. 2.   The Sponsor shall have an agreement in place to ensure that any serious adverse events or any other event as referred to in Article 80(2) are reported by the investigator or investigators to the sponsor in a timely manner. 3.   The documentation mentioned in this Annex shall be kept for a period of at least 10 years after the clinical investigation with the device in question has ended, or, in the event that the device is subsequently placed on the market, at least 10 years after the last device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years. Each Member State shall require that this documentation is kept at the disposal of the competent authorities for the period referred to in the first subparagraph in case the sponsor, or its contact person or legal representative as referred to in Article 62(2) established within its territory, goes bankrupt or ceases its activity prior to the end of this period. 4.   The Sponsor shall appoint a monitor that is independent from the investigational site to ensure that the investigation is conducted in accordance with the CIP, the principles of good clinical practice and this Regulation. 5.   The Sponsor shall complete the follow-up of investigation subjects. 6.   The Sponsor shall provide evidence that the investigation is being conducted in line with good clinical practice, for instance through internal or external inspection. 7.   The Sponsor shall prepare a clinical investigation report which includes at least the following: — Cover/introductory page or pages indicating the title of the investigation, the investigational device, the single identification number, the CIP number and the details with signatures of the coordinating investigators and the principal investigators from each investigational site. — Details of the author and date of the report. — A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations. — Investigational device description, in particular clearly defined intended purpose. — A summary of the clinical investigation plan covering objectives, design, ethical aspects, monitoring and quality measures, selection criteria, target patient populations, sample size, treatment schedules, follow-up duration, concomitant treatments, statistical plan, including hypothesis, sample size calculation and analysis methods, as well as a justification. — Results of the clinical investigation covering, with rationale and justification, subject demographics, analysis of results related to chosen endpoints, details of subgroup analysis, as well as compliance with the CIP, and covering follow-up of missing data and of patients withdrawing from the clinical investigation, or lost to follow-up. — Summary of serious adverse events, adverse device effects, device deficiencies and any relevant corrective actions. — Discussion and overall conclusions covering safety and performance results, assessment of risks and clinical benefits, discussion of clinical relevance in accordance with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device, limitations of the investigation. ANNEX XVI LIST OF GROUPS OF PRODUCTS WITHOUT AN INTENDED MEDICAL PURPOSE REFERRED TO IN ARTICLE 1(2) 1. Contact lenses or other items intended to be introduced into or onto the eye. 2. Products intended to be totally or partially introduced into the human body through surgically invasive means for the purpose of modifying the anatomy or fixation of body parts with the exception of tattooing products and piercings. 3. Substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing. 4. Equipment intended to be used to reduce, remove or destroy adipose tissue, such as equipment for liposuction, lipolysis or lipoplasty. 5. High intensity electromagnetic radiation (e.g. infra-red, visible light and ultra-violet) emitting equipment intended for use on the human body, including coherent and non-coherent sources, monochromatic and broad spectrum, such as lasers and intense pulsed light equipment, for skin resurfacing, tattoo or hair removal or other skin treatment. 6. Equipment intended for brain stimulation that apply electrical currents or magnetic or electromagnetic fields that penetrate the cranium to modify neuronal activity in the brain.

Guidance-on-Article-15-MDR-IVDR-Person-responsible-for-Regulatory-Compliance.pdf.txt

This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 1 MDCG 2019- 7 Guidance on Article 15 of the Medical Device Regulation (MDR) and in vitro Diagnostic Device Regulation (IVDR) regarding a ‘person responsible for regulatory compliance’ (PRRC) Manufacturers1 (paragraph 1) “Manufacturers shall have available within their organisation at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices. The requisite expertise shall be demonstrated by either of the following qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom -made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing. ” Clarification on qualifications It shall be noted that : - For the purpose of fulfilling the requirement laid down in point “ a” of Article 15 (1), any qualification acquired outside the EU, including any university diplomas or certificates, should have been recognised by an EU Member State as equivalent to the EU corresponding qualification. 1 Enterprises which employ at least 50 persons and whose annual turnover and/or annual balance sheet total exceeds EUR 10 million (Commission Recommendation 2003/361/Ε C of 6 May 2003) . 2 - Professional experience in regulatory a ffairs or in quality management systems relating to medical devices should be related to the EU requirements in the field . Meaning of “within their organisation” The person responsible for regulatory compliance (PRRC) appointed would need to be an employee of the organisation. Organisations with more than one legal manufacturer Organisations with more than one legal manufacturer under the parent company would need to ensure that each legal manufacturer has its own PRRC.2 Can the PRRC be located out side the EU? As to the location of the PRRC, it is important that a close linkage, of a permanent and continuous nature, is established between the PRRC and the manufacturing activities. For this reason, for manufacturers located outside the EU, it must be assumed that the PRRC should also be located outside the EU. On the other hand, for manufacturers located in the EU, it must be assumed that the PRRC should also be located in the EU. Micro and small manufacturers3 (paragraph 2) “Micro and small enterpri ses within the meaning of Commission Recommendation 2003/361/EC shall not be required to have the person responsible for regulatory compliance within their organisation but shall have such person permanently and continuously at their disposal .” Meaning of “permanently and continuously at their disposal” The micro or small enterprise may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the manufacturer can de monstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation, with which the manufacturer has established a contract lay ing down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? For micro or small enterpr ises located in the EU, it must be assumed that any person to be permanent ly and continuously at their disposal should be also located in the EU . 2 In the context of Article 15, the obligation for having available within the organisation at least one PRRC refers to the individual legal manufacturer. 3 Enterprises which employ fewer than 50 persons and whose annual turnover and/or annual balance sheet total does not exceed EUR 10 million (Commission Recommendation 2003/361/ΕC of 6 May 2003) . 3 Authorised representatives (paragraph 6) “Authorised representatives shall have permanently and continuously at their disposal at least one person responsible for regulatory compliance who possesses the requisite expertise regarding the regulatory requirements for medical devices in the Union. The requisite expertise shall be demonstrated by either of the followi ng qualifications: (a) a diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the Member State concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices; (b) four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. ” Meaning of “permanently and continuously at their disposal” The authorised representative may subcontract the responsibilities of a person responsible for regulatory compliance to a third party, so long as the qualification criteria is met and the authorised representative can demonstrate and document how they can meet their legal obligations. For example, the PRRC may be part of an external organisation with which the authorised representative has established e a contract laying down provisions so as to ensure the permanent and continuous availability of that party. The contract should mention the relevant person’s qualifications allowing compliance with points a and b of Article 15 (1). Can the PRRC be located outside the EU? Taking into account that the Authorised Representative is located in the EU, it must be assumed that any person to be permanently and continuously at its disposal should be also located in the EU . Roles and responsibilities of the person r esponsible for regulatory compliance within a manufacturer (paragraph 3) For the purpose of this position paper, the roles and responsibilities of a PRRC have been cross -referred to the roles and responsibilities of a manufacturer, as stated in Article 10 of the MDR and IVDR. This paper does not interpret the roles and responsibilities of a PRRC. We recommend that any guidance on post -market surveillance, vigilance, clinical investigations and performance studies, created at a European level, should cross -refer to Article 15, paragraph 3 to provide guidance on what a PRRC of a manufacturer would be expected to do in these areas. 4 “The person responsible for regulatory compliance shall at least be responsible for ensuring that: (a) the conformity of the dev ices is appropriately checked, in accordance with the quality management system under which the devices are manufactured, before a device is released; ” Manufacturers “of devices, other than investigational [performance study] devices, shall establish, document, implement, maintain, keep up to date and continually improve a quality management system that shall ensure compliance with this Regulation in the most effective manner and in a manner that is proportionate to the risk class and the type of device” (Article 10(9) of the MDR and Article 10(8) of the IVDR). “(b) the technical documentation and the EU declaration of conformity are drawn up and kept up- to-date; ” Manufacturers “[of devices other than custom -made devices] shall draw up and keep up to date technical documentation for those devices” (Article 10(4) of the MDR and IVDR) and “shall draw up an EU declaration of conformity” (Article 10(6) of the MDR and Article 10(5) of the IVDR). “(c) the post -market surveillance obligations are complied with in accordance with Article 10(10) [Article 10(9) of the IVDR]; ” Manufacturers “of devices shall implement and keep up to date the post -market surveillance system” (Article 10(10) of the MDR and Article 10(9) of the IVDR). “(d) the reporting obligations ref erred to in Articles 87 to 91 [Article 82 and 86 of the IVDR] are fulfilled; ” Manufacturers “shall have a system for recording and reporting of incidents and field safety corrective actions as described in Articles 87 and 88” (Article 10(13) of the MDR and Article 10(12) of the IVDR). “(e) in the case of investigational devices, the statement referred to in Section 4.1 of Chapter II of Annex XV [Section 4.1 of Annex XIV of the IVDR] is issued. ” Manufacturers shall ensure that “a signed statement by the natural or legal person responsible for the manufacture of the investigational device [for performance study] that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigati on [performance study] and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.” 5 Roles and responsibilities of the person responsible for regulatory compliance within an authorised represent ative (paragraph 3) The PRRC of an AR should be responsible for ensuring that the tasks of an AR as specified in the given mandate, in accordance with Article 11(3), are fulfilled. . Can one individual be the PRRC for a manufacturer and its authorised representative? The person responsible for regulatory compliance for an authorised representative and for an 'outside EU' manufacturer cannot be the same person. There is a clear desire within the Regulations for the authorised representative to be adding an additional level of scrutiny and ensure that the supervision and control of the manufacture of devices, and the relevant post -market surveillance and vigilance activities are adequately effected. If the two roles were conducted by the same person, the additional level of scrutiny would be undermined. For the same reason, the PRRC of a micro or small enterprise and the PRRC of the authorised representative of that same enterprise shall not belong to the same external organisation.

md_mfr_stepbystep.pdf.txt

Implementation Model for Medical Devices Regulation Step by Step Guide MEDICAL DEVICES CHANGE OF LEGISLATION 1STEP INTENTION / ACTION Pre-assessmentBrief management to ensure a clear understanding of the importance and business implications of the MDR Consider organisational challenges: management awareness, staffing capability and availability, budget implications GAP analysis and actions resulting from thisAssess impact on products, internal resources, organisation and budget Check new classification rules (MDR Classes I, IIa, IIb and III) and confirm conformity assessment routes for existing and future products Check the new definition of MD, particularly with respect to its expanded scope. This also applies to products covered in Annex XVI Review the changes needed to existing technical documentation (Technical Files) Review and upgrade quality management system (QMS) (point 3 below) Check the adequacy of available clinical evidence and risk management and identify any gaps (Article 61) Review product labelling (Annex I Chapter III) Ensure post-market surveillance (PMS) arrangements are adequate (Chapter VII Section 1) Prepare a post-market clinical follow-up plan (PMCF, Annex XIV Part B) Get ready for the new vigilance requirements (Chapter VII Section 2) Ensure the respect of traceability obligations (Chapter III) Quality Management System (QMS)Review adequacy of QMS to meet standards and processes for medical devices under the new Regulation Build new regulatory requirements into the QMS Identify/hire the person responsible for regulatory compliance within your organisation (Article 15) and be sure it is adequately qualified and trained1 2 3What you need to know! Internal market, Industry, Entrepreneurship and SMEs2Legal entitiesClarify how the company is affected: legal entities, obligation of economic operators, organisational structures and resources Consider organisational challenges: management awareness, staffing capability and availability, budget implications Ensure product liability insurance is adequate PortfolioDo a cost/benefit analysis for your product portfolio; bear in mind costs for the possible upgrade of risk class of MDs and for the new procedures for conformity assessment as well as the costs for post-market surveillance and gaps in the technical documentation, and plan your transition to the MDR accordingly Review supply chain provisions, and clarify roles and responsibilities of business partners (authorised representatives, importers, distributors) Master implementation planBuild a roadmap for implementation, including definition of sub-projects, resource requirements and a steering group, and ensure overall responsibility for MDR implementation has been established Give special consideration to certificate expiry dates, bearing in mind the transitional period, transitional provisions and availability of your Notified Bodies Notified BodiesContact the selected Notified Bodies and determine their capacity and availability to service the implementation plan Regulatory trainingEmpower and train staff through MDR implementation and transition workshops Execute master implementation planImplement the various sub-projects (clinical evaluation, technical documentation, relation with other economic operators, Unique Device Identification, labelling, registration, post-market surveillance, vigilance, and reporting IT systems) Ensure a cross-functional project management team is in place to cover all aspects of implementation Ensure overall and individual responsibilities for MDR implementation have been established Review efficiency and effectivenessImplement regular meetings on project status and progress, discrepancy and gap analyses, risks, next steps and requirements Hold regular progress reviews against the MDR implementation plan and include these in the management review process Notified Body submissionDiscuss submission dates to avoid delays in the approval process Ongoing monitoringActively monitor the still-developing European regulatory environment and guidelines expected in the coming months (check DG GROW web pages on medical devices and subscribe to the newsletter) Establish a procedure for dealing with unannounced inspections from Notified Bodies Regularly review the MDR implementation plan, identifying and addressing key areas of risk4 5 6 7 8 9 10 11 12 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ET-03-18-103-EN-N ISBN: 978-92-79-89702-3 DOI: 10.2873/66341

MDCG 2019-8 v2 Implant guidance Card.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-8 v2 MDCG 2019-8 v2 Guidance document Implant Card relating to the application of Article 18 Regulation (EU) 2017/745 of the European Pa rliament and of the Council of 5 April 2017 on medical devices March 2020 This document has been endorsed b y the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed o f representatives of all Member States and it is chaired by a representative of the European Co mmission. The document is not a European Commission document and it canno t be regarded as reflecting the official position of the European Commission. Any views express ed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices: Guidance document Implant Card relating to the app lication of Article 18 Regulati on (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medic al devices List of Content 1. Scope ............................................................................................................... 4 2. Purposes of the Implant Card ..................................................................... 4 3. Legal consideration on Implant Card design ........................................... 4 4. Information to be provided by the manufacturer on the Implant Card and information to be added by the health institution ........................... 5 5. Use of symbols .............................................................................................. 6 6. Language requirements on specific fields ................................................ 7 7. Benefits of an informativ e instruction leaflet ........................................... 7 8. Implant Card for implantable systems ...................................................... 7 Annex I examples of principle designs of Implant Cards and leaflets ....... 8 1. Scope This document provides guidance for Memb er States, concerned industry and other stakeholders on a blueprint of an implant card (IC) required by the MDR (Regulation (EU) 2017/745). It describes the intended use, cont ent and information to be provided by the manufacturer together on the IC and a definition of fields to be completed by the implanting healthcare institutions or healthcare provider s according to national law in Member States. Whereas the intended purpose and most of the da ta elements of the IC are already defined in Article 18 of the MDR, this document contains the description of other data elements which must be completed by the healthcare institution or healthcare provider and which must be considered by the individual Member State wh en implementing Article 18 MDR as required 1. 2. Purposes of the Implant Card The aim of introducing an IC has been to achieve three main objectives: 1. Enable the patient to identify the impl anted devices and to get access to other information related to the implanted device (e.g. via EUDAMED, and other websites). 2. Enable patients to identify themselves as persons requiring special care in relevant situations e.g. security checks. 3. Enabling e.g. emergency clinical staff or fi rst responder to be informed about special care/needs for relevant patients in case of emergency situations. 3. Legal consideration on Implant Card design Article 18 MDR describes the requirements rega rding the IC which shall be provided by the manufacturer together with the device. Wherea s Article 18 para 1a) describes the information which shall be provided by the manufacturer on the IC, Article 18 pa r a 2 l a y s d o w n t h e obligation of Member States to require health in stitutions to provide the IC to the concerned patient. In accordance with Article 18, 1a) the manufact urer should provide th e following information on the IC (preferably on the card itself or, alternatively, as stickers to be placed by the clinician):  Device name;  Serial number, lot number;  Unique device identification (UDI);  Name, address and the website of manufacturer;  Device type. 2 Article 18, 2 lays down that Member States shall require health institutions (or healthcare providers) inter alia to make available the IC to the relevant patient. The IC should bear their 1 This guidance doesn’t include the patient information described in Ar ticle 18 para 1 (b-d) which might be provided by the manufacturer by any means that allow rapid access to that information and that shall be stated in the language(s) determined by the concerned Member State. 2 In Article 18 1a) of the MDR, the term “device model” is used. However, this term which is not defined in the MDR, is part of the UDI-DI related info r m a t i o n t o b e p r o v i d e d t o E U D A M E D . T o a v o i d duplication and in the context of the intended purpos e of the IC (to be used in situations requiring special care or in emergency situations), it is cons idered that reference to device model in the MDR for the purpose of the IC shall be read as reference to device type, like “pacemaker”, “hip implant”, etc. When the European Medical device nomenclature is made available, a “standardised” set of terms of this nomenclature should be recommended for use in relation to the field “device type”. identity . For this purpose, the IC provided togeth er with the device should contain blank fields which shall be filled out by the health institution or healthcare provider, respectively. Since the establishment of (and the logistics behind) many different national IC designs is very expensive and of no additional benefit, Member States should ensure that, in the context of national implementation of Article 18 of the MD R, only the following information is required to be provided by the health institution or healthcare provider on the IC (together with the information provided by the manufacturer). Accordingly, a European or international blueprint for an IC which supports the purposes described in Article 18, 2 should contain the following blank fields: 1. Name of the patient or patient ID; 2. Name and address of the health institution or healthcare provider who performed the implantation; 3. Date of implantation. In order to be fit for the purposes described in Article 18, the outer dimensions of the IC should be the same as those of credit cards, ATM cards or ID cards (85.60 mm × 53.98 mm /3 3 ⁄8 × 2 1⁄8 inches) and with a radius of 2.88–3.48 mm 3. 4. Information to be provided by the manufacturer on the Implant Card and information to be adde d by the health institution The manufacturer shall provide the following necessary information: 1. Device name; 2. Device type; 3. Serial number or, where app licable, lot or batch number; 4. Unique device identification (UDI); the UDI as AIDC4 format and the UDI-DI as HRI5 5. Name and address of the manufacturer of the medical device; 6. Website of the manufacturer of the medical device. The text provided on the IC and on the instru ction for completing the IC by the healthcare institution or healthcare provider must be legible and at least 2 millimetres high. ‘Text’ includes any: number, letter, symbol, or letter or number in a symbol. In addition, the manufacturer shou ld design the IC in a way that the following blank fields to be filled out by the implanting healthcare institution or healthcare provider are available: 1. Name of the patient or patient ID; 2. Name and address of the healthcare inst itution which performed the implantation; 3. Date of implantation. 3 Dimensions to conform to the standard ISO/IEC 7810 ID-1. 4 AIDC - Automatic identification and data capture format (e.g. linear or 2D-Barcodes) 5 HRI - Human readable interpretation 5. Use of symbols To avoid national versions of the IC , the use of symbols is advisable. The following list contains symbols which have either been validated by users and have been submitted and accepted for inclusion in an upco ming international standard or already exist in the ISO database (Online Browsing Platform). The explanation of symbols on the IC should be provided in a leaflet (see section 7) or on the back of the IC, if space allows. Article 18(1) lays down that the information provided in the IC shall be stated in the language(s) determined by the concerned Member State. List of symbols recommended for use on the IC6: Patient Name or patient ID Date of implantation Name and Address of the implanting healthcare institution/provide r Name and Address of the manufacturer Information website for patients Device Name7 Serial Number Lot Number/Batch Code 6 The symbols for patient name or patient ID, name and ad dress of the implanting healthcare institution/provider, date of implantation, name and address of the manufacturer, serial number, lot number/batch code are already available and published in existing ISO standards. The symbols for device name, patient information website and UDI have been validated by users according to the ISO 15223-2 process. Note that the symbols listed here to indicate the following terms: ‘Device Name’, ‘Patient Name or Pati ent ID’, ‘Date of Implantation’, ‘Name and address of the implanting healthcare institution/provider’ on the implant card, are used in the ISO context to indicate ‘Medical Device’, ‘Patient Identification’, ‘Date’, ‘Health Care Center or Doctor’. 7 Please note that in the ISO context, the ‘MD’ symbol is used to identify that the product in question is a medical device. On the implant card, this symbol is used to indicate the device name. UDI as AIDC format UDI-DI information in a HRI format should be introduced by the wording “UDI-DI”. 6. Language requirements on specific fields Despite the nearly complete list of symbols for fields on the IC, there is currently no symbol available for the required field “Device Type”. The lack of a symbol and the purpose of this field makes it necessary that the information on the device type must be provided in the language accepted/required by the concerned Member State. There are several possibilities available to provid e this information in the necessary languages, e.g. the information is already printed on the IC in the different languages or stickers are provided with the IC and the healthcare professional selects the right one etc. 7. Benefits of an informati ve instruction leaflet8 As mentioned above (section 5), there is a need to provide, together with the IC, instructions on how to complete the IC and to explain the us ed symbols. This information shall be stated in the language(s) determined by the concerned Member State. For this reason, the use of a leaflet, containing the relevant information, to be provided together with the IC and the implantable device, is the recommended solution. As part of the risk management, the manufacturer has to investigate, by means of an ergonomic analysis or ergonomic usability test procedure, if the provided instructions are sufficient to enable the health professional to complete the IC correctly. The instructions must reflect the solution chosen by the manufacturer (e .g. pre-printed IC, blank IC with sticker(s) to be added, mixture of both). Special considerat ions might be needed when providing a system IC or an IC for a separate implantable compon ent, when there is not yet a common practice (standard) established. 8. Implant Card for implantable systems If an implantable device contains implantable components which might be replaced by other (or the same) components, for example in case of a later revision, the manufacturers should consider the use of a System IC. In Annex I to this guide an example is provided. W a y s c o u l d b e e x p l o r e d b y r e l e v a n t s t a k e h o l d e r s t o d e v e l o p c o m m o n r u l e s o n h o w t h e necessary information to be placed on the Sy stem IC is delivered with the replaceable component and how health professionals could en sure t hat the System I C is appropriately updated, when necessary. 8 This leaflet should not be confused with any possible vector of information referred to in points “b”, “c” and “d” of Article 18(1) of the MDR. UDI Annex I examples of principle designs of Implant Cards and leaf lets GENERAL NOTE: All examples contained in this Annex are to be intended as illustrative examples only.9 The basic shape of the IC shall be designed in compliance with ISO/IEC 7810 ID-1 (credit card form). The following pictures provide exam ples for individual device ICs. Example 1: Front – Not to scale (handwritten text on pre-printed content) Back – Not to scale (blank – serial printed content in production) 9 Please note that this includes translations (into languages other than English) shown in Examples throughout Annex 1, which are machine translated and not intended to be read as official translations into EU languages. International Implant Card https://www.genericmed.com/patientimplantinfo John Smith 27/05/2021 ABC Healthcare Center 123 Medical Parkway, Cork, Ireland Dr. H.C. Professional PM-5503 Pacer Advanced UDI-DI: (01)01865494261654 SN79856214 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Example 2: Back – Not to scale (blank – batch/lot printed content in production) PM-5503 Pacer Advanced UDI-DI: (01)03584124658462 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com AO.582122 Example 3 (suggested design of a foldable System IC): To be able to represent medical device syst ems in one IC, the IC shall be available in collapsible form. ABC Healthcare CenterInternational Implant Card www.genericmed.com/patientimplantinfo John Smith 27/05/2021 123 Medical Parkway Dr. H.C. Professional Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com Cork, Ireland PM-5503 Pacer Advanced Pacemaker UDI-DI: (01)85412654285216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 USA www.genericmed.com PL-55-4 Pacer Lead Pro Pacemaker Lead UDI-DI: (01)89654213882154 SN86223214 Examples of IC Leaflet Front 1 (no stickers – preferred option) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. PM-5503 Pacer Advanced (01)8541265428 5216 SN65695452 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 www.genericmed.com/patientimplantinfo Front 2 (sticker only for device type information) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare instit ution. To be filled by the healthcare institution/provider. 5. Add sticker with device type in required language. Stickers (to be detached and placed on the righ t place at the IC according to the numbers) PM-5503 Pacer Advanced (01)85412654285216 Genericmed 500 Genericmed Place, Minneapolis, MN 55123 SN65695452 www.genericmed.com/patientimplantinfo 5 Front 3 (stickers) Instruction for completion (to be provided in the language(s) determined by the concerned member State(s)) 1. Name of the patient or patient ID. To be f illed by the healthcare institution/provider. 2. Date of implantation. To be filled by the healthcare institution/provider. 3. Name and address of the healthcare institutio n/provider. To be filled by the healthcare institution/provider. 4. Manufacturer’s information website. 5. Device type in required language. 6. Device name. 7. UDI-DI Code (HRI). 8. UDI code (AIDC format). 9. Serial number. 10. Name and address of the manufacturer of the implanted medical device. NOTE: Fields 4-10 might be filled with stickers (though this is not the preferred solution) Stickers (to be detached and plac ed on the right place at the IC according to the numbers) 5, 6 9 8 7 2 081019001 002 4 10 4 Back Explanation/ transl ation of symbols Patient Name or patient ID, Име на пациента , Jméno pacienta, Patientens navn, Patientenname, Όνομα ασθενούς , Nombre del paciente, Patsiendi nimi, Potilaan nimi, Nom du patient, Ime i prezime bolesnika, Imi ę i nazwisko pacjenta, A beteg neve, Nome del paziente, Paciento vardas ir pavard ė, Pacienta v ārds, uzvārds, Naam patiënt Pasientens navn, A beteg neve, Nome do doente, Nume pacient, Meno pacienta, Ime bolnika, Patientens namn Name and Address of the implanting healthcare institution/provide r , établissement sanitaire, centro de salud, struttura sanitaria, Gesundheitseinrichtung, gezondheidszorginstelling, placówka słu żby zdrowia, здравно заведение, veselības aprūpes iestāde, εγκατάσταση για την υγεία Date of Implantation , Дата на имплантиране, Datum implantace, Implanteringsdato, Implantationsdatum, Ημερομηνία εμφύτευσης, Fecha de implantación, Implanteerimiskuupäev, Implantointipäivämäärä, Date d’implantation, Datum implantacije, Beültetés dátuma, Data dell'impianto, Implantavimo data, Implant ēšanas datums, Implantatiedatum, Data wszczepienia , Data do implante, Data implant ării, Dátum implantácie, Datum vsaditve Device Name, Nazwa urz ądzenia medy cznego, Název zdravotnických prost ředků, Medicinsk enhed, Name des Medizinprodukts, Nombre del dispositivo médico, Nom du dispositif médical, Orvosi eszköz neve, Namn på medicinsk enhet, Ime medicinske naprave Nome do dispositivo médico κατασκευαστής, Producent, Fabrikant, Produttore, Fabricante, Fa bricant, manufacturer, Hersteller Information website for patients , Webová stránka s informacemi pro pacienta, Informationswebsite for patienten, Webseite mit Informationen für Patienten, Sitio web con información para el paciente, Site d'in formations pour le patient, Információs honlap betegek számára, Sito web con le informazioni per i pazienti, Website met informatie voor patiënten, Strona internetowa z informacjami dla pacjenta Translation of serial number in required languages. Translation of LOT number in required languages. Explanation of unique device identi fier (UDI) in required languages. Place to attach the Implant card

md_guidance-manufacturers_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019 -15 rev1 MDCG 2019 -15 rev.1 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES December 2019 July 2020 rev.1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this doc ument are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 2 MDCG 2019 -15 revision 1 changes MDR postponement dates: from 2020 to 2021 GUIDANCE NOTES FOR MANUFACTURERS OF CLASS I MEDICAL DEVICES Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 3 Contents List of acronyms ................................ ................................ ................................ ................................ .... 4 Foreword ................................ ................................ ................................ ................................ ................ 5 Introduction ................................ ................................ ................................ ................................ ........... 5 Definitions ................................ ................................ ................................ ................................ .............. 8 Placing on the market of Class I medical devices: The necessary steps ................................ ......... 11 0) Integrate MDR in the Quality Management System (QMS). ................................ .................. 11 1) Confirm product as a medical device ................................ ................................ ........................ 11 2) Confirm product as a Class I medical device ................................ ................................ ............ 11 3) Procedures before placing on the market ................................ ................................ .................. 12 a) Meet the general safety and performance requirements ................................ ....................... 12 b) Conduct clinical evaluation ................................ ................................ ................................ ... 12 c) Prepare technical documentation ................................ ................................ .......................... 14 d) Request Notified Body involvement ................................ ................................ ..................... 16 e) Prepare Instructions for Use and Labelling ................................ ................................ ........... 16 4) Check compliance with general obligations for manufacturers ................................ ................ 17 5) Draw -up the EU Declaration of Conformity ................................ ................................ ............. 18 6) Affix the CE marking ................................ ................................ ................................ ................ 18 7) Registration of devices and manufacturers in Eudamed ................................ ........................... 19 8) Post Market Surveillance (PMS) ................................ ................................ ............................... 20 a) Review experience gained from Post -Market Surveillance ................................ .................. 20 b) Vigilance ................................ ................................ ................................ ............................... 20 c) Non conforming products ................................ ................................ ................................ ..... 22 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 4 List of acronyms MDD – Medical Devices Directive MDR – Medical Devices Regulation FSCA – Field Safety Corrective Action FSN - Field Safety Notice UDI - Unique Device Identifier SRN - Single Registration Number NB - Notified Body ISO - International Organization for Standardization IEC - International Electrotechnical Commission CA – Competent Authority PPE – Personal Protective Equipment QMS - Quality Management System Im – Class I devices with measuring function Is – Class I sterile devices Ir – Class I reusable surgical instruments DI – Device Identifier Eudamed - European database on medical devices MD - Medical Device CS - Common Specification PMS – Post Market Surveillance IFU – Instructions for use PMCF - Post Market Clinical Follow -up Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 5 Foreword These guidance notes do not aim to be a definitive interpretation of Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices (MDR) and are intended for guidance purposes only. Introduction The purpose of this document is to provide guidance to manufacturers of Class I medical devices (other than custom made devices) who place on the Union market medical devices (from now on referred to as devices) under their name or trade mark, to help them meet the provi sions of the MDR. This guidance should also be applicable for situations when an importer, distributor or any other legal person assumes the obligations incumbent on manufacturers, as per Article 16 (1), while not covering the exception indicated by Artic le 16 (2). The MDR has changed the scope of the medical device legislation and it now extends its application to all economic operators in the supply chain (manufacturer, authorised representative, importer and distributor) as well as a broadened range of products such as those specifically intended for the cleaning, disinfection or sterilization of devices (Article 2 (1)) and products without an intended medical purpose (such as certain aesthetic products, as indicated in Annex XVI of the MDR). In addition , more emphasis is placed on a life -cycle approach to safety, backed up by clinical data and new requirements such as transparency and traceability1. Before placing a device on the market, the manufacturer will affix the CE mark in accordance with Annex V and draw up the EU declaration of conformity, including all the information required by Annex IV. Prior to that, the manufacturer will demonstrate conformity with the MDR and compliance with the applicable general safety and performance requirements laid o ut in Annex I. In order to accomplish the abovementioned tasks, the manufacturer will carry out the following:  Put in place a quality management system and a system for risk management according to Article 10(2) and 10(9).  Conduct a clinical evaluation i n accordance with Article 61, as established in Article 10(3) and Annex XV.  Conduct a conformity assessment according to Article 52(7). In specific cases ( sterile devices, devices with measuring function, reusable surgical instruments ) defined in the referred Article, the manufacturer will request the involvement of a Notified Body (NB).  Draw up and keep up -to-date technical documentation related to devices as set out in Annexes II and III, in accordance with Article 10(4).  Draw up an EU declaration of conformity in accordance with Article 19.  Submit the required information to the electronic system for registration of economic operators (Eudamed) and comply with the registration obligation. The manufacturer will use the Single Regis tration Number (SRN) when applying to a NB for conformity assessment, if applicable and for further accessing Eudamed2 in order to fulfil its obligations related to registration of the devices.  Register the device in Eudamed assigning the Basic UDI -DI to t he device, as defined in Part C of Annex VI, and provide this to the UDI database together with the other core data elements referred in Part B of Annex VI related to that device.  Assign to the device and, if applicable, to all higher levels of packaging, a UDI which will allow identification and traceability. 1 More information can be found at https://ec.europa.eu/health/md_sector/overview 2 Regarding all references to Eudamed in this document, please be advised that for the purposes of this guidance, obligations s trictly related to Eudamed will only apply when it is fully functional and any u pdates will be published on the EU Commission webpage. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 6  Ensure that the device is accompanied by the information needed to identify it and its manufacturer, and any safety and performance information relevant to the user, or any other person, as appropria te (Article 10(11)). This information, set out according to Section 23 of Annex I, must be provided in an official Union language(s) determined by the Member State in which the device is made available to the user or patient. The particulars on the label w ill be indelible, easily legible and clearly comprehensible to the intended user or patient.  Implement a post -market surveillance system in accordance with Article 83 (Article 10(10)) proportional to the risk class and appropriate for the type of device, this includes additional aspects to be taken into account in case of devices placed on the market in sterile condition, with a measuring function or that are reusable surgical instruments. This system will be an integral part of the manufacturer's quality management system based on a post -market surveillance plan (Article 84) , which will be part of the technical documentation specified in Annex III.  Implement a system for recording and reporting incidents and field safety corrective actions as described in Articles 87 and 88 (Article 10(13)).  Put measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC3, without prejudice to more protective measures under national law. These measures will be proportional to the risk class, type of device and the size of the enterprise (Article 10(16)). Further detail on the aforementioned list of obligations is provided in the chapter “Placing Class I medical devices on the market ”. For devices placed on the market in a sterile condition, with a measuring function or which are reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI which require a NB assessment, limited t o critical aspects such as those concerning sterile condition, metrological requirements and the reuse of the device, as relevant, according with Article 52 (7 a, b and c). 3 Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of t he Member States concerning liability for defective products Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 7 Figure 1. Illustration of the conformity procedures for the assessment of Class I devices with and without NB involvement. For big and medium size enterprises, the manufacturer will have available within their organization at least one person responsible for regulatory compliance4, as established by Article 15. Micro and small enterprises5 are required to have such person permanently and continuously at their disposal. A manufacturer with a registered place of business outside the Union will designate a sole authorised representative, at least per each gener ic device group, according to a written mandate. Such a mandate will establish the tasks to be performed by the authorised representative. To enable the fulfilment of these tasks, the manufacturer ensures that the authorised representative has the necessar y documentation permanently available and up -to date. The mandate will require the authorised representative to perform at least the tasks described in Article 11(3), however the manufacturer cannot delegate its obligations laid down in Article 10(1), (2), (3), (4), (6), (7), (9), (10), (11) and (12). In case of the change of authorised representative, Article 12 establishes the minimum content of agreement to be addressed between the manufacturer, where practicable the outgoing authorised representative, a nd the incoming authorised representative. Upon request, the manufacturer will provide all the information and documentation necessary to demonstrate conformity of the device to competent authorities and cooperate with them on any corrective action. If th e manufacturer does not cooperate or does not provide the requested information or documentation, the competent authority (CA) can adopt restrictive measures. The manufacturer should periodically verify whether implementing and delegated acts, common speci fications, technical standards and guidelines might be available on the European Commission website6. Such documents might for example cover specific parts of legislation (e.g. classification of 4 See the relevant MDCG guidance on Article 15 of MDR and IVDR regarding a "person responsible for regulatory compliance" (PRRC) 5 See Commission Recommendation 2003/361/EC 6 https://ec.europa.eu/health/md_sector/overview Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 8 medical devices, clinical evaluation) or specific requirement s regarding certain medical device technologies (e.g. software, 3D printing ) that can also be applicable for Class I devices. During the transitional period, manufacturers might be tempted to refer to guidance documents developed under the Directive 93/42/ EC. However, the old guidance documents, unless otherwise updated in line with the MDR, may have only some limited indicative value under the MDR. For the purpose of the MDR, only the text of the Regulation is valid in law and sets out requirements not reflected in the old guidance. Hence, the MDR alone can be relied upon as a legal basis . Definitions For the complete list of definitions refer to Article 2 of the MDR. This is an excerpt of some definitions. Accessory for a medical device - means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s) (Article 2(2)) . Authorised representative - means any natural or legal person established within the Union who has received and accepted a written mandate from a manufacturer, located outside the Union, to act on the manufacturer's behalf in relation to specified tasks with regard to the latter's obligations under the MDR (Arti cle 2(32)). The designation of an authorised repre sentative will be in compliance with Article 11 and effective at least for all devices o f the same generic device group (Article 11(2)) . Adverse event - means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, inc luding an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device (Article 2(57)) . Benefit -risk determination - means the analysis of all assessments of benefit and risk of possible relevance for the use of the device for the intended purpose, when used in accordance with the intended purpose given by the manufacturer (Article 2(24)) . Class I medical devices with measuring function - are considered Class I medical devices which measure physiological parameters or anatomical parameter or energy, respectively, or volume of medicinal products, body liquids or other substances administered to or removed from the body and display or indicate its value in a unit of measurement (example: urine bags, non -active thermometers, measuring spoons). Note: According to section 15.2 of Annex I, measurements made by devices with a measuring function will be expressed in legal un its7. CE marking of conformity or CE marking - means a marking by which a manufacturer indicates that a device is in conformity with the applicable requirements set out in the MDR and other applicable Union harmonisation legislation providing for its affix ing (Article 2(43)) . Note: CE marking will be made in accordance with Annex V. Clinical evaluation - means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify th e safety and performance, including clinical benefits, of the device when used as intended by the manufacturer. (Article 2(44)). Clinical data - means information concerning safety or performance that is generated from the use of a device and is sourced fr om the following:  clinical investigation(s) of the device concerned, 7 In conformance to the provisions of Council Directive 80/181/EEC Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 9  clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,  reports published in peer re viewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,  clinically relevant information coming from post -market surveillance, in particular the post - market clinical follow -up. (Article 2(48)) Conformity Assessment – The process demonstrating whether the requirements of the MDR relating to a device have been fulfilled. (Article 2(40)). This process depends on the medical device classification, according to the procedures described in the MDR, in particular Article 52 (7) applicable for class I devices. Distributor - means any natural or legal person in the supply chain, other than the manufacturer or the importer that makes a device available on the market, up until the point of putting into service (Article 2(34)) . Economic operator - means a manufacturer, an authorised representative, an importer, a distributor or the person referre d to in Article 22(1) and 22(3) (Article 2(35)) . Field safety corrective action - means corrective action taken by a manufacturer for technical or medical reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market (Article 2(68)) . Field safety notice - means a com munication sent by a manufacturer to users or customers in relation to a field safety corrective action (Article 2(69)) . Harmonised standard - means a European standard as defined in point (1)(c) of Article 2 of Regulation (EU) N° 1025/20128, (as referred on the Article 2(70)) – means a European standard adopted on the basis of a request made by the Commission for the application of Union harmonisation legislation. Importer - means any natural or legal person established within the Union that places a devic e from a third country on the Union market (Article 2(33)). Intended purpose/intended use - means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (Article 2(12)). Instructions for use - means the information provided by the manufacturer to inform the user of a device's intended purpose and proper use, and of any precautions to be taken (Article 2(14)). Label - means the written, printed or graphic information appearing either on the device itself, or on the packaging of each unit or on the packaging of multiple devices (Article 2(13)). Medical device - means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: ‒ diagnosis, prevention, m onitoring, prediction, prognosis, treatment or alleviation of disease, ‒ diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, ‒ investigation, replacement or modification of the anatomy or of a physiological or path ological process or state, ‒ providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, 8 Regulation (EU) No 1025/2012 of the European Parliament and of the Council , of 25 October 2012 , on European standardization Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 10 and which does not achieve its principal intended action by pharmacological, immuno logical or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: ‒ devices for the control or support of conception; ‒ products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point. (Article 2(1)) Manufacturer - means a natural or legal person who manufactures or fully refur bishes a device or has a device designed, manufactured or fully refurbished, and markets that device under its name or trademark ; (Article 2(30)). Notified Body - means a conformity assessment body designated in accordance with the MDR (Article 2(42)). Placing on the market - means the first making available of a device, other than an investigational device, on the Union market (Article 2(28)). Post-market surveillance - means all activities carried out by manufacturers in cooperation with other economic op erators to institute and keep up to date a systematic procedure to proactively collect and review experience gained from devices they place on the market, make available on the market or put into service for the purpose of identifying any need to immediate ly apply any necessary corrective or preventive actions (Article 2(60)). Risk - means the combination of the probability of occurrence of harm and the severity of that harm (Article 2(23)). Serious incident - means any incident that directly or indirectly led, might have led or might lead to any of the following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat; ((Article 2( 65)) Serious public health threat - means an event which could result in imminent risk of death, serious deterioration in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time (Article 2(66)) . Unique Device Identifier (UDI) - means a series of numeric or alphanumeric characters that is created through internationally accepted device identification and coding standards and that allows unambiguous identification of specific devices on the market (Article 2(15)). User - means any healthcare professional or lay person who uses a device (Article 2(37)). Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 11 Placing Class I medical devices on the market: The necessary steps Manufacturers that intend to place Class I medical devices on the market must guarantee compliance with all the requirements below. Please note that some of the described requirements are inter -dependent and can be performed in a differe nt order than the one presented. For Class I devices already placed on the market in accordance with the MDD, the manufacturer will conduct a gap analysis in order to guarantee that all the necessary requirements outlined below are fully completed at the d ate of the application of MDR. 0) Integrate MDR in the Quality Management System (QMS). The applicable provisions of the MDR will be integrated into the QMS of the manufacturer. This will allow the correct assessment/decision to be made and the proper documented evidence to be created, ensuring compliance with the following requirements. 1) Confirm product as a medical device Confirm that the product qualifies as a medical device as defined in Article 2(1) in accordance with its intended purpose and principal mode of action. If the manufacturer assigns several different intended purposes to their product, not all of which fall under the scope of the MDR, such a product qualifies as a medical device only with respect to those intended medical purposes which are covered by Article 2(1). This is applicable, for instance, for the case of examination gloves that are intended by the manufacturer to be used to protect the patient (medical purpose - MD) and also to protect the healthcare professional (protecti on purpose – PPE9). In that case the relevant requirements of both legislations will be applicable. In the case of accessories to medical devices, despite not being medical devices per se, they are covered by MDR provisions and fall under the term “device” in the meaning of the MDR. However, accessories to devices covered by the MDR by virtue of its Annex XVI are not covered by the MDR. For borderline products where such a determination could be difficult, please consult primarily the information10 available on the European Commission website. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 2) Confirm product as a Class I medical device Consult Annex VIII of the MDR to confirm that the product is correc tly classified as Class I. It should be noted that some Class I devices according to MDD will be reclassified under the MDR considering the new classification rules of that annex, this is the case for most software (rule 11) and devices that are composed o f substances or of combination of substances (rule 21) . For devices that were reclassified from Class I to higher risk classes by application of the MDR, the present guideline cannot be applied. The application of the classification rules will be governe d by the intended purpose of the device and 9 Directive 89/686/EEC is repealed with effect from 21 April 2018 by Regulation (EU) 2016/425 10 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 12 their inherent risks linked to the duration of use, part of the body, whether it is active or not, whether it is invasive or non -invasive. If more than one rule according to Annex VIII applies to the intended pur poses of the device, the highest classification applies to the device, i.e. it must be classified on the basis of the most critical specified use. For classification issues, please primarily consult the information11 available on the European Commission web site. Your CA may be able to provide guidance on where to find published information and regulatory requirements. 3) Procedures before placing on the market a) Meet the general safety and performance requirements The devices will meet the general safety and per formance requirements set out in Annex I of the MDR which apply to them, taking into account the purposes intended by their manufacturers. Particular attention will be given to devices that are also machinery, within the meaning of Article 2(2), point (a) , Machinery Directive 2006/42/EC12, where the relevant requirements of that directive will also be covered given their specificity (according to Article 1(12)). The manufacturer will establish and implement a risk management system, which will allow for the identification and analysis of the hazards associated with each device, estimation and evaluation of the associated risks, elimination or control of residual risks and evaluation of the adopted measures based on the information collected from the post -market surveillance system. The risk management will be understood as a continuous iterative process throughout the entire lifecycle of a device, requiring regular systematic updating. To carry out this process the manufacturer can find solutions in common sp ecifications, or in harmonised standards, published in the Official Journal of the European Union, or in other referential materials. Where a harmonised standard exists but the manufacturer is following other referential, the application of that referentia l should guarantee at least the same level of safety and performance. Conformity with the relevant harmonized standards will provide presumption of conformity with the requirements of the MDR covered by those standards or parts thereof. Where common speci fications are available the manufacturer is obliged to follow them unless they can duly justify that they have adopted a solution at least with the same level of safety and performance. The risk management, clinical evaluation processes and PMS will be inter-dependent and will be periodically updated. b) Conduct clinical evaluation All devices, regardless of risk classification, require a clinical evaluation as part of the technical documentation requirements of the MD R13. The manufacturer will specify and justify the level of clinical evidence necessary to demonstrate 11 Guidelines available on https://ec.europa.eu/health/md_sector/new_regulations/guidance_en%20 12 Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/EC (OJ L 157, 9.6.2006, p. 24) 13 For further, see Annex II of the MDR Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 13 conformity with the relevant general safety and performance requirements described in Annex I. That level of clinical evidence will be appropriate in view of the characteristics of the device and its intended purpose. In order to do that, manufacturers will plan, conduct and document a clinical evaluation in accordance with Article 61 and Part A of Annex XIV. Guidance on the process of conducting clinical eval uation is also available on the Commission website.14 Conformity to Annex I requirements can only be assumed when the following items are aligned with each other:  Risk management;  The information materials supplied by the manufacturer, including: o labelling , o instructions for use (where required), o available promotional materials, o any accompanying documents foreseen by the manufacturer;  The clinical evaluation (the device description used for the clinical evaluation, other contents of the clinical evaluati on report);  The available clinical data (such as results of clinical investigations, publications, Post Market Surveillance studies, clinical registries, etc.). The MDR reinforces the need to consider the following aspects when carrying out a clinical eval uation: • Consideration of available alternative treatment options is required as part of clinical evaluation for the MDR15. Whilst the existence of better alternative treatment options does not influence the compliance of the device with the MDR, the manufacturer needs to be able to justify the clinical benefit of using their device if alternatives are available. • The incorpo ration of clinical data obtained throughout the life cycle of the device from the manufacturers post -market clinical follow -up plan and post -market surveillance plan to update the clinic al evaluation and documentation16. • The acceptability of the benefit -risk ratio must be based upon sufficient clinical data and will be continuously monitored and reassessed from clinical data collected through the post - mark et surveillance phase. The post -market surveillance plan should incorporate suitable indicators and thr eshold values to be used in this reassessment 17. If available clinical data are not sufficient to demonstrate compliance with the MDR, further clinical data will be obtained or generated by clinical investigations. For devices which are currently certifie d with respect to the Directive 93/42/EC, and for which the available clinical data are not sufficient to demonstrate compliance with MDR, additional clinical data may be obtained by post -market clinical follow -up studies of the device. Sometimes, even dat a from the general post -market follow -up might suffice to close the gap18. Note : if a clinical investigation is required, then the Member State requires advance notification of the proposal and the provisions of Article 62 and Annex XV will be applicable. 14 https://ec.europa.eu/health/md_sector/new_regulations/guidance_en 15 MDR, Article 61(3)(c) 16 MDR, Article 61(11) 17 MDR, Article 61(1) and Annex III 1.1b 18 An MDCG guidance is intended to be published on this matter including ‘sufficient clinical da ta’ in 2020 and will be availabl e at the EU Commission webpage Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 14 In duly justified and substantiated cases, some Class I devices manufacturers may exceptionally demonstrate that the conformity with general safety and performance requirements based on clinical data is not deemed appropriate. Such a justification by the m anufacturer must be based upon an evaluation of evidence in accordance with Article 61(10). The clinical evaluation, risk management processes and PMS will be inter -dependent and will be periodically updated. c) Prepare technical documentation The manufactur er will draw up and keep up to date the technical documentation that demonstrates the conformity of their devices with the technical requirements of the MDR. This technical documentation must be prepared according to Annex II and III and prior to drawing u p the EU declaration of conformity. The technical documentation and, if applicable, its summary, will be drawn up and presented by the manufacturer in a clear, organised, readily searchable and unambiguous manner. The manufacturer must make the technical d ocumentation available to the CA, the authorised representative (when applicable) and NB (when applicable). The technical documentation will be prepared following review of the general safety and performance requirements and relevant technical provisions o f the MDR and, if applicable, of the Machinery Directive19 and will cover all the relevant aspects from Annex II and III, such as: - Rationale for the qualification as a medical device and the risk class attributed. - Description and specification - A general d escription of the device, including its intended purpose and intended users/patient population and, if applicable, accessories and variants of the product (for example trade names, model numbers, references, sizes). In addition , the Basic UDI-DI as per Par t C of Annex VI will be provided. - Technical Specifications of the device - Specifications including details of raw materials, drawings of components and/or master patterns and any quality control procedures. - Information to be supplied by the manufacturer - Labels on the device and packaging, such as single unit packaging, sales packaging, transport packaging in case of specific management conditions and instruction for use (if applicable), in the languages determined by the Member States where the device is envisaged to be sold. - Reference to previous generations of the device and to similar devices - Provide an overview of previous generation(s) of the device and similar devices available on the market as ap plicable - Design and manufacturing information – Information that allows the understanding of the design and manufacturing of a device, including the results of qualifications tests and design calculations relevant to the intended use of the product, includ ing connections to other devices in order for it to operate as intended. If the manufacturer can provide information showing that a safe design has been established for a number of years and that product has been performing as intended during that time suc h information is likely to be sufficient to cover this 19 According to Article 1 (12) Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 15 requirement. The identification of all sites, suppliers and sub -contractors, where design and manufacturing activities are performed will also be included. - General safety and performance requirements – information for the demonstration of conformity with the general safety and performance requirements, set out in Annex I. In order to do this, the manufacturer will refer to all the methods and solutions used for conformity demonstration with each safety and performance requirement, including harmonised standards and/or common specifications (CS). The same applies for the requirements contained in the Machinery Directive. - Demonstration of conformity with the requirements set out in Annex I should typically be presented in the form of a checklist. This should list all requirements referred to in Annex I and specify: (1) the applicability of each requirement to the device, (2) the solution adopted by the man ufacturer to comply with each applicable requirement, (3) the reference to any possible CS or harmonized standards applied in full or in part and (4) the reference to where to find evidence of the solution adopted in the technical documentation. Manufacturers wil l list the relevant harmonised standards (concerning for example sterilisation, labelling and information to be supplied with the device, biocompatibility, specific groups of products) which have been applied in full or in part. If harmonised standards hav e not been applied in full, additional data will be required and provided detailing remaining solutions adopted to meet the concerned requirements. Information on standards harmonised under the MDR will be made available in the Official Journal of the Euro pean Union. Changes on the harmonised standards used to demonstrate the conformity of device will be adequately taken into account in a timely manner. Please note that no standard harmonized under the Directive 93/42/EC, has ever covered all the requirements of the Annex I to that Directive. Hence, it is not likely that any one standard harmonized under the MDR will cover all the requirements of the Anne x I to the MDR. The scope of coverage is indicated in the so -called Annex Z to the European “EN” standard. The scope of coverage is never to be found in the ISO or IEC standard text. - Benefit -risk analysis (sections 1 and 8 of Annex I) and Risk management ( section 3 of Annex I). - Pre-clinical and Clinical evaluation data – Information to be provided on the results from pre - clinical and clinical evaluation. - The post -market surveillance system - The technical documentation on post -market surveillance to be dr awn up by the manufacturer in accordance with Articles 83 to 85 will be presented in a clear, organized, readily searchable and unambiguous manner. It shall address and cover the elements of point 1.1 of Annex III. The plan will cover the post -market clini cal follow up plan as referred to in part B of Annex XIV or a justification as to why it is not applicable. The PMS report of article 85 shall be part of the technical documentation on post -market surveillance. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 16 - Records - Manufacturers will keep the techn ical documentation, the EU declaration of conformity and, if applicable, a copy of any relevant certificate, including any amendments and supplements, issued in accordance with Article 56, available for the competent authorities for a period of at least 10 years after the last device covered by the EU declaration of conformity has been placed on the market (Article 10(8)). Availability of documentation – In case of request by the CA, the manufacturer will provide the required technical documentation in an official Union language determined by the Member State concerned (Article 10(14)). d) Request Notified Body involvement In the case of devices placed on the market in sterile condition, having a measuring function or being reusable surgical instruments, the manufacturer will apply the procedures set out in Chapters I and III of Annex IX, or in Part A of Annex XI of MDR. This requires the involvement of a NB. In all other cases the intervention of a NB is not required for Class I devices. If involvement of the NB is needed it is limited: - In the case of devices placed on the market in sterile condition, to the aspects of manufacture concerned with securing and maintaining sterile conditions; - In the case of devices with a measuring function, to the aspects of man ufacture concerned with the conformity of the devices with the metrological requirements; - In the case of reusable surgical instruments20, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance a nd functional testing and the related instructions for use. Manufacturers can choose any NB designated according to the MDR for the relevant codes and corresponding types of devices as established by Regulation (EU) 2017/2185 (code MDS 1005 for “Devices in sterile condition”, code MDS 1006 for “Reusable surgical instruments” and code MDS 1010 for “Devices with a measuring function”) . The list of designated NBs is available in the NANDO database at the following link: http://ec.europa.eu/growth/tools -databases/nando/ Please note that notification under the Directive 93/42/EC, become s void after the application of the MDR on the 26 May 202 1. Hence, it is necessary to consult the NANDO database for the MDR. e) Prepare Instructions for Use and Labelling Each device must be accompanied by any safety and performance information needed to use it safely and to identify the device as well as the manufacturer and/or the authorised representative, taking account of the training and knowledge of the potential users. This information comprises the label, device packaging and the data in the instructions for use. By way of derogation to the general principles, no instructions for use are required for Class I de vices if they can be used properly and safely without such instruction. An exception is most likely posed for Class Ir devices as reprocessing (cleaning and sterilization) will require an instruction. The requirements regarding the information to be suppl ied with the device will be found in Annex I, Chapter III (23). In the labelling and instructions for use as well as in promotional materials of the device, the manufacturer may not (Article 7): 20 Please also note that involvement of a Notified Body in the case of reusable surgical instruments is a new requirement under the MDR, which did not exist under the MDD. Manufacturers of such products are advised to take this into consideration for their pl ans to meet the provisions of the MDR before its application on the 26 May 202 1. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 17 - Ascribe functions and properties to the device which the devi ce does not have; - Create a false impression regarding treatment or diagnosis, functions or properties which the device does not have; - Fail to inform the user or the patient of a likely risk associated with the use of the device in line with its intended purpose; - Suggest uses for the device other than those stated to form part of the intended purpose for which the conformity assessment was carried out. National language requirements must be taken into account in relation to the labelling and instructions for use. Versions of labelling and IFU ( in each of the relevant national languages) will be included in the technical documentation. Note : According to Article 16(2), a distributor or importer may provide a translation of the information provided according to Section 23 of Annex I. The manufacturer will be informed about the intended translation and receive a copy 28 days prior to the date of making the device available in the respective country. It is advisable to perform a review of the translation, as a w rong or misleading translation can cause harm to patients or others, leading to possible liability of the manufacturer. Where appropriate, the information supplied by the manufacturer will take the form of internationally recognised symbols. Any symbol or identification colour used will conform to harmonised standards or common specifications (CS). In areas for which no harmonised standards or CS exist, the symbols and colours will be described in the documentation supplied with the device. The label should have the indication that the product is a “medical device”. 4) Check compliance with general obligations for manufacturers Before placing a device on the market, the manufacturer will make sure to comply with the general obligations for manufacturers as est ablished in Article 10. Special attention will be given to the establishment of an appropriate QMS that will ensure compliance with the MDR in the most effective manner, for example by means of an internal audit. The QMS will be documented, implemented, m aintained, kept up to date and continually improved and will cover at least the following aspects: a) a strategy for regulatory compliance; b) identification of applicable general safety and performance requirements and exploration of options to address those requirements; c) responsibility of the management; d) resource management, including selection and control of suppliers and sub -contractors; e) risk management; f) clinical evaluation, including post market clinical follow -up (PMCF); g) product realisation, including planning, design, development, production and service provision; h) verification of the UDI assignments; i) setting -up, implementation and ma intenance of a post -market surveillance system; j) handling communication with competent authorities, notified bodies, other economic operators, customers and/or other stakeholders; k) processes for reporting of serious incidents and field safety corrective ac tions in the context of vigilance; l) management of corrective and preventive actions and verification of their effectiveness; m) processes for monitoring and measurement of output, data analysis and product improvement. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 18 The QMS will be established at least in parallel, if not prior to chapter 3 a) and 3 b) as described in this guidance note. Natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Therefore, manufacturers sha ll, in a manner that is proportionate to the risk class, type of device and size of the enterprise, have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC, without prejudice to mor e protective measures under national law. 5) Draw -up the EU Declaration of Conformity The EU declaration of conformity, referred to in Article 19, is the procedure whereby the manufacturer, who fulfils the obligations imposed by Article 52(7), declares that the devices concerned fulfil the requirements of the MDR which apply to them. The declaration of conformity will contain as a minimum all information referred to in Annex IV and will be available to the CA. The manufacturer will continuously update the EU declaration of conformity and will translate it into an official union language or languages required by Member States in which the device is made available. If, in addition to the MDR, a device is covered by other Union legislation which also requires an EU declaration of conformity, the manufacturers will elaborate a single EU declaration of conformity where all the Union legislation applied to the product are referred to. By drawing up the EU declaration of conformity the manufacturer assumes the respon sibility for the regulatory compliance of the device with all Union legislation applicable to it. Before affixing a CE mark, for class Ir, Im and Is devices, the manufacturer will have an EC certificate issued by NB according to the Annex IX, Chapter I and III, or to Annex XI, Part A. 6) Affix the CE marking All Class I medical devices placed on the mar ket will bear the CE marking of conformity, which will be affixed in a visible, legible and indelible form on the device or on its sterile packaging. Where such affixing is not possible or not warranted on account of the nature of the device, the CE markin g shall be affixed to the packaging. The CE marking shall also appear on the instructions for use, as well as on any sales packaging. In the case of Class I medical devices placed on the market in a sterile condition and/or devices with measuring function and/or reusable surgical instruments, the CE marking will be accompanied by the identification number of the relevant NB. It is prohibited to affix marks which are likely to mislead third parties with regard to the meaning of the CE marking. Other additio nal marks may be affixed to the device, to the packaging or the instructions for use, but must not impair the visibility or legibility of the CE marking. The CE marking format will be in compliance with Annex V. Where the device is very small the minimum d imensions of the CE mark may be waived. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 19 7) Registration of devices and manufacturers in Eudamed Before placing a device on the market, the manufacturer of a Class I medical device will register the device in Eudamed. In order to register the device, the manufacturer will submit to the electronic system referred to in Article 30 the information referred to in Section 1 of Part A of Annex VI, provided that they have not already been registered in accordance with Article 31. In cases where the conformity ass essment procedure requires the involvement of a NB pursuant to Article 52, the information referred to in Section 1 of Part A of Annex VI will be provided to that electronic system before applying to the NB. After having verified the data about the manufac turer, the CA will validate it in Eudamed and the manufacturer will obtain a SRN from said electronic system. The manufacturer will use the SRN when applying to a NB for conformity assessment and for accessing Eudamed in order to fulfil its obligations und er Article 29. Note: Authorised representatives and importers are also required to register to get an SRN in order to access Eudamed and provide data, as appropriate The registration of a device in Eudamed by the manufacturer includes:  Assignment of a UDI -DI (with a Basic UDI -DI) as defined in Part C of Annex VI to the device (in accordance with the rules of the issuing entity referred to in Article 27(2) and introduction of the UDI -DI (with a Basic UDI -DI) to the UDI database together with the other core d ata elements referred to in Part B of Annex VI related to that device.  Entering, or if already provided, verifying in Eudamed the information referred to in Section 2 of Part A of Annex VI, with the exception of Section 2.2 thereof, and thereafter keeping the information updated. If the manufacturer has its devices designed or manufactured by another legal or natural person, the information on the identity of that person will be part of the information (Section 2.13 of Part A of Annex VI) to be submitted to Eudamed before the registration of the device. Note 1 – The Unique Device Identification system will allow the identification and facilitate the traceability of devices (as referred on Article 27). [Special attention will be given to point 11 of Article 27]. Note 2 – The Basic UDI -DI as defined in Part C of Annex VI is the primary identifier of a device model. It is the main key for records in the UDI database and is referenced in relevant certificates and EU declarations of conformity21. Note 3 – For Class I devices placed on the market according to MDD, afte r the date of application of MDR manufacturers will have in consideration the guidance documents applicable to legacy devices timelines22 and registration in Eudamed23. 21 For more information on the Basic UDI -DI, please refer to https://ec.europa.eu/docsroom/documents/28667 22 See at EU Commission webpage the relevant guidance on timelines for registration of device data elements in EUDAMED23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED 23 See at EU Commission webpage the relevant guidance on the registration of legacy devices in EUDAMED Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 20 Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 21 All devices including legacy devices of the manufacturer portfolio which are placed on the market or put into service will have to be registered in Eudamed. However, until Eudamed is fully functional the manufacturer of a Class I medical device, or, where the manufacturer has no place of business in the EU, its authorised representative must inform the CA of the country in which they have their registered place of business and provide a description of the device that is sufficient to identify it. The manufacturer or its authorised representative will contact their relevant CA for the required procedures and forms required for such notifications. A fee might be applicable. 8) Post Market Surveillance (PMS) After placing the Class I device on the market, the manufacturer will follow the next PMS steps: a) Review experience gained from Post -Market Sur veillance The manufacturer will put in place the required post market surveillance (PMS) system and actively keep this PMS up to date in accordance with Article 83 of MDR. This includes actively and regularly collecting the user experience from devices on the market, reviewing these and ensuring timely implementation of any necessary corrective action, taking account of the nature and risks in relation to the product. In addition, there should be an evaluation of whether the intended benefits are achieved a nd whether the benefit -risk profile stays positive. The manufacturer will involve the distributors of the device and where applicable, the authorised representative and importers of the device in this system, in order to obtain the relevant information from the market. This system will be part of the QMS, and be supported by the manufacturer’s PMS plan, which must address a range of information (Annex III), such as information from the vigilance context, information from trending and trend reporting, inf ormation and data on any undesirable side -effects, information from reports, complaints and incidents, provided by users and economic operators, related to the device. Moreover, the manufacturer will gather and assess the relevant information such as techn ical literature, databases, registers review and public information for the device itself as well as for similar devices already present on the market. A PMS report will be prepared according to Article 85, summarizing the results and conclusions of the analysis of all of the data from the market. This report will be updated when necessary, for example the intended benefits are not achieved or there is a change in the benefit -risk balance. The report can be requested by the CA at any time. Data gathered from PMS system must be used to actively update the clinical evaluation, benefit -risk determination, improve risk management, as well as other technical documentation on a regular basis. b) Vigilance The manufacturer is responsible for reporting all serious incidents and field safety corrective actions (FSCA) to the relevant CAs, according to Article 87 (1) of the MDR. After serious incident notification, the manufacturer is obliged to make investigations, according to Article 89, which will include a risk assessment of the incident. If needed, a FSCA will be implemented in order to reduce the risk associated with the use of the device. The manufacturer will involve the distributors of the device and, where applicable, the authorised representative and import ers in the system, in order to obtain the information needed from the market, especially for FSCA and issued field safety notices (FSN) to ensure that required actions are followed and completed in a timely manner. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 22 When Eudamed is available, serious incide nts and FSCAs will be submitted via this electronic system only. Manufacturers will report any serious incident immediately after they have established the causal relationship between that incident and their device or that such a causal relationship is re asonably possible. The timeframe to report serious incidents must not exceed the following upper limits:  In the event of a serious public health threat, a report will be submitted not later than 2 days after becoming aware of the threat. (Article 87 (4))  In the event of death or an unanticipated deterioration in a person’s state of health a report will be submitted not later than 10 days after becoming aware of the serious incident. (Article 87 (5))  In all other cases not later than 15 days after becoming aware of the serious incident (Article 87 (3)) Where necessary to ensure timely reporting of serious incidents, the manufacturer may submit an initial report that is incomplete followed up by a complete report. If, after becoming aware of a potentially reportable incident, the manufacturer is uncertain about whether the incident is reportable, it shall nevertheless submit a report. Serious incidents will be reported only to the competent authority of the country in which the serious incident occurred via Eu damed. The manufacturer will provide a final report to that competent authority via Eudamed setting out its findings from the investigation. The report will set out conclusions and - where relevant - indicate corrective actions to be taken. When the compet ent authority notifies a manufacturer of a suspected serious incident, communicated to the competent authority by a healthcare professional, patient or user, the manufacturer is obliged to:  submit a report of this serious incident to the notifying competen t authority via Eudamed within the timeframes described above;  submit an explanatory statement, to the competent authority, if the manufacturer believes the suspected serious incident does not fulfil the reporting criteria. In case the competent authority disagrees with the explanatory statement provided by the manufacturer a report of the serious incident may be required to be provided to the competent authority that does not agree via Eudamed by the manufacturer. If a FSCA is undertaken, manufacturers wil l without unnecessary delay report the field safety corrective action via Eudamed in advance of the carrying out of the FSCA unless urgency demands the manufacturer to undertake the actions immediately. Manufacturers will ensure that the information relate d to the FSCA is brought without delay to the attention of users of the device in question by means of a FSN. Except in cases of urgency, the content of the draft FSN will be submitted to the evaluating competent authority or to the coordinating competent authority to allow it to make comments. Unless duly justified by the situation of the individual Member State, the content of the field safety notice will be consistent in all Member States. Manufacturers will also report the FSN(s) to Eudamed. Class I Guidance MDCG MSWG - MDCG 2019 -15 rev1 23 The FSN w ill allow the correct identification of the manufacturer ( by including the, if issued, SRN), the device or devices affected (by including the relevant UDIs) and the FSN will explain, in a clear manner, without understating the level of risk, the reasons fo r the FSCA. This includes a clear reference to the device deficiency and the associated risks for patients, users or other persons and will clearly indicate all action to be taken by the users. Manufacturers will report by the means of a trend report to Eudamed any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side -effects, when it could have a significant impact on the benefit -risk analysis and which have led o r may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. Manufacturers will, if they exist, follow national provisions in the field of vigilance specifically in but not limited to the case of field safety corrective actions:  The allowed languages used to communicate with users by means of the Field Safety Notice. Manufacturers are asked to check if templates exist (on European Commission website) on any of the reporta ble forms and make sure that all the necessary information according to these templates is provided. This will be only applicable until Eudamed is available. Manufacturers should keep concerned economic operators informed of reported serious incidents and FSCA activities. c) Non-conforming products If a manufacturer has reasons to believe that a device which they have placed on the market or put into service is not in conformity with the MDR they will immediately take the necessary corrective action to bring t hat device into conformity, to withdraw it or to recall it, as appropriate. The manufacturer will inform the distributors of the device in question and, if applicable, the authorised representative and importers. If the device presents a serious risk, the manufacturer will immediately inform the competent authorities of the Member States in which the manufacturer made the device available and, where applicable, the notified body that issued a certificate for the device, in particular, of the non -compliance and of any corrective action taken.

mdcg_2019_3_rev1_cecp_en.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 1 of 4 MDCG 2019 -3 Rev. 1 Interpretation of Article 54(2)b April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 2 of 4 MDCG 2019 -3 Rev. 1 changes Addendum on procedural aspects New Interpretation of Article 54(2)b Article 54(2) of the MDR lays down three criteria that exempt devices from the pre - market clinical evaluation consultation procedure with the involvement of expert panels. In particular that article states that: “The procedure referred to in paragraph 1 shall not be required for the devices referred to therein: (a) in the case of renewal of a certificate issued under this Regulation; (b) where the device has been designed by modifying a device already marketed by the same manufacturer for the same intended purpose, provided that the manufacturer has demonstrated to the satisfaction of the notified body that the modifications do not ad versely affect the benefit -risk ratio of the device; or (c) where the principles of the clinical evaluation of the device type or category have been addressed in a CS referred to in Article 9 and the notified body confirms that the clinical evaluation of the manufacturer for this device is in compliance with the relevant CS for clinical evaluation of that kind of device”. Interpretation of point (b) of Article 54(2) is unclear, notably in relation to the application of the word “marketed”. In fact, while in point “a” the co -legislator explicitly indicates that the certificates referred to are those issued under the new Regulation, in point “b” there is no indication of whether a “device already marketed” refers to devices already marketed under the Directi ves or the Regulations. This has raised questions from the public and from Member States. As we are about to launch the procedures for the establishment of expert panels, clarification of this issue is extremely urgent, notably due to its impact on the fu ture workload of panels and hence on relevant budget and workload estimations. The following considerations seem to indicate that the expression “device already marketed” cannot be intended to refer to a device already marketed uniquely under the new Regu lation :  If the co -legislators had decided to restrict the application of point “b” to devices marketed uniquely under the MDR, they would have explicitly stated so, as they did for point “a”;  Article 54, together with other Articles (such as Article 61(6) and Article 120(3)), was written at the end of the negotiation process with a view to smoothen the Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 3 of 4 implementation of the new Regulation. Therefore the interpretation of the exemption should be understood in line with the spirit and intention of the co - legislators. It has to be noted that, in respect to devices that have been marketed already under the relevant Directives, the word “modification” shall be meant as limited only to those modifications needed in order to comply with the new legal requiremen ts introduced by the MDR1 2. Addendum - Procedural aspects Together with the application to be lodged under the applicable conformity assessment procedure, the manufacturer will provide the notified body with:  a statement that it has marketed the device in question for the same intended purpose under the relevant Directive,  copy of the last issued certificate(s) together with the certificate history, and  a description of the modifications introduced to comply with the MDR As part of its technical documen tation assessment according to the MDR, the notified body will verify that the “modifications”, as referred to in the main document, do not adversely affect the benefit -risk ratio. In particular, the notified body will verify:  that the device in question h ad a valid certificate under the Directives,  in case the certificate has been withdrawn, suspended3 or expired, if there is an impact on compliance with the general safety and performance requirements, and  that there is no pending assessment of changes fo r the device or outstanding non-compliance. In addition, the notified body will verify the description of modifications provided and assess if these modifications are limited only to those needed in order to comply with the new legal requirements introdu ced by the MDR. Limitations of the intended purpose of the device should not trigger the consultation procedure in accordance to Art. 54. 1 These devices will anyhow be subject to all applicable new MDR requirements, including those ones related to the clinical evaluation, and will need to be assessed by notified bodies against these new (and higher) requirements. This aspect together with the increased notified bodies’ oversight foreseen under MDR should guarantee a high standard of safety for these products. 2 From a practical perspective, u nder the scenario where those products had to be subject to clinical evaluation consultation procedure with the involvement of expert panels, as a result of the application of criteria set in Annex IX 5c, in most if not all of the cases, the panel would de cide not to give an opinion. Therefore , a very significant additional workload and financial burden would be created for an extremely limited added value. 3 Certificates for which the rationale for withdrawal or suspension is linked to lack of complian ce with essential requirements may adversely affect the benefit -risk ratio of the device and will require a clinical evaluation consultation procedure. Medical Devices Medical Device Coordination Group Document MDCG 201 9-3 Rev.1 Page 4 of 4 In case that any of the abovementioned conditions are not fulfilled the notified body will follow the consultation procedure in accordance to Art. 54. The assessment of the above conditions will be documented by the notified body in accordance with Section 4.6 of Annex VII in the clinical evaluation assessment report that will be made available to competent authorities in accordance with Art. 54 (1) and (3). Clarifications in respect to the applicability of Art. 54(2)b with regard to devices already marketed under the MDR are to be provided in a separate guidance.

mdcg_2019_11_guidance_qualification_classification_software.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2019-11 MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR October 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 1 of 28 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR Guidance on Qualification and Classification of Software October 201 9 Page 2 of 28 Table of Contents 1. Scope and purpose of this document 3 2. Definitions and abbreviations 3 3. Qualification 6 3.1. Introduction to qualification criteria 6 3.2. Medical Device Software (MDSW) 7 3.3. ‘Software driving or influencing the use of a medical device’ 8 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device 10 4. Classification of MDSW per MDR 2017/745 12 4.1. Implementing Rules 12 4.2. Classification Rules 12 5. Classification and implemen ting rules per IVDR 2017/746 15 5.1. Implementing Rules: 15 5.2. Classification Rules: 15 6. Considerations on placing on the market and conformity asse ssment of MDSW 16 6.1. Option 1: as a medical device in its own right 16 6.2. Option 2: as an integral component/part of a device 17 7. Modules 17 8. Consideration of changes to an MDSW 18 9. Annex I: Illustrative examples of qualifica tion of software used in the healthcare environment 18 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 24 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 26 12. Annex IV – Classification examples 27 Page 3 of 28 1. Scope and purpose of this document This document, which primarily targets medical software manufacturers, defines the criteria for the qualification of software falling within the scope of the new medical devices regulations1 and provides guidance on the application of classification criteria for software under Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR.2 The guidance also provides information related to placing on the market. The classification criteria (classification rules) are set out in Annex VIII of the Medical Devices Regulation (EU) 2017/745 (MDR) and Annex VIII of the In vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR). The criteria specified in this document shall also apply to applications (commonly referred to as apps), may they be operating on a mobile phone, in the cloud or on other platforms. 2. Definitions and abbreviations Intended purpose : According to Regulation (EU) 2017/745 – MDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation;3 According to Regulation (EU) 2017/746 – IVDR, “Intended purpose” means the use for which a device is intended according to the data supplied by the manufacturer on the label, in the instructions for use or in promotional or sales materials or statements or as specified by the manufacturer in the performance evaluation; 4 Accessory: According to Regulation (EU) 2017/745 – MDR, “Acc essory for a medical device” means an article which, whilst not being itself a medical device, is intended by its manufacturer to be used together with one or several particular medical device(s) to specifically enable the medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the medical device(s) in terms of its/their intended purpose(s); 5 According to Regulation (EU) 2017/746 – IVDR, “Accessory for an in vitro diagnostic medical device” means an article which, whilst not being itself an in vitro diagnostic medical device, is intended by its manufacturer to be used together with one or several particular in vitro diagnostic medical device(s) to specifically enable the in vitro diagnostic medical device(s) to be used in accordance with its/their intended purpose(s) or to specifically and directly assist the medical functionality of the in vitro diagnostic medical device(s) in terms of its/their intended purpose(s);6 Note: Software accessory may be driving or influencing the use of a medical device. Note: Manufacturers must describe in the technical documentation accessories of a medical device or an in vitro diagnostic medical device which are intended to be used in combination with it; and in case 1 The use of “The Medical Devices Regulations” from here on out refers to both Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR. 2 It shall be noted that the term “standalone software” which was used in the text of the medical device directives, is no longer used in the context of the Medical Device Regulation. The rationale of the change is that software should be qualified and classified depending on its intended purpose uniquely, regardless of its location. 3 Article 2(12) of Regulation (EU) 2017/745 – MDR 4 Article 2(12) of Regulation (EU) 2017/746 – IVDR 5 Article 2(2) of Regulation (EU) 2017/745 – MDR 6 Article 2(4) of Regulation (EU) 2017/746 – IVDR Page 4 of 28 of medical devices they must include in the instructions for use information allowing the selection of the corresponding software and accessories.7 Placing on the market: According to Regulation (EU) 2017/745 – MDR, “Placing on the market” means the first making available of a device, other than an investigational device, on the Union market; 8 According to Regulation (EU) 2017/746 – IVDR, “Placing on the market” means the first making available of a device, other than a device for performance study, on the Union market;9 Putting into service: According to Regulation (EU) 2017/745 – MDR, “Put ting into service” means the stage at which a device, other than an investigational device, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose;10 According to Regulation (EU) 2017/746 – IVDR, “Putti ng into service” means the stage at which a device, other than a device for performance study, has been made available to the final user as being ready for use on the Union market for the first time for its intended purpose; 11 Medical device : “medical device” means any instrument, apparatus, appliance, software , implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, - investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, - providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means. The following products shall also be deemed to be medical devices: - devices for the control or support of conception; - products specifically intended for the cleaning, disinfection or sterilisation of devices as referred to in Article 1(4) and of those referred to in the first paragraph of this point.12 Active medical device: “active device” means any device, the operation of which depends on a source of energy other than that generated by the human body for that purpose, or by gravity, and which acts by changing the density of or converting that energy. Devices intended to transmit energy, substances or other elements between an active device and the patient, without any significant change, shall not be deemed to be active devices. Software shall also be deemed to be an active device; 13 7 Article 32.2(c), Annex I, Chapter III Section 23.4(f), Annex II Section 1.1(h) of Regulation (EU) 2017/745 – MDRArticle 29.2(c) and Annex II Section 1.1(m) of Regulation (EU) 2017/746 – IVDR 8 Article 2(28) of Regulation (EU) 2017/745 – MDR 9 Article 2(21) of Regulation (EU) 2017/746 – IVDR 10 Article 2(29) of Regulation (EU) 2017/745 – MDR 11 Article 2(22) of Regulation (EU) 2017/746 – IVDR 12 Article 2(1) of Regulation (EU) 2017/745 – MDR 13 Article 2(4) of Regulation (EU) 2017/745 – MDR Page 5 of 28 In vitro diagnostic medical device: “In vitro diagnostic medical device” means any medical device which is a reagent, reagent product, calibrator, control material, kit, instru ment, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following: - concerning a physiological or pathological process or state; - concerning congenital physical or mental impairments; - concerning the predisposition to a medical condition or a disease; - to determine the safety and compatibility with potential recipients; - to predict treatment response or reactions; - to define or monitoring therapeutic measures. Specimen receptacles shall also be deemed to be in vitro diagnostic medical devices;14 Software: For the purpose of this guidance, “software” is defined as a set of instructions that processes input data and creates output data. Input data : Any data provided to software in order to obtain ou tput data after computation of this data can be considered as input data. Input data examples (non-exhaustive): - Data given through the use of a human data-input device such as a keyboard, mouse, stylus, or touch screen; - Data given through speech recognition; - Digital document: formatted for general purpose such as Word file or pdf file or jpeg image, formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document. Note that digital documents have to be differentiated from software able to read such documents; - Data received from/transmitted by devices. Output data : Any data produced by a software can be considered as an output data. Output data examples (non- exhaustive): - Screen display data (such as layout with number, characters, picture, graphics, etc.); - Print data (such as layout with number, characters, picture, graphics, etc.); - Audio data; - Digital document (formatted for a general purpose such as Word file or pdf file or jpeg image, or formatted for medical purpose such as DICOM file or ECG records or Electronic Health Record, unformatted document). - Haptic buzzing as an alternative to audio sound Software driving or influencing the use of a device Software which is intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: (a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device (b) or supply output related to the (hardware) functioning of that device Note: Software driving or influencing the use of a (hardware) medical device may be qualified as an accessory for a (hardware) medical device. 14 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 6 of 28 Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination, for a purpose as specified in the definition of a “medical device” in the medical devices regulation15 or in vitro diagnostic medical devices regulation.16 3. Qualification 3.1. Introduction to qualification criteria The purpose of this section is to clarify what software is in itself subject to the medical devices regulations. Software must have a medical purpose on its own to be qualified as a medical device software (MDSW). It should be noted that the intended purpose as described by the manufacturer of the software is relevant for the qualification and classification of any device. In order to be qualified as medical device software, the product must first fulfil the definition of software according to this guidance and the definiti on of a medical device according to Article 2(1) of Regulation (EU) 2017/745 – MDR. To be qualified as an in vitro diagnostic medical device software, the product must additionally fulfil the definition of an in vitro diagnostic medical device according to Article 2(2) of Regulati on (EU) 2017/746 – IVDR. Where a given product does not fall under the definition of a medical device, or is excluded by the scope of the Medical Devices Regulations, other Community and/or national legislation may be applicable. Software that does not meet th e definition of a medical device or an in vitro diagnostic medical device (i.e. software that is not MDSW) but is intended by the manufacturer to be an accessory for a medical device, or an in vitro diagnostic medical device, falls respectively under the scope of the Regulation (EU) 2017/745 – MDR or Regulation (EU) 2017/746 – IVDR. Software can directly control a (hardware) medical device (e.g. radiotherapy treatment software), can provide immediate decision-triggering information (e .g. blood glucose meter software), or can provide support for healthcare professionals (e.g. ECG interpretation software). It is important to clarify that not all software used within healthcare is qualified as a medical device. For example, “Simple search”, which refers to the retrieval of records by matching record metadata against record search criteria or to the retrieval of information does not qualify as medical device software (e.g. library functions). However, software which is intended to process, an alyse, create or modify medical information may be qualified as a medical device software if the creation or modification of that information is governed by a medical intended purpose. For example, the software which alters the representation of data for a medical purpose would qualify as a medical device software. (e.g. “searching image for findings that support a clinical hypothesis as to th e diagnosis or evolution of therapy” or “software which locally amplifies the contrast of the finding on an image display so that it serves as a decision support or suggests an action to be taken by the user”). However, altering the representation of data for embellishment/cosmetic or compatibility purposes does not readily qualify the software as medical device software. Software intended for non-medical purposes (excludi ng MDR Annex XVI devices), such as invoicing or staff planning, does not qualify as a medical device software. These software do not fall under the Medical Devices Regulations. 15 Article 2(1) of Regulation (EU) 2017/745 – MDR 16 Article 2(2) of Regulation (EU) 2017/746 – IVDR Page 7 of 28 A task such as e-mailing, web or voice messaging, data parsing, word processing, and back-up is by itself not considered as having a medical purpose. Additionally, software may run on different operating systems or in virtual environments. These operating systems or virtual environments do not impact the qualification criteria. It must be highlighted that the risk of harm to patients, users of the software, or any other person, related to the use of the software within healthcare, including a possible malfunction is not a criterion on whether the software qualifies as a medical device. 3.2. Medical Device Software (MDSW) Medical device software is software that is intended to be used, alone or in combination , for a purpose as specified in the definition of a “medical device” in the MDR or IVDR, regardless of whether the software is independent or driving or influencing the use of a device. Note 1: MDSW may be independent , by having its own intended medical purpose and thus meeting the definition of a medical device or in vitro diagnostic medical device on its own (i.e. alone ) MDSW that uses maternal parameters such as ag e, concentration of serum markers and information obtained through foetal ultrasound examination for evaluating the risk of trisomy 21. MDSW that receives measurements from transrectal ultrasound findings, age, and in vitro diagnostic instruments and calculates a patient’s risk of developing prostate cancer. Mass Spectrometry MDSW intended to analyse LC-MS/MS data to be used for microorganism identification and detection of antibiotic resistance. MDSW smartwatch app, which is intended to send alarm notifications to the user and/or health practitioner when it recognises irregular heartbeats for the purpose of detecting cardiac arrhythmia. Note 2: If the software drives or influences a (hardware) medical device and also has a medical purpose, then it is qualified as a MDSW Melanoma image analysis software intended to drive a near-infrared laser light scanner. MDSW intended to measure and transmit blood glucose levels, calculate insulin dose required and drive the insulin pump to administer the calculated dosage (closed loop insulin delivery system). Note 3: Software may be qualified as MDSW regardless of its location (e.g. operating in the cloud, on a computer, on a mobile phone, or as an additional functionality on a hardware medical device). MDSW that is intended to operate a point of care test from a remote location. Note 4: MDSW may be intended to be used by healthcare professionals or laypersons (e.g. patients or other users).17, 18 MDSW that provides insulin dose recommendations to a patient regardless of the method of delivery of the prescribed dose, whether via an insulin pump, insulin pen or insulin syringe. 17 Where MDSW is intended to be used by a lay person, the manufacturer shall apply safety and performance requirements outlined in MDR Annex I. 22 and 23.4 (w); or IVDR Annex I. 9.4 and 20.4.2. 18 MDSW which can be considered as an IVD for self-testing shall be considered as a device intended to be used by laypersons. Page 8 of 28 Manufacturers must ensure that all regulatory requirements for placing on the market and conformity assessment have been fulfilled. As set out in Article 7 of MDR and IVDR, this also entails that any claims, relating to the intended medical purpose of their MDSW are supported by clinical evidence. If this is not the case, the software would not meet the requirements of the regulations and therefore may not be CE marked as a medical device, nor present said claims. 3.3. ‘Software driving or influencing the use of a medical device’ Is software intended to drive or influence the use of a (hardware) medical device and does not have or perform a medical purpose on its own , nor does it create information on its own for one or more of the medical purposes described in the definition of a medical device or an in vitro diagnostic medical device. This software can, but is not limited to: a) operate, modify the state of, or control the device either through an interface (e.g., software, hardware) or via the operator of this device b) or supply output related to the (hardware) functioning of that device Note: Software that is driving or influencing the use of a medical device is covered by the medical devices regulations either as a part/component of a device or as an accessory for a medical device. (refer to Figure 2, box 2). Software that is intended to be used to operate a clinical chemistry analyser. Software with built-in electronic controls for IVD quality control procedures. These quality control procedures are intended to provide users with assurance that the device is performing within specifications. Decision steps for qualification of software as MDSW (Figure 1) Decision step 1 : if the product is software according to Section 2 (Definitions and Abbreviations) of this guidance, then it may be a medical device software, proceed to decision step 2; if the product is not software according to the definition of this guidance, then it is not covered by this guidance but may still be covered by the Medical Devices Regulations. Decision step 2 : if the product is an MDR Annex XVI device, or is an accessory for a medical device19, or is software driving or influencing the use of a medical device, then it must be considered as part of that device in its regulatory process or independently if it is an accessory. If it is not, proceed to decision step 3. Decision step 3 : if the software does perform an action on data, or performs an action beyond storage, archival, communication20, simple search, lossless compression (i.e. using a compression procedure that allows the exact reconstruction of the original data) then it may be a medical device software (Refer to section 3.1 for more guidance on these software functions) proceed to step 4. Decision step 4 : is the action for the benefit of individual patients? Examples of software which are not considered as being for the benefit of individual patients are those which are intended only to aggregate population data, provide generic diagnostic or treatment pathways (not directed to individual patients), scientific literature, medical atlases, models and templates as well as software intended only for epidemiological studies or registers. Decision step 5: Is the software medical device software (MDSW) according to the definition of this guidance? 19 According to Article 2(2) of the Medical Devices Regulation or In Vitro Diagnostic Medical Devices Regulation. 20 Communication: The flow of information from one point, known as the source, to another, the receiver; Source: IEEE 610.10-1994. Page 9 of 28 Page 10 of 28 3.4. Qualification criteria of MDSW as an in vitro diagnostic medical device Medical Device Software (MDSW) fulfilling the definition of an in vitro diagnostic medical device falls under the in vitro diagnostic medical devices Regulation (EU) 2017/746. Provided that MDSW is intended specifically by its manufacturer to be used together with an in vitro diagnostic medical device to enable it to be used in accordance with its in tended purpose, this MDSW falls under the scope of the in vitro diagnostic medical devices regulation and shall be treated as an In Vitro Diagnostic MDSW (IVD MDSW) in its own right. In cases when software is driving or influencing the use of a (hardware) device, the software should be considered as falling under the respective regulation of the driven or influenced (hardware) device. Software that analyses and interprets the optical density delivered by an ELISA reader, line or spot pattern of a blot. Such software takes raw data outputs and use clinical algorithms for diagnostic and/or prognostic purposes, in which case it qualifies as IVD MDSW. Decision steps for qualification of MDSW as either a medical device or an in vitro diagnostic medical device (Figure 2) Decision Step 1: Does the Medical Device Software (MDSW) provide information within the scope of the in vitro diagnostic medical device definition? MDSW which provides information according to Re gulation (EU) 2017/746 – IVDR Article 2(2) (a) to (f) should qualify as In Vitro Diagnostic Medical Device Software (IVD MDSW) (a) concerning a physiological or pathological process or state (by investigation of this process or state); or (b) concerning congenital physical or mental impairments (c) concerning the predisposition to a medical condition or a disease; (d) to determine the safety and compatibility with potential recipients; (e) to predict treatment response or reactions; (f) to define or monitoring therapeutic measures. A MDSW which falls under the definition set out in EU Article 2 (1) of Regulation (EU) 2017/745 – MDR should qualify as Medical Device Software (MD MDSW). In specific, the following considerations should apply on the prov ision of information by software on: (g) diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease (h) diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability, (i) investigation, replacement or modification of the anatomy or of a physiological or pathological process or state, (j) control or support of conception; (k) products specifically intended for the cleaning, disinfection or sterilization of devices as referred to in Article 1(4) and Annex XVI products. Decision Step 2 : Does the MDSW create information based on data obtained by in vitro diagnostic medical devices only? If the information provided is based on data obtained solely from in vitro diagnostic medical devices, then the software is an in vitro diagnostic medical device and is therefore an IVD MDSW. If the data analysed is obtained from a combination of both in vitro diagnostic medical devices and medical devices, proceed to step 3. Page 11 of 28 Decision Step 3 : Is the intended purpose substantially driven by data sources coming from in vitro diagnostic medical devices? If yes, then the appli cable legislation is Regulation (EU) 2017/746. If the intended purpose is substantially driven by data sources coming from medical devices, then the applicable legislation is Regulation (EU) 2017/745. In the condition where the intended purpose of the MDSW output data fulfils both the medical device and in vitro diagnostic medical device definitions set out in the MDR and IVDR (refer to Decision Step 2), a weighting of the data sources based on the significance of the information21 in relation to fulfilling the intended purpose should be conducted to aid the manufacturer in determining which regulation to apply. Annex II of this guidance offers some prescrip tive examples of how such a weighting may be performed. 21 A qualitative approach is intended to drive the weighting of data. The weighing aims to assess the contribution of each data towards achieving the result. Page 12 of 28 4. Classification of MDSW per MDR 2017/745 4.1. Implementing Rules All implementing rules in Annex VIII of Regulation (EU) 2017/745 shall be considered. Special considerations on Implementing Rule 3.3 and 3.5: The first sentence of implementing rule 3.3 of Annex VIII clarifies the regime applicable to software driving or influencing the use of a device: ‘Software, which drives or influences the use of a device, shall fall within the same class as the device’ The second sentence of implementing rule 3.3 of Annex VIII clarifies that the regime applicable to Independent MDSW: ‘If software is independent of any other device, it shall be classified in its own right’ This rule should also be considered at least as an orientation for finding the correct (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. Therefore, Medical Device Software that both achieves its own intended purpose and also drives or influences the use of a (hardware) device for a medical purpose is classified on its own, based on the intended purpose achieved. In such a case, however, the risk class shall not be lower than the risk class of the hardware medical device. Implementing rule 3.5 of Annex VIII is relevant for all devices and states that ‘If several rules, or if, within the same rule, seve ral sub-rules, apply to the same device based on the device’s intended purpose, the strictest rule and sub-rule resulting in higher classification will apply’ Melanoma image analysis software intended to be used with a near-infrared laser light scanner , which is considered class IIa per Rule 10. The software “drives or influences the use of” the near- infrared laser light scanner as it is intended to take control of the scanner by letting it execute proprietary multi-exposure programs for the detection of melanoma. As such, implementing rule 3.3 applies. However, Rule 11 would also apply based on the intended medical purpose of the software e.g. cancer diagnosis. The MDSW would be classified as class III based on Rule 11 (see section Classification Rules) and per implementing rule 3.5 of Annex VIII. 4.2. Classification Rules Rules 9, 10 and 12 mainly categorise the risks related to the exchange of energy/substances between the body and diagnostic or therapeutic active devices, taking into account the different healthcare situations (condition of patients). MDSW, in the majority of cases, does not (directly) relate to such risks. It relates to the consequences of indirect harm from failure to provide correct information. Therefore, in line with Recital 5 of the Medical Device Regulation and international guidance from the IMDRF (International Medical Device Regulators Forum)22, Rule 11 was introduced into the MDR and is intended to address the risks related to the information provided by an active device, such as MDSW. Rule 11, in particular, describes and categorises the significance of the information provided by the active device to the healthcare decision (patient management) in combination with the healthcare situation (patient condition). As software is defined as an active device, for the classification of active (hardware) devices, which also includes MDSW providing information for patient management, Rules 9, 10, 11, 12, 13, 15 and 22 IMDRF is a voluntary group of medical device regulators from around the world who have come together to build on the strong foundational work of the Global Harmonization Task Force on Medical Devices (GHTF) and aims to accelerate international medical device regulatory harmonization and convergence. Page 13 of 28 22 of Annex VIII MDR 2017/ 745 should be considered. In line with implementation rule 3.5, the strictest rule or sub-rule should hence apply. MDSW should be classified in the same way, rega rdless of the software's location or the type of interconnection between the software and a (hardware) device. 4.2.1. Rule 11 – Software for decisions with diagnosis or therapeutic purposes or software intended to monitor physiological processes Rule 11 states: Software intended to provide information which is used to take decisions with diagnosis or therapeutic purposes is classified as class IIa, except if such decisions have an impact that may cause: death or an irreversible deterioration of a person's state of health, in which case it is in class III; or a serious deterioration of a person's state of health or a surgical intervention, in which case it is classified as class IIb. Software intended to monitor physiological processes is classified as class IIa, except if it is intended for monitoring of vital physiological parameters, where the nature of variations of those parameters is such that it could result in immediate danger to the patient, in which case it is classified as class IIb. All other software is classified as class I. The text of Rule 11 can be divided into what are essentially three sub-rules that are applied depending on the intended use/purpose of the MDSW: 11a: (3 first paragraphs of Rule 11) intended to provide information which is used to take decisions with diagnostic or therapeutic purposes; 11b: (Paragraph 4 of Rule 11) intended to monitor physiological processes or parameters; 11c: (Paragraph 5 of Rule 11) all other uses. Sub-rule 11a): The wording “intended to provide information which is used to take decisions with diagnosis or therapeutic purposes” describes, in very general terms, the “mode of action” which is characteristic of all MDSW. Therefore, this sub-rule is generall y applicable to all MDSW (excluding those MDSW that have no medical purpose). Sub-rule 11a), states that MDSW (which is intende d to provide information which is used to take decisions with diagnosis or therapeutic purposes) is classified as class IIa. There are two exceptions from sub-rule 11a) that ar e mainly intended to apply a risk classification based on the significance of the provided information and the potential impact of an (incorrect) decision made using information from the MDSW.23 Accordingly, MDSW that is intended to provide information which is used to take decisions with diagnosis and therapeutic purposes, is at a higher risk class where such decisions, if based on incorrect information from the MDSW, are reasonably likely to have an impact that may cause: i. death or an irreversible deterioration of a person's state of health, in which case it is in class III; ii. serious deterioration of a person's state of health or surgical intervention, in which case it is classified as class IIb. 23 Compare IMDRF/SaMD WG/N12FINAL:2014 which states that there are two major factors that provide adequate description of the intended use of software: A. - Significance of the information provided by the software to the healthcare decision and B. - State of the healthcare situation or patient condition. Page 14 of 28 The MDR contains several references to “serious deterioration of a person’s state of health” and “surgical intervention”, notably in the vigilance or clinical investigation context. Further horizontal guidance could be provided in the future and will be available at: https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en Rule 11 was also introduced to mirror the regulatory guidance developed at international level and notably in the context of the International Medi cal Device Regulators Forum (IMDRF). The IMDRF framework for risk categorisation of software as a medical device (SaMD) (“IMDRF Risk Framework”) categorises the risk of software based on the combination of the significance of the information provided by the software to the healthcare decision and the healthcare situation or patient condition. IMDRF also developed a table for assisting operators in identifying the appropriate risk category for their own product. Such a table could provide operators placing MDSW on the EU market with some useful indications on the risk class applicable to their products as a result of the application of Rule 11 of the MDR. For this purpose, a table is provided in Annex III to this document which lists the IMDRF risk categories and the possible corresponding MDR risk classes accor ding to Rule 11 of the MDR. It must be noted that this table does not take into account MDSW which is Class I. Sub-rule 11b): MDSW that is intended to monitor physiological processes will, under most circumstances, provide “information which is used to take decisions with diagnosis or therapeutic purposes and hence fall under sub-rule 11a. Sub-rule 11b) should therefore be considered as a specific rule for MDSW intended only for monitoring purposes. Sub-rule 11b) was introduced to ensure that MDSW which has the same intended purpose as (hardware) devices which would fall under rule 10, third indent, are in the same risk class. However, this sub rule applies to MDSW intended to be used for monitoring any/all physiological processes and not just vital physiological processes (equivalent to rule 10, third indent). Vital physiological processes and parameters include, for example, respiration, heart rate, cerebral functions, blood gases, blood pressure and body temperature. Sub-rule 11c): Sub-rule 11c) implies that all other MDSW is classified as class I. 4.2.2. Rule 12 – Active devices intended to administer and/or remove substances As software devices cannot physically administer and/or remove substances, please refer to the implementation rule 3.3 of Annex VIII for MDSW covered by this rule. 4.2.3. Rule 13 – All other active devices Taking into consideration all implementing and classification rules applicable to active devices, if no other rule applies, all other active devices are class I. 24 4.2.4. Rule 15 - Devices used for contraception Rule 15 applies to devices used for contraception or prevention of the transmission of sexually transmitted diseases. Software used for contraception will be classified as class IIb. 24 Specific implementation or classification rules for active Annex XVI devices (which might also include software) are expected to be provided together with the relevant Common Specifications for those devices. Page 15 of 28 4.2.5. Rule 22 – Closed loop systems Active therapeutic devices with an integrated or incorporated diagnostic function which significantly determines the patient management by the device, such as closed loop systems or automated external defibrillators, are classified as class III. See also implementing rule 3.3 fo r MDSW covered by this rule. Further horizontal Guidance on the application of MD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . This is expected to provide useful orientation in relation to the application of non-software specific classification rules. 5. Classification and implementing rules per IVDR 2017/746 5.1. Implementing Rules: All implementing rules in Annex VIII of Regulation (EU) 2017/746 shall be considered. Special considerations on Implementing Rule 1.4 and 1.9: Implementing rule 1.4 is only applicable for software which drives or influences the use of an in vitro diagnostic medical device. This rule should also be considered at least as an orientation for finding the right (minimum) classification of software which is placed on the market in combination with a (hardware) medical device. According to the second sentence of implementing rule 1.4 , if the software is independent of any other device, it shall be classified in its own right. Examples for applying this implementing rule under the in vitro diagnostic medical devices regulation:  Software that is exclusively intended to drive or influence the use of an instrument intended by the manufacturer specifically to be used for in vitro diagnostic procedures is classified in the same class as the instrument.  A software that is intended to operate (driving) a C-reactive protein (CRP) measuring analyser from a remote location is classified in the same class as the analyser i.e. if the analyser is a classified as class A then the software operating the analyser falls into Class A.  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring; this is an independent IVD MDSW and is classified on its own. Implementing rule 1.9 states that if several classification rules apply to the same device based on the devices’ intended purpose, the rule resulting in higher classification will apply. To classify In Vitro Diagnostic Medical Device Software (IVD MDSW) which is independent of any other device, see the MDCG Guidance on Classification of IVDs when available at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en . 5.2. Classification Rules: In determining the proper classification of MDSW under the IVDR, the manufacturer shall consider all classification and implementing rules of Annex VIII of the IVD Regulation (EU) 2017/746. As spelled out by Implementing Rule 1.1 of Annex VIII of Regulation (EU) 2017/746, the application of the classification rules shall be governed by the intended purpose of the MDSW. Page 16 of 28 Guidance on the application of the IVD classification and implementing rules can be found at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en25 Examples for the classification of MDSW under the IVDR:  Software intended to be installed on a fully automated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA, intended to screen for and diagnose diabetes and monitor diabetic patients, should be in class C per Rule 3(k).  Software within a PAP stain automated cervical cytology screening system, intended to classify the PAP cervical smear as either normal or suspicious, should be in class C per Rule 3(h).  Software for the interpretatio n of automated readings of line immunoassay for the confirmation and determination of antibodie s to HIV-1, HIV-1 group O and HIV-2 in human serum and plasma, should be in class D per Rule 1.  Software that uses maternal parameters such as age, concentration of serum markers and information obtained through foetal ultrasound ex amination for evaluating the risk of trisomy 21, should be in class C per Rule 3(l). Classification examples in Annex IV are provided for guidance purposes and aim to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules must also be considered. 6. Considerations on placing on the market and conformity assessment of MDSW The type of interconnection between the MDSW and the device (e.g. embedded systems, wires, Wi-Fi, Bluetooth) does not affect the qualification of the software as a device under the MDR and IVDR (e.g. whether the software is incorporated in a device or is at a different location). However, MDSW can be placed on the market in two different ways: as a medical device or in-vitro diagnostic medical device in its own right or as an integral component or part of a hardware device. 6.1. Option 1: as a medical d evice in its own right MDSW may be placed on the market or put into service in its own right.  MDSW intended to be installed on a fully aut omated enzyme-linked immunosorbent assay (ELISA) analyser, and intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW app that provides a 10-year risk of cardiovascular disease from data input by a lay user.  MDSW app that calculates anticoagulant dosage fo r patients in oral anticoagulant therapy, from INR test results input by IVD instrume nts and other manually entered patient data.  MDSW app that analyses digital images of stained HEp-2 cell substrates from a microscope, for detecting antinuclear antibody (ANA) patterns to guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. Conformity assessment: 25 Please note that at the time of the adoption of this document, the referenced Guidance on the application of IVDR classification and implementing rules was under finalisation. Page 17 of 28 MDSW placed on the market as a device or put into service in its own right shall undergo an appropriate regulatory process that shall take into consideration the qualification, classification and intended purpose of the MDSW. 6.2. Option 2: as an integral component/part of a device MDSW may be placed on the market or put into service as an integral component/part of a device.  MDSW contained within a blood gas analyser that enables a user to run tests on the instrument.  MDSW that is part of a handheld hardware device intended for near-patient testing (POCT: point of care testing) for the determinat ion of the blood glucose concentration.  A fully automated enzyme-linked immunosorb ent assay (ELISA) analyser, composed of hardware and MDSW, intended to determine the Human HbA1c concentration in serum from the results obtained with a Human HbA1c ELISA.  MDSW that is part of a pulse oximeter intended to digitally filter the noise from low perfusion performance and motion artefacts, to calculate the ratio of red light/infrared light and to use a lookup table based on Beer-Lambert law to convert the ratio into the oxygen saturation in a person’s blood (SpO2). Conformity assessment: MDSW that is placed on the market or put into se rvice solely as an integral component/part of a (hardware) device may not have to undergo its own regulatory process. 26 In this case, the MDSW shall be assessed through the regulatory process applied to the device as a whole, as it is placed on the market. Applying the classification rules to these hardware devices, which is de-facto a combination of the hardware device and the MDSW, requires careful consideration of the intended purpose of the MDSW. This must also be analysed when later changes to the MDSW are done. Note: MDSW could be independent under both scenarios described in 6.1 and 6.2, despite the presentation in which it is placed on the market. 7. Modules Some medical device software may be segregated into a number of applications where each of these applications is correlated with a module. Some of these modules have a medical purpose, some not. Such modules may be intended to cover many needs, e.g.:  Collect and maintain administrative patient data;  Keep on file the medical history of the patient;  Invoicing and other accounting functions;  Provide a link to the social security system for reimbursement;  Provide a link to drug prescription systems (with possible link to drug dispensing outlets);  Provide expert system assistance for medical decision making (e.g. radiotherapy dose planner). 26 Note: MDSW that is intended specifically to replace a part or com ponent of a device and that significantly changes the performance or safety characteristics or the intended purpose of the device shall be considered to be a device and shall meet the requirements laid down in this Regulation (see Article 23.2 (2)). Page 18 of 28 This raises the issue as to whether the whole product can be CE marked when not all applications have a medical purpose. Computer programmes used in healthcare can have applications which consist of both medical device and non-medical device modules. The modules which are subject to the Medical Devices Regulations (figure 1 and 2) must comply with the requirements of the medical device regulations and must carry the CE marking. The non-medical device modules are not subject to the requirements for medical devices. It is the obligation of the manufacturer to identify the boundaries and the interfaces of the different modules. The boundaries of the modules which are subject to the medical device regulations should be clearly identified by the manufacturer based on the intended use. If the modules which are subject to the medical device regulations are intended for use in combination with other modules of the whole software stru cture, other devices or equipment, the whole combination, including the connection system, must be safe and must not impair the specified performances of the modules which are subject to the medical device regulations. 27 8. Consideration of changes to an MDSW Manufacturers shall evaluate the potential impact of any changes to the function, intended use, essential design, and manufacturing characteristics on the software’s qualification as MDSW and its classification (including the classification of the combination of the MDSW with another medical device). It is to be noted that a change to or the addition of functionality to a software may lead it to be qualified as MDSW, or a revision of the classificati on of the MDSW. Similarly, a module that is added to a software might be qualified as a MDSW on its own. When determining the risk class of a combinati on of a modified MDSW and a medical device, the intended purpose and functionality of that (new) combination must be considered. Note: For all MDSW, the manufacturer shall ensure safety and performance throughout the lifecycle of the software, through a continuous process of clinical and/or performance evaluation and risk management. 9. Annex I: Illustrative examples of qualification of software used in the healthcare environment Software for a medical purpose is rapidly evolving. Thus, the list of examples provided below is not exhaustive. The examples have been drafted in light of today’s state of the art, in order to give the reader a better understanding of the application of the principles set out in the guideline. The Manual on borderline and classification in the Community regulatory framework for medical devices contains many examples related to qualification of software and apps, under the current 27 i.e. general safety and performance requirements 14.1 of EU MDR 2017/745 and 13.1 of EU IVDR 2017/746 Page 19 of 28 Directives28. The Manual is currently under revision for adaptation to MDRs. In light of the technological progress, further examples will be regularly published in both the Manual and in this guidance. a) Hospital Information Systems Hospital Information Systems mean, in this context, systems that support the process of patient management. Typically they are intended for patient admission, for scheduling patient appointments, for insurance and billing purposes. These Hospital Information Systems are not qualified as medical devices. However, they may be used with additional modules, as described hereafter. These modules might be qualified in their own right as medical devices. b) Decision Support Software In general, these are computer based tools which combine general medical information databases and algorithms with patient-specific data. They are intended to provide healthcare professionals and/or users with recommendations for diagnosis, prognosis, monitoring and treatment of individual patients. Based on Figure 1, they are qualified as medical devices.  Radiotherapy treatment planning systems 29 are intended to calculate the dosage of ionizing irradiation to be applied to a specific patient . They are considered to control, monitor or directly influence the source of ionizing radiation and are qualified as medical devices.  Drug planning systems (e.g. chemotherapy) are intended to calculate the drug dosage to be administered to a specific patient and therefore are qualified as medical devices.  Computer Aided Detection systems are intended to provide information that may suggest or exclude medical conditions are qualified as medical devices (MDSW). For example, such systems would be able to automatically analyse x-ray images or interpret ECGs. c) Information Systems Information Systems that are intended only to transfer, store, convert, format, archive data are not qualified as medical devices in themselves. However, they may be used with additional modules which maybe qualified in their own right as medical devices (MDSW). c.1.) Electronic Patient Record Systems Electronic patient record systems are intended to store and transfer electronic patient records. They archive all kinds of documents and data related to a specific patient. The electronic patient records should not be qualified as a medical device, i.e. an electronic patient record that simply replaces a patient’s paper file does not meet the definition of a medical device. The modules used with electronic patient record system modules that might be qualified in their own right as medical devices (MDSW) are for example:  An image viewer with functionality for diagnosis based on digital images;  A medication module 28 http://ec.europa.eu/DocsRoom/documents/12867/a ttachments/1/translations/en/renditions/native 29 See EN 62083 “Requirements for the safety and radiotherapy treatment planning systems” Page 20 of 28 c.1.1.) Clinical Information Systems – CIS / Patient Data Manag ement Systems – PDMS A CIS/PDMS is a software-based system primarily intended to store and transfer patient information generated in association with the patient’s intensive care treatment (e.g. intensive care units). Usually the system contains information such as patient identification, vital intensive care parameters and other documented clinical observations. These CIS/PDMS are not qualified as medical devices. Modules that are intended to provide additional information that contributes to diagnosis, therapy and follow-up (e.g. generate alarms) are qualified as medical devices. c.1.2.) Pre-hospital Electrocardiograph (ECG) System A system for managing pre-hospital ECG is a software-based system intended for ambulance services to store and transfer information from patients to a doctor at remote location. Usually the system contains information about patient identification, vital parameters and other documented clinical observations. These Pre-hospital Electrocardiograph (ECG) Systems are not qualified as medical devices. Modules that create and provide new patient treatment information to the paramedics or to the doctor at a remote location to start the patient’s treatment while the patient is being transported are qualified as medical devices. c.1.3.) Picture Archive Communication System (PACS) The Manual on Borderline and Classification in th e Community Regulatory Framework for Medical Devices addresses the qualification of PACS. 30 The transposition of this Directive Guidance to the Regulations is currently underway and will be published at https://ec.europa.eu/growth/sectors/medical-devices/new-regulations/guidance_en d) Communication Systems The healthcare sector uses communication systems (e.g. email systems, mobile telecommunication systems, video communication systems, paging, etc.) to transfer electronic information. Different types of messages are sent such as prescription, referrals, images, patient records, etc. Most of the communication systems handle types of messages other than medical information. This communication system is intended for general purpos es, and is used for transferring both medical and non-medical information. Communication systems are normally based on software for general purposes, and do not fall within the definition of a medical device. Communication system modules might be used with other modules that might be qualified in their own right as medical devices (MDSW). A software module generating alarms based on th e monitoring and analysis of patient specific physiological parameters is qualified as a medical device (MDSW). d.1) Telemedicine systems Telemedicine Systems are intended to allow monitoring and/or delivery of healthcare to patients at locations remote from where the healthcare professional is located. 30 https://ec.europa.eu/docsroom/documents/35582/attachments/1/translations/en/renditions/native Page 21 of 28 d.1.1.) Telesurgery Telesurgery is intended to conduct a surgical procedure from a remote location. Virtual reality technology may be used to support a remote surgeon to control a surgical robot performing the surgical procedure. Telesurgery systems should be qualified as medical devices according to Figure 2 of this document. Remote control software used in combination with telesurgery robots is a software that drives or influences the use of a medical device. Communication modules themselves are not medical devices. Other modules that are intended to influence the su rgery procedure are qualified as medical devices (MDSW). e) Web systems for monitoring of data A web system for the monitoring of clinical data typically interacts with a medical device (e.g. implanted devices or homecare devices), and uses a transmitter to send the information over the internet, a landline telephone or a mobile network. The information is collected and stored on a web server usually run by an external party who is generally the manufacturer of the system. The information can be reached by authorized health professionals or the patient through an internet connection.  Monitoring of performance of medical devices: Modules that are intended to monitor the medical performance of medical devices fall under the medical device regulations. This includes the clinical performance and failures that could affect medical performance of the device. One example of such a product is a web system for monitoring of active implants such as pacemakers or Intra Cardiac Defibrillators (ICDs).  Monitoring of non-medical performance of medical devices Modules that are intended to perform administrative monitoring of non-medical performance of medical devices do not necessarily fall under the scope of the medical devices regulations. Software for the monitoring of medical devices in hospital systems for the purpose of maintenance and repair. f) In vitro diagnostic medical device software f.1.) Laboratory Information Systems (LIS) and Work Area Managers (WAM) Laboratory Information System (LIS) and Work Area Managers (WAM) mean, in this context, systems that support the process from patient sample to patient result. Typically, they have pre- analytical functions for ordering, sorting and distribution of test samples. The main task is the management and validation of incoming information obtained from in vitro diagnostic medical device analysers connected to the system, such as calibration, quality control, product expiry and feedback (e.g. retesting of samples needed) through interconnections with various analytical instruments (technical and clinical validation). Finally the post-analytical process allows communication of laboratory results, statistics and optional reporting to external databases. The software normally supports the following functions:  Ordering of laboratory tests, samples with labels and sorting;  Technical and clinical validation, connection to analytic instruments;  Laboratory results and reports on paper, fax or electronic records that can be directly returned to e.g. the ordering clinic’s patient record;  Analytical instruments can be interfaced with Hospital Information Systems (HIS), Electronic Patient Record Systems, Infectious control databases, etc. Page 22 of 28 Note : software intended to modify the representation of available in vitro diagnostic medical device results is not considered an in vitro diagnostic medical device, e.g. basic operations of arithmetic (e.g. mean, conversion of units) and/or plotting of results in function of time, and/or a comparison of the result to the limits of acceptance set by the user. The results are available, readable and understandable without the intervention of the software. Laboratory Information Systems (LIS) and Work Area Managers (WAM) are not qualified as medical devices in themselves. However, they may be used with additional modules. These modules might be qualified in their own right as medical devices. A module whose intended purpose is to assess the criticality of tests required and to perform automatic reprioritisation of the order based on patient data is qualified as a MDSW. f.2.) Expert system MDSW which is intended to provide information within the scope of the in vitro diagnostic medical devices definition by capturing and analysing together one or multiple results obtained for one patient by means of in vitro examination of body samples (possibly combined with information from medical devices and non-medical devices).  MDSW that integrates genotype of multiple genes to predict risk a disease or medical condition developing or recurring;  MDSW that uses an algorithm to characterise viral resistances to various drugs, based on a nucleotide sequence generated by genotyping assays. This software serves to generate new information (virus resistance profile) from avai lable information on the genotype of the virus;  MDSW intended to be used in microbiology for the identification of clinical isolates and/or the detection of antimicrobial resistances. Refer to Figure 2 of this guidance if data is obtained from both in vitro diagnostic medical devices and medical devices. f.3.) Interpretation of raw data In the case where MDSW is necessary to render raw data, readable for the user, obtained from an in vitro diagnostic medical device by means of in vitro examination of body samples, this MDSW is to be considered driving or influencing the use of the in vitro diagnostic medical device when it is specifically intended to be used together with this in vitro diagnostic medical device to enable it to be used in accordance with its intended purpose. MDSW intended for the analysis and interpretatio n of enzyme-linked immunosorbent assay (ELISA) reader optical density results, line patterns or spot patterns of a blot. f.4.) Home care monitoring, wired or mobile Software intended for archiving patient result s or for transferring results obtained from in vitro diagnostic medical devices from the home environment to the healthcare provider is not an in vitro diagnostic medical device. The results are available, readable and understandable by the user without the intervention of the software. f.5.) Image Management System (IMS) An IMS is a software-based system primarily intended to be networked with digital pathology systems, e.g., whole slide scanners, scanning microscopes, as well as LIS. It does not contain controls for the direct operation of the digital pathology syst ems, and is intended to access, display, annotate, manage, store, archive and share collections of digitised patient images. IMS may be configured to Page 23 of 28 provide limited or extensive capabilities to further visualise or analyse patient images acquired from networked digital pathology systems. An IMS only used for viewing, archiving and transmitting images are not considered medical devices in themselves. However, these IMS may be used with additional modules that might be qualified in their own right as medical devices (MDSW). IMS that incorporate functions to support post-processing of images for diagnostics purposes, e.g., image processing functions which alter image data or complex quantitative functions to aid in diagnosis, are qualified as MDSW. Page 24 of 28 10. Annex II - Qualification examples of Medical Device Software (MDSW) according to Figures 1 and 2 Figure 1 - Example 1: A software module which runs on an in vitro diagnostic medical device instrument and tracks how the laboratory is performing in real-time on key operational metrics such as test volumes, turnaround times, pending tests, and quality control. Its intent is to improve a laboratory’s operations by providing real-time monitoring of performance metrics that can drive change management and continuous improvement initiatives within the lab. The software is configurable so that customers can choose the metrics on which they would like to focus. Qualification: Step 1 is concluded with a “yes” as the software is a product which uses a set of instructions (or algorithm) to process input data and create output data. Step 2 determines that the software is not an MDR Annex XVI device, nor is it an accessory for a medical device, nor a software driving or influencing the use of a medical device. Step 3 is answered “yes” since the software is doing more than storage, archival, communication or simple search of information. Step 4 is answered “no” as the software does not perform this action for the benefit of individual patients. The conclusion is that the software does not fall under the Medical Devices Regulations. This is appropriate since the software is intended to be a Laboratory Information Systems (LIS), which is not considered a medical device. Figure 2 - Example 2: MDSW intended to generate a risk score in order to trigger care processes to help reduce ICU transfers, readmissions, adverse events and length of stay. The risk score by default includes respiratory rate, heart rate, blood pressure and Sp O2, but a user can configure it to include other parameters, including in vitro diagnostic medical device results. Qualification: In decision Step 1, the MDSW can be understood to meet criteria (a), (f) and (h), it is therefore answered “yes”. Step 2 is answered with a “No” as an in vitr o diagnostic medical device result may be included in the in the calculation. Step 3 directs the significance of the medical device derived information as driving the intended purpose, re sulting in the qualification of the software as an MD MDSW (as the data received from the in vitro diagnostic medical device is not deemed decisive for the overall calculation result (output) achieved by the MDSW) Figure 2 - Example 3: A MDSW algorithm intended to provide information on the statistical predisposition for Down syndrome (Trisomy 21) and Edwards syndrome (Trisomy 18) in the first and second trimesters of pregnancy. 31 The MDSW analyses input data from various in vitro diagnostic medical device assays32 as well as, ultrasound measurements of the nasal bone or neck fold. The MDSW provides clinicians/obstetricians with a risk factor score for a foetus’s likelihood of having genetic mutations in the first or second trimester of pregnancy. The risk score suggests whether or not additional diagnostic testing is needed to confirm the genetic mutations of Trisomy 21, Trisomy 18. 33 Qualification: Step 1 can be answered “yes” as the software bears a medical purpose and fulfils the definition of MDSW. The MDSW meets criteria (c) as it provides information according to the in vitro 31 The software can also detect neural tube defects (NTD) in the second trimester as well as the risk for Patau’s syndrome (Trisomy 13). 32 AFP (LKAP, L2KAP), Unconjugated Estriol (LKUE3, L2KUE3), hCG (LKCG, L2KCG), free β-hCG (LKFB, L2KFB), PAPP A (LKPC, L2KPC) 33 or neural tube defects and Trisomy 13 Page 25 of 28 diagnostic medical devices definition. Decision step 2 is answered “no” as an imaging measurement is included in the calculation. Step 3 is answered “yes” as the intended purpose is substantially driven by in vitro diagnostic medical device data resulting in the qualification of the software as an IVD MDSW (as the data received from the in vitro diagnostic medical devices (markers) are deemed decisive for the overall calculation result (output) achieved by the MDSW). Figure 2- Example 4: A bioinformatics MDSW intended to analyse digi tal Next Generation Sequencing (NGS) raw data coming from sequenced patient’s cancer genomes. It allows the detection and visualisation of somatic genome alterations (such as substitutions, small insertions and deletions (indels), copy number alterations, and genomic rearrangements) across a selected number of genes. Additionally, it is also capable of determining genomic signatures* (such as microsatellite instability [MSI] and/or tumour mutational burden [TMB]). The types of somatic genome alterations and genomic signatures detected depend on the test chosen. The MDSW assists the user in identifying and visualising genomic alterations and is intended to identify somatic genome alterations to support diagnosis and treatment decisions. Qualification: Decision step 1 is concluded with a “yes” as the MDSW is intended for analysing congenital data to provide information on the predisposition to a medical condition or disease, thus meeting criteria (b) and (c) laid out in the decision step. As the MDSW processes data coming only from in vitro diagnostic medical devices into the calculation, then the software is qualified as an IVD MDSW according to Step 2. Page 26 of 28 11. Annex III - Usability of the IMDRF risk classification framework in the context of the MDR 34 The table below, which is intended for illustrative purposes only, may provide operators placing MDSW on the EU market with some useful indicative orientation on the risk class applicable to their products as a result of the application of Rule 11 a of the MDR. Note: MDR 2017/745 Sub-rule 11(a), point i., referr ing above to MDR class III, aligns with IMDRF risk category IV . Sub-rule 11(a), point ii.,, referring above to MDR class IIb, aligns with IMDRF risk category III products mentioned in section 7.2 of the mentioned IMDRF document. The IMDRF risk category II and IMDRF risk category I products are classified as MDR class IIa as per Rule 11. This table does not take into account MDSW which is Class I. Significance of Information provided by the MDSW to a healthcare situation related to diagnosis/therapy State of Healthcare situation or patient condition High Treat or diagnose ~ IMDRF 5.1.1 Medium Drives clinical management ~ IMDRF 5.1.2 Low Informs clinical management (everything else) Critical situation or patient condition ~ IMDRF 5.2.1 Class III Category IV.i Class IIb Category III.i Class IIa Category II.i Serious situation or patient condition ~ IMDRF 5.2.2 Class IIb Category III.ii Class IIa Category II.ii Class IIa Category I.ii Non-serious situation or patient condition (everything else) Class IIa Category II.iii Class IIa Category I.iii Class IIa Category I.i Table 1: Classification Guidance on Rule 11 34 Annex III and IV are not relevant for IVD MDSW. See sec tion 4.2 in order to classify IVD MDSW. MDCG Guidance on Classification of IVDs should also be considered. Page 27 of 28 12. Annex IV – Classification examples The examples are provided for guidance purposes only, to illustrate how a particular rule may be applied to a device. The indicated classification in the example is not a confirmation of the final classification of the device, as other rules might also be considered. Moreover, the proposed classification reflects the specific intended purpose, or the healthcare context or situation, in which the device is used as described in the example itself. Any change to the intended purpose or the healthcare context/situation in which that same device is used might result in a different risk class.  MDSW intended to perform diagnosis by means of image analysis for making treatment decisions in patients with acute stroke should be classified as class III under Rule 11(a) - IMDRF Risk Category IV.i as the healthcare situation (stroke) is critical and the significance of the information is “treat or diagnose”.  Cognitive therapy MDSW that includes a diagnostic function which is intended to feed back to the software to determine follow-up therapy , e.g. software adapts treatment of depression based on diagnostic feedback, should be in class III per Rule 22 . When a specialist determines the necessary cognitive therapy base d on the outcome provided by the MDSW, the MDSW would be classified as class IIa per Rule 11(a). - IMDRF Risk Category II.ii as the healthcare situation is serious and the significance of the information is to “drive clinical management”.  Medical devices including MDSW intended to be used for continuous surveillance of vital physiological processes in anaesthesia, intensive care or emergency care should be classified as class IIb per (Rule 11(b)) .  Medical devices, including MDSW intended to monitor physiological processes that are not considered to be vital, and devices intended to be used to obtain readings of vital physiological signals in routine check-ups incl uding monitoring at home should be classified as class IIa (Rule 11(b)).  A mobile app intended to analyse a user’s he artbeat, detect abnormalities and inform a physician accordingly should be classified as class IIb per Rule 11(a) , if the information provided by the software is intended to guide the physician in the diagnosis. - IMDRF Risk Category III.i as the information drives clinical management.  Diagnostic MDSW intended for scoring depression based on inputted data on a patient’s symptoms (e.g. mood, anxiety) should be classified as class IIb under Rule 11(a) , - (IMDRF Risk Category III.ii) as the healthcare situation (depression) is serious and the significance of the information is “diagnosis”).  Ambulatory respiratory ventilation systems MD SW intended for long-term use (e.g. at home) that alert the user/operator to any disconnection or deviation to the programmed respiratory volume should be classified as class IIb per Rule 9 .  Active devices, such as electronic thermometers and stethoscopes, which include MDSW intended for direct diagnosis may be classified as class IIa per Rule 10 , third indent since body temperature and heart rate are considered decisive information for diagnosis (implementing rule 3.7), where the nature of the variations of these parameters would not result in immediate danger to the patient.  MDSW intended to rank therapeutic suggestions for a health care professional based on patient history, imaging test results, and patient characteristics, for example, MDSW that lists and ranks all available chemotherapy options for BRCA-positive individuals, should be classified as class IIa per Rule 11(a) Page 28 of 28 - IMDRF Risk Category II.i as it informs clinical management for cancer, a critical disease.  MDSW app intended to support conception by calculating the user’s fertility status based on a validated statistical algorithm. The user inputs health data including basal body temperature (BBT) and menstruation days to track and predict ovulation. The fertility status of the current day is reflected by one of three indicator lights: red (fertile), green (infertile) or yellow (learning phase/cycle fluctuation). This MDSW app should be classified as class I per Rule 11c.

md_mfr_factsheet.pdf.txt

Factsheet for Manufacturers of Medical Devices What you need to know!MEDICAL DEVICES CHANGE OF LEGISLATION This Factsheet is aimed at manufacturers of medical devices. For a general overview of the impact of the In-Vitro Medical Devices Regulation (IVDR) on manufacturers see the Factsheet for manufacturers of in-vitro diagnostic medical devices. Refer - ences to Annexes and Articles in this factsheet refer to the MDR (2017/745/EU). The new Medical Devices Regulation (2017/745/EU) (MDR) and the In-vitro Diagnostic Medical Devices Regulation (2017/746/EU) (IVDR) bring EU legislation into line with technical advances, chang - es in medical science, and progress in law making. The new Regulations will create a robust, transparent, and sustainable regulatory framework, recognised internationally, that improves clinical safety and creates fair market access for manufacturers. In contrast to Directives, Regulations do not need to be transposed into national law. The MDR and the IVDR will therefore reduce the risks of discrepancies in inter - pretation across the EU market. Transitional periods are planned to smooth the application of the new Regulations. However, you should bear in mind that con - sultants, in-house professionals, and Notified Bodies will all get busier as the deadline draws closer. Act now to be ready on time! Medical Devices Regulation (MDR) background The MDR will replace the existing Medical Devices Directive (93/42/EEC) (MDD) and the Active Implantable Medical Devices Directive (90/385/EEC) (AIMDD). The MDR was published in May 2017, marking the start of a three-year period of transition from the MDD and the AIMDD. During the transitional period the MDR will come into force gradually, start - ing with the provisions related to the designation of Notified Bodies and the ability of manufacturers to apply for new certificates under the MDR. The transitional period will end on 26 May 2020, the “Date of Application” (DoA) of the Regulation. From that date the MDR will apply fully. 1 Internal market, Industry, Entrepreneurship and SMEs Ref. Ares(2018)3873669 - 20/07/20182To avoid market disruption and allow a smooth transition from the Directives to the Regulation, several transitional provisions are in place (Article 120). Some devices with certificates issued under the Directives (AIMDD/MDD certificates) may continue to be placed on the market until 27 May 20241, and made avail - able until 27 May 20252 . During the transition phase, products certified under the Direc - tives and products certified under the Regulation will coexist on the market. Both will have equal status under the law, and no discrimination in public tenders may take place. What has changed? In terms of their impacts on manufacturers and products, the Directives and the MDR largely share the same basic regulatory requirements. No existing requirements have been removed, but the MDR adds new requirements. Compared to the current Directives, the MDR places more em - phasis on a life-cycle approach to safety, backed up by clinical data. The MDR brings more stringent requirements for the designation of Notified Bodies, with increased control and monitoring by the national competent authorities and the Commission. The MDR reclassifies certain devices and has a wider scope. For instance, the MDR explicitly covers all devices for cleaning, sterilising or disinfecting other medical devices (Article 2.1); re - processed single-use medical devices (Article 17)3; and certain devices with no intended medical purpose (Annex XVI). The MDR also covers internet sales of medical devices and med - ical devices used for diagnostic or therapeutic services offered at a distance (Article 6). The MDR introduces a clinical evaluation consultation procedure for some Class IIb devices and for implantable Class III devices by an independent expert panel (Article 54). A new Unique Device Identification system (Article 27) will significantly enhance the traceability and the effectiveness of post-market safety-related activities. The MDR will also provide increased transparency, with infor - mation on devices and studies being made public. The new Eu - ropean Database for Medical Devices – Eudamed – will play a central role in making data available and increasing both the quantity and quality of data (Article 33). 1 For definition see Article 2 paragraph 282 2 For definition see Article 2 paragraph 27 3 Reprocessing and further use of single-use devices may only take place where permitted by national law and only in accordance with this Article. 4 EEA: European Economic Area What does this mean in practice? Scope (Article 1) The scope of the MDR has broadened, so as a manufacturer you must check your product portfolios to find out whether more of your devices fall within the scope of the Regulation compared to the Directives. Pay attention to products listed in Annex XVI, which will be covered by the Regulation once the respective Im - plementing Regulation setting out common specifications has been adopted. The list of products excluded from the scope can be found in paragraph 6. Some products that combined a medi - cal device and an in-vitro diagnostic device or a medicinal prod - uct follow specific rules (see paragraphs 7, 8, 9). It is now explicit that devices and services sold online fall under the scope of this Regulation (Article 6). Definitions (Article 2) The definition of a medical device has been slightly modified and there are more definitions of terms in the Regulation than in the Directives, in order to ensure a common understanding at EU level. Examples include: Unique Device Identifier (Definition 15), clinical data (Definition 48), clinical evidence (Definition 51), and serious incident (Definition 65). Obligations of manufacturers The obligations of the different actors and their relations are now clearly stated in the Regulation. According to Article 10, manufacturers shall have systems for risk management (paragraph 2) and quality management (paragraph 9); conduct clinical evaluations (paragraph 3); com - pile technical documentation (paragraph 4); and apply a confor - mity assessment procedure (paragraph 6). Manufacturers are also responsible for their devices once they are on the market (paragraphs 12, 13, 14). They must have systems in place to cover their financial responsibility for harm caused by defective devices (paragraph 16). Every manufacturer shall have a named person responsible for regulatory compliance (Article 15). Manufacturers of some implantable devices will have to provide an implant card for the patient (Article 18). Once they have completed all these obligations, manufacturers shall draw up a declaration of conformity (Article 19) and apply CE marking to their devices (Article 20). Manufacturers outside the EU/EEA shall have a contract with an authorised representative inside the EU/EEA4 (Article 11).3The obligations of authorised representatives (Article 11), importers (Article 13) and distributors (Article 14) are also clearly described. Risk classes of devices As a manufacturer you must check your portfolio of products to determine whether some of your devices will be reclassified or will need to be scrutinised by a Notified Body. Determining the risk class of a medical device is essential in specifying the steps required for CE marking (Article 51), especially in terms of the choice of conformity assessment procedure and clinical requirements. The MDR sets out 22 rules for determining risk classes (Annex VIII), compared to 18 rules under the Directive. You should pay special attention to rules regarding: invasive devices, surgically invasive devices and implantable devices (Section 5: Rules 5 to 8); active devices (Section 6: Rules 9 to 13, for example, soft - ware now falls under Rule 11); devices utilising tissues and cells (Rule 18); devices incorporating nanomaterials (Rule 19); and devices composed of substances (Rule 21). Notified Bodies (Chapter IV) Notified Bodies have to be designated under the new Regula - tion. They will be required to meet more stringent criteria, par - ticularly in terms of clinical competence. Notified Bodies can apply to be designated from 26 November 2017. The process of designation, which might take 12 months or more, involves assessors from different national and European authorities. This means that the first Notified Bodies designated under the new Regulation might be available by the end of 2018. The database of Notified Bodies (NANDO) can be found here. http://ec.europa.eu/growth/tools-databases/nando/ As a manufacturer you must verify whether your Notified Body will be designated under the new Regulation and whether the scope of its designation will cover all your products. You must also start working with your Notified Body to plan the timing of certification for your product portfolio, taking into account the availability of your Notified Body, the need for additional data on devices and the transitional provisions in the new Regulation. Device identification A system of unique device identifiers (UDIs) will enhance the identification (Article 27) and traceability (Article 25) of MDs. This is a completely new feature of the Regulation. Each MD – and as applicable, each package – will have a UDI composed of two parts: a device identifier (UDI-DI) specific to a device, and a production identifier (UDI-PI) to identify the unit producing the device.Manufacturers are responsible for entering the necessary data on the European database (Eudamed), which includes the UDI database, and for keeping it up to date. Conformity assessment (Chapter V Section 2) The assessment of the conformity of a device for CE marking varies according to the risk class and specific features of certain devices (Article 52). The intervention of a Notified Body is need - ed for all Class IIa, IIb and III devices, as well as some specific Class I devices (see paragraphs 7a5, b6, and c7). The different routes of assessment according to the class of the device are described in Article 52 and the Annexes IX, X, XI. In some cases manufacturers have some choice regarding the conformity as - sessment route. For certain Class III and Class IIb devices there is a new clinical evaluation consultation procedure to be carried out by an inde - pendent expert panel, based on the clinical evaluation assess - ment report of the Notified Body (Article 54). Annex I specifies the general safety and performance require - ments, while Annexes II and III specify the makeup of the tech - nical documentation. The scope of the Quality Management System (Article 10 para - graph 9) now includes clinical evaluation and post-marketing clinical follow-up (PMCF). A clinical evaluation plan must pre - cede the clinical evaluation itself (Annex XIV, Part A). Common specifications defining additional requirements may be put in place for certain devices (Article 9). Clinical requirements (Chapter VI) The new Regulation reinforces the requirements for clinical evaluation (Article 61), introducing some of the biggest changes compared to the previous regime. As under the Directives, it includes the collection of clinical data already available in the literature as well as the setting up of any necessary clinical investigations. The concept of equiva - lence with other devices for which clinical data already exists can still be used, but only in a limited number of situations, and the new rules are tighter (Article 61 paragraphs 4, 5, 6). Article 62 and Annex XV set out the new and more precise re - quirements for clinical investigations. With only certain excep - tions, implantable and Class III medical devices must now go through clinical investigations. For all Class III devices, and for Class IIb devices intended to administer a medicinal product (or remove it from the body), the manufacturer has the option to consult a group of European experts to obtain an upstream review of its intended clinical de - velopment strategy (Article 61 paragraph 2). 5 “Devices placed on the market in sterile condition, to the aspects relating to establishing, securing and maintaining sterile conditions”. 6 “Devices with a measuring function, to the aspects relating to the conformity of the devices with the metrological requirements”. 7 “Reusable surgical instruments, to the aspects relating to the reuse of the device, in particular cleaning, disinfection, sterilization, maintenance and functional testing and the related instructions for use”.4Summary of safety and clinical performance (Article 32) For Class III and implantable devices, manufacturers shall draw up a summary of their safety and clinical performance in a form that intended users (and patients, if relevant) can understand. This summary will form part of the technical documentation sent to the Notified Body Timing your transition to the new Regulation As a manufacturer, the timing of your transition to the MDR is up to you. From 26 May 2020, all new certificates will have to be delivered according to the Regulation. The certificates delivered under the Directives can be valid until their date of validity for a maximum of four years (27 May 20248 at the latest). However, in the latter case, the requirements of the new Regulation relating to post-mar - ket surveillance, market surveillance, vigilance, and the registration of economic operators and devices shall apply from the Date of Application (Article 120 paragraph 3). Class I devices (other than those that have a valid certificate under the Directive) will have to conform to the new Regulation from 26 May 2020. Class I (except sterile devices, devices with a measuring func - tion and reusable surgical instruments) and Class IIa might be easiest to start with. Classes IIb and III will be more challenging because of the more stringent requirements for clinical data. As a manufacturer, you can start now by making sure that: 1. all your products are classified appropriately; 2. all product documentation and evidence of compliance will be available in a timely fashion and conforms with the MDR; and 3. you have the necessary systems in place to handle clinical evaluation, quality management, post-market surveillance, and liability for defective devices. More information For more information on any of the above topics, please refer to the Medical Devices section on the DG GROW website. https://ec.europa.eu/growth/sectors/medical-devices_en Frequently asked questions Below you can find an extract from the FAQs of the Competent Authorities for Medical Devices. For a complete list, see: http://www.camd-europe.eu/sites/default/files/media/docu - ments/FAQ_MDR_180117_V1.0.pdf . When does the Medical Devices Regulation (MDR) apply? The MDR (EU) 2017/745 will apply from 26 May 2020 – the “Date of Application” (DoA). Some provisions of the MDR will come into force earlier (e.g. regarding Notified Bodies and the Medical Device Coordination Group). Some will apply later (e.g. regarding UDI labelling). When do the existing Directive cease to apply? In general, Directives 90/385/EEC and 93/42/EEC will be repealed on 26 May 2020 (the DoA). However, there are some exceptions, such as: • for the continued marketing of devices that comply with the Directives (see below); and • to serve as a backup in case Eudamed is not fully functional by the DoA. What is the applicable legislation up to 26 May 2020? Until the Date of Application, the laws and regulations adopted by Member States in accordance with the Directives will contin - ue to apply. However, there are some exceptions. Is it possible to place devices on the market that are compliant with the MDR prior to the DoA? Yes, you may certainly place MDR-compliant devices on the market before the end of the transitional period. This applies to devices in all risk classes, and includes, for example, cus - tom-made devices, systems and procedure packs. However, devices subject to the “clinical evaluation consultation procedure”, which covers certain devices in Classes IIb and III, may not be placed on the market before the Medical Device Coordination Group (MDCG) and the expert panels have been established. Depending on the risk class of the device, conformity assess - ment may involve an appropriate Notified Body. This require - ment may create further delays before such devices can be marketed due to the delays in the availability of appropriate Notified Bodies for all technologies. 8 There are some exceptions described in Article 120 paragraph 25As a manufacturer, which obligations of the Regulation do I need to fulfil in order to place compliant devices on the market before the DoA? You should meet as many obligations as possible, bearing in mind that the complete MDR infrastructure, including Eudamed, is unlikely to be complete before the Date of Application. Both the device and the manufacturer must comply with the MDR. You should assess the conformity of your device – a pro - cess that may require the involvement of a Notified Body. Other important points include: • Clinical evaluation • Risk management • Quality Management System (QMS) • Post-market surveillance • Technical documentation and other reports • Liability for defective devices. Until Eudamed is fully operational, some parts of the Directives will have to substitute for the corresponding requirements of the Regulation. These include the registration of devices and economic operators. A person responsible for regulatory compliance needs to be available but not necessarily registered until Eudamed is operational. Do certificates issued by Notified Bodies under the existing Directives remain valid after the DoA? Yes, AIMDD/MDD certificates will generally remain valid un - til their indicated expiry dates. This applies to all the certifi - cates commonly issued by Notified Bodies, including the EC Design- Examination Certificates, Certificates of Conformity, EC Type Examination Certificates, the EC Certificate Full Quality Assurance System, and the EC Certificate Production Quality Assurance.However, all certificates issued after 25 May 2017 will be void at the latest by 27 May 2024. After this date there will be no more valid AIMDD/MDD certificates. Is it possible to have valid MDR and AIMDD/MDD certificates in parallel until 27 May 2024? Yes. Can manufacturers still place on the market/put into service Directive-compliant devices after the end of the transition period? Yes, under certain conditions there will be an option to con - tinue placing on the market/putting into service devices that comply with the Directives until their existing certificates ex - pire. This may avoid the immediate need for a new certificate under the MDR. To use this option, all the existing certificates will have to be val - id (including, for example, the QMS), the purpose and nature of the device must not change, and you must follow the new MDR rules for registration, surveillance and vigilance. What is the “sell-off” provision about? The “sell-off” provision is intended to limit the time during which devices that are compliant with the Directives and have already been placed on the market may be made available. Any devices that are still within the supply chain and that have not reached their final user as being ready for use, for example a hospital, on 27 May 2025 are no longer marketable and must be withdrawn. Once a Directive-compliant device has been made available to the final user by the deadline, the further making available of this device is not subject to/covered by the Regulation. © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39). ISBN: 978-92-79-89634-7 DOI: 10.2873/614436 ET-03-18-102-EN-N

cnd_general_principles_en.pdf.txt

Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 1 of 13 The CND Nomenclature ‘Classificazione Nazionale Dispositivi medici’ Table of Contents 1. Background and General Principles ................................ ................................ ................................ ...... 2 2. The CND structure ................................ ................................ ................................ ................................ .. 4 Anatomic Categories – by anatomical area of use: ................................ ................................ ................... 6 Functional Categories – by intended use or clinical method: ................................ ................................ .... 6 Special Categories – by other criteria: ................................ ................................ ................................ ....... 6 Groups: the second hierarchical level ................................ ................................ ................................ ........ 7 Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) ........... 7 3. External links ................................ ................................ ................................ ................................ ........... 8 The purpose of this document is to provide information regarding the basic principles and the structure of the Italian “Classificazione Nazionale Dispositivi medici” (CND) . In March 2019, an d according to the criteri a set out by the Medical Device Coordination Group1 (MDCG) , the CND was selected as the basis for the future European M edical Device Nomenclature (EMDN ). The EMDN will support the functi oning of EUDAMED as stated by the MDCG and in accordance with Articles 23 of Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746. 1 (MDCG 2018 -2) – Future EU medical device nomenclature: Description of requirements Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 2 of 13 1. Background and General Principles2 In 2005, the Italian Ministry of Health set out that the CND would be the official Italian medical device classification and nomenclature. Since then, t he CND has been implemented not only in Italy, but also in Portugal and Greece. About 15.000 manufacturers3 from various countries have used the CND for the registration of medical devices and in vitro diagnostic medical devices in the Italian database. The distribution of manufacturers of medical devices and in vitro diagnostic medical devices per countr y is reported below in Figure 1. Fig. 1 Distribution of manufacturers of medical devices per countr y The CND nomenclature is one of the tools used in the governance of the medical device sector and is characteri sed by its refined and hierarchical structure . It aims to support the improvement of patient safety and the quality of health systems by enabling information to be communicated in a standard ised manner . Updates and maintenance of CND: 2 The principles and rules presented thereafter are the ones historically established/followed when building the CND nomenclature u p to the last update in 2018. This is without prejudice to the new rules that will govern the EMDN which will be established by th e MDCG. 3 Source NSIS: data updated on 10 August 2019 31,6% 15,2% 10,2% 9,8% 3,9% 3,6% 2,7% 2,5% 2,0% 18,5% 0,0%5,0%10,0%15,0%20,0%25,0%30,0%35,0%Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 3 of 13 The construction of the CND , its subsequent updates and maintenance have been based on three fundamental principles. A) Participative approach: For the update and maintenance of a qualitative nomenclature, highly differentiated and qualified expertise is required. As the medical device sector is acknowledged for its heterogeneity and complex ity, a broad participation of all stakeholders (economic operators and healthcare professional from NHS - at all levels of its organisation ) is essential. B) Qualified validation of proposals : Nomenclature and Classification proposals are technically validated based on assessment s of actual need . Factors taken into consideration are:  other existing nomenclature and classification systems available at international level  consumption and expense information  assessment with sector experts from the different disciplines C) Formal adoption and free public availability: The CND system , which represents the basis of the whole information system on medical devices is formally approved and thus constitutes an offici al reference, freely available to all stakeholders. More information on previous updates of the CND up to 2018 can be found in Annex I of this document. The following pr oducts are currently not included in the CND :  Medicinal products  Cosmetics products  Human blood and its derivatives;  Organs, tissues and cells of human origin, products including human tissues and cells and products derived therefrom.  Organs, tissues and cells of animal origin except medical devices manufactured using animal devitalized tissues o r devitalized products derived from animal tissue.  Individual Protection Devices Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 4 of 13 2. he CND structure The CND is characterised by its alphanumeric structure that is established in a multi -level hierarchical tree . It clusters medical devices in three main levels:  Category: the first hierarchical level  Group: the second hierarchical level  Type: the third hierarchical level (which if necessary, expands into several levels of detail (1°, 2°, 3°, 4° e 5°)) Each medical device is classified by an alphanumeric code consisting of a letter referring to the “Category”, a couple of numbers referring to the “Group” and a series of other couples of numbers referring to the “Type” (whose amount depends on the level o f detail) up to a maximum of 7 levels . Each level isidentified by: •an alphanumeric code (max 13 digits ) A ## ## ## ## ## ## Level 1: C ategoriesLevel 2: GroupsLevel from 3 to 7: TypesMedical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 5 of 13 Categories: the first hierarchical level The first hierarchical level of the CND is defined as a “Category”. There are 22 categories, each identif ied by a letter of the alphabet: Each “Category ” includes devices regulated under Directive 93/42/EEC, 90/385/EEC or 98/79/EC or following a dedicated prescription from reimbursement rules in Italy. These “categories” are used for the same specific apparatus, anatomical district or organ or as a replace ment of them (anatomical categories), or devices characterised by similar use, intended use or clinical m ethod (functional categories). Considering these criteria and the ramified tree structure with different detail level, the following Anatomic (8), Fun ctional (9) and Special (5) Categories have been defined: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 6 of 13 Anatomic Categories – by anatomic al area of use: • B – HEMATOLOGY AND HEMOTRANSFUSION DEVICES • C – CARDIOCIRCULATORY DEVICES • F – DYALISIS DEVICES • G – GASTROINTESTINAL DEVICES • N – DEVICES FOR NERVOUS AND MEDULLAR SYSTEMS • Q – DENTAL, OPHTALMOLOGIC AND ENT DEVICES • R – RESPIRATORY SISTEM AND ANAESTHESIA DEVICES • U –UROGENITAL APPARATUS DEVICES Functional Categories – by intended use or clinical method: • A – DEVICES FOR ADMINISTRATION, COLLECTING AND PICKING • D – DISINFECTANTS, ANTISEPTICS AND P ROTEOLYTICS FOR MEDICAL DEVICES (regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • H – SUTURE DEVICES • K – ENDOTHERAPY AND ELECTROSURGICAL DEVICES • L – REUSABLE SURGICAL INSTRUMENT S • M – DEVICES FOR GENERIC AND SPECIALISTIC MEDICATION • S – STERILIZATION DEVICES • T – PROTECTION DEVICES AND INCONTINENCE AIDS ( regulated by Italian Legislative Decree No. 46/97 and European Directive 93/42/EEC ) • V – MEDICAL DEVICES - VARIOUS Special Categories – by other criteria : • J – ACTIVE -IMPLANTABLE DEVICES : MDs regulated by Directive 385/90 EEC • P – IMPLANTABLE PROSTHETIC DEVICES AND OSTEOSYNTHESIS DEVICES : non-active implantable MDs • Y – SUPPORTS OR TECHNICAL AIDS FOR DISABLED PERSONS • W – IN VITRO DIAGNOSTIC DEVICES MDs regulated by Directive 98/79 EEC • Z – MEDICAL EQUIPMENT AND RELATED ACCESSORIES AND MATERIALS Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 7 of 13 Groups : the second hierarchical level The second hierarchical level s are called “Group s”. There are 146 anatomical/functional Medical Devices Gr oups 4, which represent the various differentiations that distinguish devices contained in the Categories. They are identified by two -digit nu mbers from 01 to 99 for each Category. Number “90” identifies the gr oups of devices having various characteristics that are not related to existing gro ups. Number “99” “Altri – Others” is reserved to medical d evices that are not included in already existing Groups and will be categori sed in later updates. Type: the third hierarchical level (expands into several levels of detail (1°, 2°, 3°, 4° and 5°)) The “Type” represents the third hierarchical level . If necessary, it expands into several level s of detail (1°, 2°, 3°, 4° and 5°). The group of every type includes medical devices characteri sed by a high affinity of use, intended use or s imilar clinical method. In case of doubt, the peculiar characteristics of the medical device under examination should be considered for a proper collocation or search proces s (i.e. the anatomic -functional characteristics and/or the intended use declared by the manufacture r). As explained, the term “ot hers” marked with the code “99 ”on the first detail level is suitable for devices not included i n existing types. The “99” types will be submitted for later updates. Th e code reserved to the generic term “others” must be used by users only if it is not possible to classify the medical device in existing typologies . This type is subject to continuous checks and monitoring. Regarding accessories, e very accessory follows the CND classification code of the medical device that it is associated with , according to the intended use given by the manufacturer . If an accessory can be used with multiple medical devices belonging to several group s, it must be placed in the prevalent type. 4 Updated as of the Italian Ministerial Decree of 13 March 2018. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 8 of 13 3. External links For more information, please consult the Italian Ministry website at: http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=328&area=dispositivi - medici&menu=classificazione The fo llowing documents may also be of use :  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 ( PDF format)  National Classification of Medical Devices (CND) - as modified by Ministerial Decree 13.03.2018 (XLSX format)  English translation of National Classification of Medical Devices Codes (as modified by Minister ial Decree 13.03.2018 -pdf, format).  English translation of National Classification of Medical Devices Codes (as modified by Ministerial Decree 13.03.2018 -XLSX format).  Search code and description of the CND  Search in alphabetical order Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 9 of 13 Annex I – CND updates up to 2018 The periodical updating process of the CND was schematically subdivided into four main phases:  Phase 1: Collection of proposals This phase is open to all stakeholders who submit proposals for the definition of new classifications or for the revision of existing ones.  Phase 2: Preliminary technical evaluation and elaboration of the proposal. The MoH MD Technical Team (MDTT) analyses th e collected proposals, the existing systems and the contents of the medical devices database to identify elements useful for classification.  Phase 3: “Widespread validation” of the proposal. The proposal is formally evaluated in three steps: A) the regional levels of the NHS involving clinical professionals in technical sessions B) Technical Health Committee - medical devices section of the Ministry of Health C) State - Regions Conference  Phase 4: Formal adoption of the proposal Finally, the proposal is approved by formal MoH act and published on the Italian Official journal as well as the website of the Italian MoH Most of the inputs adopted for updating purposes are listed below:  The analysis of the terminal typologies "90" and "99": Implemented and consolidated, it originates from the analysis of information within the Italian databank and consider s data from all the medical device s registered and classified in the CND terminal types with code " 90" ( - various) and "99" ( - other) of specific categories or groups identified. In fact, the classification system had already foreseen ab origine that medical devices that are not placed in a specific “typology” are classified in the generic typologies in dicated with the codes 90 and 99.  Manufacturer requests: When a manufacturer is unable to classify a medical device in an appropriate way inside the CND terminal level, a specific request for the introduction of a new CND class is required, with a communic ation to the MoH of a rationale and the technical characteristics and / or intended use that differentiate the device from the specific terminal classes already represented in the CND.  The analysis of CND coming from vigilance system: Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 10 of 13 Market surveillance and the vigilance system are part of the institutional activities of the MOH. The lack of classificatory level can emerge in order to identify products that need particular attention for public health. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 11 of 13  The analysis of consumption by the NHS: The revision of the CND made through the processing of the consumption data of the Monitoring Database is based on identification of medical devices with great economic relevance or price variability.  The analysis coming from HTA Report s: Health Technology Assessment documents are periodically published by the Ministry of Health. These reports are considered when evaluating the revision of the CND. The following principles were considered in the revision of the CND:  the number of levels in the CND structure can be inc reased up to a maximum of seven, by coherently applying the homogeneity of the classification rules and of the coding system defined for the first CND structure.  for the definition of a new CND branch the number of manufacturers manufacturing the medical devices that will be placed in the new typology of the CND should be more than 1;  significant characteristics of medical devices detected by NHS professionals should be evaluated  the proposal of relocation of medical devices placed in class 90 or 99 should be consistent.  for the definition of a new CND branch significant differences of price between similar medical devices could be considered if necessary:  for the definition of a new CND branch an assessments related to the use of medical devices is conside red (quantity and number of users in NHS); For each update proposal of the CND, the information associated to the devices registered in the Italian database were analysed and, if necessary, the information detect ed by the “Consumption Monitoring Database” were processed. Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 12 of 13 Annex II – CND VERSIONS Art. No. 57 of the Italian Law n° 289 of the 27 December 2002 stated the requirement of the establishment of a Commission on Medical Devices (CUD) as a technical advisory board to the Ministry of H ealth. The CUD has the task of defining and updating the repertoire of medical devices and classifying all medical devices in specific classes and sub -classes. The CUD d efined the first version of the Classificazione Nazionale dei Dispositivi Medici (CND) on July 2005 (Italian Ministerial Decree of 22 Sept .2005). In Vitro Diagnostic Medical Devices (regulated by European Directive No. 98/79 EEC and Italian Legislative De cree No. 332/2000) were not included in the first version of the Classification , although they belong to a class of Medical Devices. The Italian Financial Law of 2006 (Law No. 266 of the year 2005, art. 1, par. 409) established that the CND has to be appr oved by a decree of the Minister of Health in agreement with the State - Regions Conference. The CUD considered it appropriate to review and update the CND with the inclusion of in vitro diagnostic medical devices before proceeding with the State -Regions Con ference . Therefore, on 20 February 2007 , and after a revision of the classification, the Health Minister decreed the approval of the Classificazione Nazionale dei Dispositivi Medici (CND) drawn up by the CUD. The classification refers to the medical device s regulated by Italian legislative decrees N°. 507/92, N°. 46/97, N°. 332/2000 and subsequent amendments. In 28 March2013, the Italian D.P.R. n.44, replaced the Commission on Medical Devices (CUD) with the Technical Committee section F on medical devices. The Classification represented the first step towards the establishment of the Italian Repertoire of the Medical Devices. According to the art. N° 2 of The Italian Financial Law No. 266, the Technical Committee section F (previously CUD) , review the CND a nd make the necessary changes and updates. Every update is approved by a Ministerial Decree: 1. Decree of the Italian Ministry of Health (13 Mar 2008) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in th e Official Gazette - GU No. 125 of 29/05/2008. Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_2_file.pdf Medical Devices January 2020 DG Health and Food Safety Directorate Health systems, medical products and innovation Unit Medical Devices Page 13 of 13 www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_3_file.xls 2. Decree of the Italian Ministry of Health (12 Feb 2010) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.119 of 24/05/2010. Links: http://www.salute.gov.it/imgs/C_1 7_pagineAree_328_listaFile_itemName_5_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_7_file.xls 3. Decree of the Italian Ministry of Heal th (7 Oct 2011) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No.259 of 7/11/2011.Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_9_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_10 _file.xls 4. Decree of the Italian Ministry of Health (29 July 2013) regarding Modification and update of Classificazione Nazionale dei Dispositivi Medici (CND) published in the Official Gazette - GU No. 258 of 04/11/2013). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_16_file.pdf www.sa lute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_17_file.xlsx 5. Decree of the Italian Ministry of Health (8 J une 2016 ) regarding Modification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, n. 242 del 15/10/2016). 6. Decree of the Italian Ministry of Health (13 march 2018) regarding Mod ification and update of the Classificazione Nazionale dei Dispositivi Medici (CND ) published in the Official Gazette G.U. Serie Generale, No. 116 del 21/05/2018). Links: http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_15_file.pdf www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_18_file.xlsx

mdcg_2019_2_gui_udi_dev_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 1 of 3 MDCG 201 9-2 Guidance on application of UDI rules to device -part of products referred to in Article 1(8), 1(9) and 1(10) of Regulation 745/2017 February 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 2 of 3 1. Scope Article 1(8),1(9), 1(10) of the Medical Device Regulation (EU) 2017/745 (MDR) set the basic criteria to determine whether and to what extent the relevant legislation on medical devices, medicinal products, human tissue and cells apply to certain products c ontaining a medical device part. In particular, “8. Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in poin t 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation. However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament an d of the Council, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned. 9. Any device which is intende d to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal produ ct. However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned.” 10. Any device which, when placed on the market or put into service, incorporates, as an integral part, non -viable tissues or cells of human origin or their de rivatives that have an action ancillary to that of the device shall be assessed and authorised in accordance with this Regulation. In that case, the provisions for donation, procurement and testing laid down in Directive 2004/23/EC shall apply. However, if the action of those tissues or cells or their derivatives is principal and not ancillary to that of the device and the product is not governed by Regulation (EC) No 1394/2007, the product shall be governed by Directive 2004/23/EC. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned”. Medical Devices Medical Devices Coordination Group Document MDCG 201 9-2 Page 3 of 3 2. Application to UDI rules to the device part of products referred to in point 1 that are governed by the medical device Regulations EXAMPLES: - Catheters coated with heparin or an antibiotic - Soft tissue fillers incorporating local anaesthetics - Implantable infusion pump - Spacer devices for use with metered dose inhalers - Bone void filler with an antibiotic - Bone void filler with animal growth factors, where the action of the growth factors is demonstrated to be ancillary to that of the physical filler If a product referred to in point 1 is assessed and authorised in accordance with the Medical device regulations, the device part will be subject to all UDI -related obligations. 3. Application to UDI rules to the device part of combination products that do not fall under the medical device Regulations EXAMPLES: - Non-reusable autoinjectors containing a medicinal product as integral part - Nebulizers precharged with a specific medicinal product - Patches for transdermal drug delivery - Wound dressings impregnated with an antibiotic, where the primary intended purpose is to administer the antibioti c to the wound - Bone void filler with animal growth factors, where the action of the growth factors cannot be demonstrated to be ancillary to that of the physical filler In general terms, if a product referred to in point 1 is governed by the medicinal product or tissue and cell legislation, the device part is required to comply only with the relevant general safety and performance requirements set out in Annex I to the Regulation on medical devices. This cannot be interpreted as meaning that the relevant o bligations related to UDI, as laid down in Chapter III and Annex VI of the Regulation on medical devices, apply to the medical device part or the package of the relevant combination. For this reason, the medical device part is not mandatorily required to c omply with any UDI -related obligation. This also means that a UDI is not needed on the package that combines the medicinal product and the medical device1 2. 1 However, if the medical device part bears a UDI on its label, that should not be deemed as being in contrast with the applicable medical device legislation 2 For products such as prefilled syringes which are made on the b asis of a UDI direct part marked (MDR compliant) syringe it shall be noted that, while UDI rules do not apply to the device part of the integral product, the direct mark UDI on the syringe shall not be removed unless that mark compromises the safety and pe rformance of the integral product.

mdcg_2018_4_udi_core_spp_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 1 of 3 MDCG 2018 -4 Annex: UDI database Definitions/Descriptions and formats of the UDI core elements for systems or procedure packs October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission . The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 2 of 3 In accordance with Article 29(2) and Annex VI, Part B of the MDR, in the case of systems and procedure packs, the system or procedure pack producer shall provide to the UDI database the UDI -DI and all of the following information1: 1. quantity per package configuration (meaning the quantity of systems or procedure packs in a package, whenever applicable) 2. the Basic UDI -DI as referred to in Article 29 (MDR) and any additional UDI - DIs, 2a. Indication of s pecific medical purpose of the system or procedure pack 3. the manner in which the system or procedure pack is controlled (expiry date or manufacturing date, lot number, serial number), 5. name and address of the system or procedure pack producer (as indic ated on the label), 6. the SRN of the system or procedure pack producer 8. The medical device nomenclature code as provided for in Article 26 (MDR)2 9. risk class (to be intended as the highest risk class of the device components of the system or procedure pack), 10. if applicable, name or trade name, 11.A. name or, if applicable, system or procedure pack model associated with the BASIC UDI -DI in the statement drawn in accordance with Article 22.1 of the MDR 11.B. reference or catalogue number, or product n umber found on the system or procedure pack label or accompanying packaging to identify a system or procedure pack 13. additional product description, 14. if applicable, storage and/or handling conditions of the system or procedure pack (as indicated on th e label or in the instructions for use), 15. if applicable, additional trade names of the system/procedure pack, 18. labelled sterile (y/n) (meaning that the system or procedure pack in its entirety is labelled as sterile), 19. need for sterilisation before use (y/n) 22. URL for additional information, such as electronic instructions for use (optional), 23. if applicable, critical warnings or contra -indications 1 Please note that format and definition of all UDI data elements are provided at https://ec.europa.eu/docsroom/documents/28669 2 Applicability of this data element to systems and procedure packs is to be determined at the time of designation of the future EU nomenclature for medical devices (foreseen end of 2018/beginning 2019). Medical Devices Medical Devices Coordination Group Document MDCG 2018 -4 Page 3 of 3 24. status of the system or procedure pack (on the market, no longer placed on the market, recalled, field safety corrective action initiated). Whenever a label is referred to, the label of the entire system/procedure pack shall be meant, in accordance with Article 22(5) of Regulation 745/2017. ,

faq_udi_en.pdf.txt

Introduction to the new UDI system and the obligations of operators The existing regulatory framework on medical devices dates back to the 1990s and consists of three Directives. Two new Regulations (Regulation (EU) 745/2017 on medical devices and Regulation (EU) 746/2017 on In Vitro diagnostic medical devices) were adopted in April 2017 and entered into force on 25 May 2017. The general application dates of the two Regulations are 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices, though different timelines apply for certain specific provisions. These Regulations introduce an EU identification sys - tem for medical devices based on a Unique Device Identifier (UDI). 1The UDI system will facilitate easier traceability of medical devices, significantly enhance the effectiveness of the post-mar - ket safety-related activities for devices and allow for better monitoring by competent authorities. It will also help to reduce medical errors and to fight against falsified devices. The use of the UDI system finally should also improve purchasing and waste disposal policies and stock-management by health institutions and other economic operators. 1 IMDRF/UDI WG/N7FINAL:2013 UDI Guidance Unique Device Identification (UDI) of Medical Device s 2 IMDRF/UDI WG/N48 FINAL: 2019 Unique Device Identification system (UDI system) Application Guide - DOCX (12.5Mb)The new system will be applied to all medical devices except custom-made and performance study/investigational devices and is substantially based on internationally recognised principles, notably by using definitions that are compatible with those used by major trade partners.1,2MEDICAL DEVICES CHANGE OF LEGISLATION What you need to know! Unique Device Identification (UDI) System under the EU medical devices Regulations 2017/745 and 2017/746European Commission Health and Food Safety 2Article 27 of Regulation (EU) 2017/745 (‘MDR’) and Article 24 of Regulation (EU) 2017/746 (‘IVDR’) lay down that the UDI system shall consist of: a. the production of a UDI that comprises a UDI device identifier (‘UDI-DI’) specific to a manufacturer and a device, providing access to the information, and a UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI; b. the placing of the UDI carrier on the label of the device or on its packaging or in case of reusable devices on the device itself (direct marking); c. the storage of the UDI by economic operators, health insti - tutions and healthcare professionals, in accordance with the conditions laid down in paragraphs 8 and 9, respectively, of the Articles; d. the establishment of an electronic database for Unique Device Identification (the ‘UDI database’), which is part of the Eudamed database, in accordance with Article 28 of MDR and Article 25 of IVDR. In accordance with the new rules, any manufacturer shall thus assign a unique UDI to a device and to all higher levels of packag - ing before placing that device on the market except custom-made medical devices and performance study/investigational devices. The UDI carrier shall be placed on the label of the device and on all higher levels of packaging and in case of reusable devices on the device itself (direct marking). The manufacturer shall also ensure that the information – related to the device in question - referred to in Part B and Part A, Section 2, of Annex VI of the relevant Regulation, is correctly submitted to the European Database on Medical Devices (Eudamed) as required by Article 27(3) of MDR and Article 24(3) of IVDR. The manufacturer shall also maintain unique UDIs for its devices. NOTE: Timelines related to those obligations are indicated under question 6 of this document. Within the EU, the manufacturer shall assign to their devices, together with a UDI, also a Basic UDI-DI, which is not yet required by other jurisdictions. The Basic UDI-DI is the main key in Eudamed and relevant documentation (e.g. certificates, declaration of conformity, technical documentation and summary of safety and clinical performance) and will also be the access key for device-related information entered in the database. UDI issuing entities designated by the European Commission operate a system for the assignment of UDI in the EU.3 3 Issuing entities have been designated on 6 June 2019 via the Commission Implementing Decision (EU) 2019/939 .Frequently Asked Questions and Answers 1. What is the UDI? The UDI is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific medical device on the market. The UDI is comprised of the UDI-DI and UDI-PI. The unique identifier may include information on the lot or serial number and be able to be applied anywhere in the world. The production of a UDI comprises the following: • A UDI device identifier (‘UDI-DI’) specific to a device, providing access to the information laid down in Part B of Annex VI. • A UDI production identifier (‘UDI-PI’) that identifies the unit of device production and if applicable the packaged devices, as specified in Part C of Annex VI. 2. What is the Basic UDI-DI? The Basic UDI-DI is the main access key for device-related information in the Eudamed database and it is referenced in relevant documentation [e.g. certificates (including certificate of free sale), EU declaration of conformity, technical documentation and summary of safety and (clinical) performance)]. It is intended to identify and connect devices with the same intended purpose, risk class and essential design and manufac - turing characteristics. It is independent/separate from the packaging/labelling of the device and it does not appear on any trade item. Any Basic UDI-DI shall identify the devices (group) covered by that Basic UDI-DI in a unique manner. MDCG 2018-1 v3 guidance provides additional information on Basic UDI-DI. 3. Which products are subject to the UDI system? The UDI system should apply to all devices, except custom-made and performance study/investigational devices.34. Who is responsible for placing the UDI carrier on the device itself, on the label and on the package of a device? The manufacturer is responsible for complying with all UDI related requirements. This includes the assignment of the UDI (and Basic UDI-DI), the UDI (and Basic UDI-DI) registration in the Eudamed database and the placement of the UDI carrier on the label of the device or on its packaging or, in case of reusable devices, on the device itself (direct marking). 4.1 What happens in the case of Article 16 of the MDR and IVDR? Which obligations do economic operators have regarding UDI when assuming obligation incumbent on manufacturers per Article 16 of the MDR and IVDR? Any distributor, importer or other natural or legal person that assumes the obligations incumbent on manufacturers in accord - ance with Article 16(1), assumes all the relevant responsibilities related to UDI, including UDI labelling. The distributor or importer carrying out the operations described in Article 16(2) (providing translation or repackaging of devices) shall ensure that: • the activities are performed by means and under conditions that in no way compromise the readability of the UDI carrier and its information identifying the actual device. • the specific procedures are part of the distributor’s or import - er’s quality management system. A dedicated guideline with additional information on this aspect is available at the MDCG 2018-6 guidance document . 5. What is the procedure for systems and procedure packs to undergo a UDI registration? Systems and procedure packs shall undergo a UDI registration, as described in Article 29(2) of MDR. Before placing on the market a system or procedure pack pursuant to Article 22(1) and (3), that is not a custom-made device, the system or procedure pack producer shall assign to the system or procedure pack, in compliance with the rules of the issuing entity, a Basic UDI-DI and shall provide it to the Eudamed database together with the other relevant core data elements listed in the MDCG 2018-4 guidance document .6. What is the mandatory deadline for a device to comply with the UDI requirements? The obligation for UDI assignment applies as from the date of application of the two new Regulations, i.e. 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices. The obligation for submission of UDI data in the EUDAMED database applies from 26 November 2022 for medical devices and 26 November 2023 for in vitro diagnostic medical devices (provided that EUDAMED is fully functional before the date of application of the respective Regulation; otherwise, this obligation applies 24 months after EUDAMED has become fully functional) However, manufacturers will be in a position to voluntarily comply with registration obligations as from 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices. It shall be noted that, provided that Eudamed is fully functional, at any time after 26 May 2021 for medical devices and 26 May 2022 for In Vitro diagnostic medical devices, the full registration of devices (Article 29 of MDR and Article 26 of IVDR) remains a pre-condition for the possible registration of their relevant serious incident in Eudamed. The MDCG 2019-4 guidance document provides more information on this subject. The obligation for placing the UDI carrier applies according to the following timelines: Device as per Regulation (EU) 2017/745 (MDR)Implantable devices and Class III devicesClass IIa and Class IIb devicesClass I devices Placing UDI-carriers on the labels of devices MDR Article 123(3)(f), Article 27(4)26 May 202126 May 202326 May 2025 Direct marking of the reusable devices MDR Article 123(3)(g), Article 27(4)26 May 202326 May 202526 May 2027 Device as per Regulation (EU) 2017/746 (IVDR)Class D IVDsClass C and B IVDsClass A IVDs Placing UDI-carriers on the labels of devices IVDR Article 113(3)(e), Article 24(4)26 May 202326 May 202526 May 2027 NOTE: Devices which are compliant with the Regulations may be placed on the market ahead of the general application date of 26 May 2021 (MDR) and 26 May 2022 (IVDR). For more information on this aspect, please consult FAQ - MDR Transitional Provisions and FAQ - IVDR Transitional Provisions .47. Are devices, which are compliant with the Medical Device Directives (MDD and AIMDD) and placed on the market after the applica - tion date of the Regulations (legacy devices), continue to be subject to UDI requirements? In order to facilitate the transition to the new system, the new Regulations give manufacturers the possibility to place products on the market after the general application dates of the new Regulations (and until 26 May 2024 at the latest) by virtue of valid Directive certificates.4 These legacy devices are not subject to UDI obligations but they should be registered in the Eudamed database. Timelines for registration as described under question 6 also apply to these products. More information on the operational aspects of the registration of legacy devices is available at the MDCG 2019-5 guidance document . 8. What is the role of the UDI issuing entities? Who designates them? The issuing entities operate a system for the assignment of UDIs. Following a call for applications launched at the end of 2018, the Commission has designated the following entities: a. GS1 AISBL b. Health Industry Business Communications Council (HIBCC) c. International Council for Commonality in Blood Banking Automation (ICCBBA) d. Informationsstelle für Arzneispezialitäten (IFA) GmbH For more information, please refer to the relevant implementing act designating the entities: Commission Implementing Decision (EU) 2019/939 of 6 June 2019 designating issuing entities designated to operate a system for the assignment of Unique Device Identifiers (UDIs) in the field of medical devices. 4 For additional information on the general conditions for legacy devices to be placed on the market after the general application dates of the new Regulations, see the MDR and IVDR transitional FAQs published by the CAMD Transitional Task-force 9. How should a UDI appear on the label or package of a device? The UDI Carrier [Automated Identification for Data Capture (AIDC) and human readable interpretation (HRI) representation of the UDI] shall be on the label or on the device itself and on all higher levels of device packaging. In the event of significant space constraints on the unit of use packaging, the UDI carrier may be placed on the next higher packaging level. Higher levels of packaging shall have their own unique UDI. Please note that shipping containers shall be exempted from the requirement. The UDI must appear in a plain-text version/human readable information (HRI) and in a form that uses AIDC technology. AIDC means any technology that conveys the unique device identifier or the device identifier of a device in a form that can be entered into an electronic patient record or another computer system via an automated process. The HRI consists of legible characters that can easily be read by people. If there are significant constraints limiting the use of both AIDC and HRI on the label, only the AIDC format shall be required to appear on the label. For devices intended to be used outside healthcare facilities, such as devices for home care, the HRI shall, however, appear on the label even if this results in there being no space for the AIDC. For other specific requirements related to the UDI carrier, please consult Section 4 of Annex VI Part C of the two Regulations. For single-use devices of classes I and IIa medical devices and class A and class B IVD medical devices packaged and labelled individually, the UDI carrier shall not be required to appear on the packaging but it shall appear on a higher level of packaging, e.g. a carton containing several (individually packaged) devices. However, when the healthcare provider is not expected to have access, in cases such as in home healthcare settings, to the higher level of device packaging, the UDI shall be placed on the packaging (of the individual device). For devices exclusively intended for retail point of sale, the UDI- PIs in AIDC shall not be required to appear on the point of sale packaging. If the UDI carrier is readily readable or, in the case of AIDC, scannable, through the device’s packaging, the placing of the UDI carrier on the packaging shall not be required.510. Are there any requirements for the PI (Production Identifier) information? If a lot number, serial number, software identification or expiry date appears on the label, it shall be part of the UDI-PI. If there is also a manufacturing date on the label, it does not need to be included in the UDI-PI. If there is only a manufacturing date on the label, this shall be used as the UDI-PI. The different types of UDI-PIs include serial number, lot number, software identification and manufacturing date and/or expiry date. The UDI-PI characteristics such as the lot or serial number shall be defined by the manufacturer. However: • For active implantable devices, the UDI-PI shall include at least the serial number; for other implantable devices, the serial number or lot number. • A configurable device UDI-PI shall be assigned to each indi - vidual configurable device. It is important to note that no UDI-PI information can be included in the UDI database. 11. What changes in the medical device would require a new UDI-DI? A new UDI-DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability. In particular, a new UDI-DI shall be required in the case of any change of the following elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilisation before use, quantity of devices provided in a package, critical warnings or contra-indications and CMR/Endocrine disruptors. A UDI-DI shall be associated with one and only one Basic UDI-DI. Additional information on this aspect is available at MDCG 2018-1 v3 guidance document .12. What are the obligations of economic operators and health institutions in relation to UDI? According to the two medical devices Regulations, manufacturers shall be responsible for the UDI assignment and placement of the UDI carrier, the initial submission and updates of the identifying information and other device data elements in the Eudamed database. Manufacturers shall update the relevant database record within 30 days of a change being made to an element, which does not require a new UDI-DI. Distributors and importers shall verify that, where applicable, a UDI has been assigned by the manufacturer. All economic operators and health institutions shall store and keep preferably by electronic means the UDI of the devices, which they have supplied or with which they have been supplied if those devices belong to class III implantable devices. Please note that the Commission may decide to adopt implementing acts to expand the scope of devices for which economic operators shall store and keep the UDI. 13. Is the software subject to UDI rules? The UDI shall be assigned at the system level of the software. Only software that is commercially available on its own and software that constitutes a device in itself shall be subject to that requirement. The software identification shall be considered the manufacturing control mechanism and shall be displayed in the UDI-PI. UDI requirements for software are laid down in Annex VI Part C of the two medical device Regulations. A dedicated guideline with additional information on this aspect is available at MDCG 2018-5 guidance document .614. Direct marking of reusable devices. Are there exemptions? Devices that are reusable shall bear a UDI carrier on the device itself. The UDI carrier for reusable devices that require disinfection, ster - ilisation or refurbishing between patient uses shall be permanent and readable after each process performed to make the device ready for the subsequent use throughout the intended lifetime of the device. The UDI carrier shall be readable during normal use and throughout the intended lifetime of the (reusable) device. The requirements shall not apply to the device in case of the following circumstances: • any type of direct marking would interfere with the safety or performance of the device; • the device cannot be directly marked because it is not tech - nologically feasible. 15. Is there an adjudication process for ad-hoc exemptions foreseen for medical devices? An adjudication process to allow for ad-hoc exemptions is not envisaged in the EU. All devices are therefore subject in principle to UDI requirements, with the only exceptions explicitly stated in the Regulation.However, the UDI Expert Group will analyse requests for adap - tation of UDI requirements to certain specific device types and recommend the Medical Device Coordination Group (MDCG) to issue dedicated guidelines, where necessary. 16. What are the UDI and device data sets to be provided in Eudamed? Dedicated guidelines containing information on this aspect are available at https://ec.europa.eu/health/md_sector/ new_regulations/guidance . Guidance Further information on EUDAMED is available at https://ec.europa. eu/health/md_eudamed/overview_en . NOTE: The Commission intends to expand this document on a regular basis based on the assessment of most frequently asked questions and/ or of other specific needs. ET-02-18-963-EN-N Funded under the Third EU Health Programme ISBN:XXXXX DOI: XXXXX01/08/2020 © European Union, [2018] Reuse is authorised provided the source is acknowledged. The reuse policy of European Commission documents is regulated by Decision 2011/833/EU (OJ L 330, 14.12.2011, p. 39).https://ec.europa.eu/health/ md_sector/overview_en

mdcg_2019_1_budi_rules_ie_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2019 -1 Page 1 of 2 MDCG 201 9-1 MDCG guiding principles for issuing entities rules on Basic UDI -DI January 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commissio n document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2019 -1 Page 2 of 2 In order to ensure, to the maximum possible extent, the quality of the code value entered in Eudamed, the Basic UDI -DI requirements on format should be as close as possible to the ones for the UDI -DI. In particular,  the Basic UDI -DI code value sha ll have maximum 25 characters, so that it does not differ too significantly from the maximum length of the UDI -DI as established by the issuing entities;  a check digit/character must be part of the Basic UDI -DI, based on an algorithm defined by the issuin g entity. This algorithm shall be provided by the issuing entities to the Commission and to the manufacturers.

MDCG 2018-1 v3 Guidance on basic UDI-DI and changes to UDI-DI.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2018-1 v3 MDCG 2018-1 v3 Guidance on BASIC UDI-DI and changes to UDI-DI March 2020 This document has been endorsed b y the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed o f representatives of all Member States and it is chaired by a representative of the European Co mmission. The document is not a European Commission document and it canno t be regarded as reflecting the official position of the European Commission. Any views express ed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on BASIC UDI-DI and changes to UDI-DI Introduction The new Medical Device Regulations (EU) 2017/745 and (EU) 2017/746 introduce a Unique Device Identification (UDI) system for medical devices. Main provisions related to the establishment of the UDI system are contained in Chapter III and Annex VI of the two medical device Regulations. The main features of the UDI system and relevant obligations for operators will be provided in a dedicated Q/A paper to be published by the Commission in spring 2018. This guidance is intended to provide a clarification on the notion of Basic UDI-DI, its use in relevant documentation and the factors triggering UDI-DI changes. ----------------------------- The Basic UDI-DI The Basic UDI-DI is the main key in the database and relevant documentation (e.g. certificates, declaration of conformity, technical documentation and summary of safety and clinical performance) to connect devices with same intended purpose, risk class and essential design and manufacturing characteristics. It is independent/separate from the packaging/labelling of the device and it does not appear on any trade item. Any Basic UDI-DI shall identify the devices (group) covered by that Basic UDI-DI in a unique manner. Link with between Basic UDI -DIs and certificates or declaration of conformity In accordance with Annex XII of the medical device Regulations, the scope of the certificates shall unambiguously identify the device or devices covered. The scope of EU technical documentation assessment certificates, EU type-examination certificates and EU product verification certificates shall include, together with the Basic UDI-DI, a clear identification, including the name, model and type, of the device or devices, the intended purpose, as included by the manufacturer in the instructions for use and in relation to which the device has been assessed in the conformity assessment procedure and the risk classification. Each of the abovementioned certificates shall identify and cover all devices associated with the same Basic UDI-DI, that is referred to in that certificate. The association between different Basic UDI-DIs, where applicable, shall be identified through the technical dossiers. In accordance with Annex IV of the two Regulations, the declaration of conformity shall contain the Basic UDI-DI and the product and trade name, product code, 3 catalogue number or other unambig uous reference allowi ng identif ication and traceability of the device covered by the EU declaration of conformity. Changes of UDI-DI A new UDI—DI shall be required whenever there is a change that could lead to misidentification of the device and/or ambiguity in its traceability. In particular, a new UDI-DI shall be required in the case of any change of the following elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilization before use, quantity of devices provided in a package, critical warnings or contra-indications (e.g. containing latex or DEHP), CMR/Endocrine disruptors 1 2. A UDI-DI shall be associated with one and only one Basic UDI-DI. Regarding changes to the specific data elements listed below 3, the following considerations should be noted: 1. Is the Device Directly Marked (Yes/No) The database design will force the creation of a new UDI-DI only if there is a change from Yes to No and not vice versa for this data element. 2. Manner in which production of the device Is controlled (expiry date or manufacturing date, lot number, serial number, software identification) - Type of UDI-PI As long as there is no change to the la bel, a change to this data element will not require the allocation of a new UDI-DI. 1 It should be noted that a new regulatory decision classifying an existing product as CMR/Endocrine disruptor might not result in a new UDI-DI for products already containing that substance. The decision on whether to assign a new UDI-DI should be based on the conformit y assessment of the product with regard to the impact of the information provided and the significance of the change. 2 Specific attention shall be paid to the fact that changes of colour or language might also require a new UDI- DI when those changes might lead to misidentification of produc t or change the product safety/performance. For example: A- Change of colour coding of e.g. connectors, latex-free surgi cal gloves, blood tubes B- Two identical self-testing de vices, that exist in parallel a nd cannot be substitute d due to local labelling requirements (IVD Article 10(10) of Regulation 746/2017), requi res different UDI-DIs Specifications of EU designated issuing entity should be used a s a reference source to identify other possible examples. 3 Please refer to Guidance UDIWG 2018-1 on "UDI database. Defini tions, descriptions and formats of the UDI core elements’ available at https://ec.europa.eu/docsroom/documents/28669 4 WARNING: This guidance does not address requirements for reprocessed devices, systems or procedure packs, software, Annex XVI, nor for cases of parallel trade or own brand labelling. Specific requirement s for those products are addressed in specific guidance.

mdcg_2018_5_software_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 1 of 3 MDCG 2018 -5 UDI Assignment to Medical Device Software October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 2 of 3 Specific consideration on UDI rules for software UDI Assignment to Medical Device Software - Scope of UDI requirements for software In accordance with Annex VI, Part C of the Medical Device Regulation (EU) 2017/745 (MDR) and the In -Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR), only software which is commercially available on its own as well as software which constitutes a device in itself shall be subject to UDI requirements. - Basic UDI -DI In line with the general Guidance on Basic UDI -DI and changes to UDI -DI1, the Basic UDI-DI connects software with same intended purpose, risk class and essential design and manufacturing characteristics. - Changes to UDI -DI in accordance with Annex VI Part C, Section 6.5 of the MDR and Section 6.2 of the IVDR, a new UDI -DI is required whenever there is a modification that changes the original performance, the safety of the software or the interpretation of data . Such modifications include new or modified algorithms, database structures, operating platforms, architecture, user i nterfaces and new channels for interoperability . Such changes would be considered “significant.” The Guidance on Basic UDI -DI and changes to UDI -DI2, defines standard rules on triggers that entail the creation of a new UDI -DI. It lays down that a new UDI —DI shall be required whenever there is a change that could lead to misidentification of a device and/or ambiguity in its traceability. In particular, a new UDI -DI shall be required in the case of any change of the following device related elements: name or trade name, device version or model, labelled as single use, packaged sterile, need for sterilization before use, quantity of devices provided in a package, critical warnings or contra -indications (e.g. containing latex or DEHP3), CMR4/Endocrine disruptors , colour, language. Not all those data elements are however applicable to software. 1 The Guidance is available at https://ec.europa.eu/docsroom/documents/28667 2 The Guidance is available at https://ec.europa.eu/docsroom/documents/28667 3 DEHP stands for Bis(2 -ethylhexyl) phthalate 4 CMR stands for carcinogenic, mutagenic, or toxic for reproduction Medical Devices Medical Devices Coordination Group Document MDCG 2018 -5 Page 3 of 3 It can therefore be concluded that, in the specific case of software, - Any change of the Basic UDI -DI5 - Any changes which impact the original performance, safety, or the interpretation of data6 - A change to the name or trade name, version or model number, critical warnings or contra -indications, user interface language would require a new UDI -DI. This is to guarantee the traceability and correct identification of the med ical device software. - Minor software revisions In accordance with Annex VI, Part C, point 6.5.4 of the MDR and Annex VI, Part C, point 6.2.4 of the IVDR, minor software revisions require a new UDI -PI and not a new UDI-DI. Minor software revisions are generally associated with bug fixes, usability enhancements that are not for safety purposes, security patches or operating efficiency. Minor software revisions shall be identified by a defined manufacturer - specific form of identification. - Evaluation of ch anges to software by the manufacturers As part of their maintenance and post -market surveillance activities, manufacturers should evaluate the possible impact of any changes to the function of software on the software’s qualification as medical device soft ware, its classification, its intended purpose and essential design and manufacturing characteristics, as that could trigger a new Basic UDI -DI. Likewise, any changes shall be assessed in defining the need of a new UDI -DI. UDI Placement Criteria UDI plac ement criteria for software are laid down in Annex VI, Part C, point 6.5.4 of the MDR and Annex VI, Part C, point 6.2.4 of the IVDR. Additional considerations on this aspect will be provided in future guidance. 5 This is a general rule. As indicated in the Guidance on Basic UDI -DI and changes to UDI -DI (available at https://ec.europa.eu/docsroom/documents/28667 ), "a UDI-DI shall be associated with one an d only one Basic UDI-DI”. 6 Annex VI, Part C, point 6.5.2 of the MDR and Annex VI, Part C, point 6 .2.2 of the IVDR

mdcg_2018_7_languages_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 1 of 3 MDCG 2018 -7 Provisional considerations regarding language issues associated with the UDI database (Annex VI, Part A Section 2 and Part B of the Medical Device Regulation (EU) 2017/745 (MDR) and the In -Vitro Diagnostic Medical Device Regulation (EU) 2017/746 (IVDR )) October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecti ng the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 2 of 3 General principles In consideration of the following: - In accordance with Article 28(3) MDR and Article 25(3) IVDR, the core data elements to be provided to the UDI database shall be accessible to the public, - Annex VI Part C of the MDR and IVDR on the UDI System requires explicitly in its section 5.10 that the user interface of the UDI database shall be available in all official languages of the Union and that the use of free - text fields shall, however, be minimized in order to reduce translations, - one of the main declared purposes of th e European database on medical devices (Eudamed) as per Recitals 43 -46 and Article 33(1a) of the MDR and Recitals 40 -43 of the IVDR is to enable the public (including the healthcare professionals) to be adequately informed about devices placed on the marke t, it is essential that the information in the UDI database is publicly available and easily understandable by any European citizen. Use of free -text and translation Among the UDI core data elements of Part B of Annex VI of the MDR and IVDR, only three data elements ("Additional product description", "Storage and handling conditions" and "Critical warnings or contra -indications") are expected to have a free - text format, while a fourth data element (nomenclature term) is associated with a text allowing to understand the meaning of the associated code (description). As to the nomenclature, ideally, all the terms/description associated with the nomenclature codes should be translated in the different Union official languages. However, it could be also consi dered having terms available only in English, particularly taking into account that the nomenclature will have a code. Appropriate budget and legal verifications will be made on this matter, in the context of the designation procedure for the new nomenclat ure. Among the three data elements that use free -text, one is an optional field: "Additional product description". It should be provided in English as well as in the languages of those countries where the device is made available. A data field will be av ailable for each relevant language. For the data elements "Storage and handling conditions" and "Critical warnings or contra -indications", relevant information (as per Annex I Section 23.2 of the MDR and Annex I Section 20.2 of the IVDR: (k) "any special s torage and/or handling conditions" and (m) "warning or precautions to be taken") should be provided in Medical Devices Medical Devices Coordination Group Document MDCG 2018 -7 Page 3 of 3 English as well as in the languages of those countries where the device is made available. It shall be noted that, as laid down in the provisional guid ance related to formats and definitions of UDI data elements, only storage/handling conditions and critical warnings or contra -indications, that are required to be on the label, shall be transmitted to the UDI database. With respect to those two data eleme nts, the possibility to use (in EUDAMED) – as an alternative option - symbols and/or list of reference that can categorise and provide enough information understandable by anyone is currently being explored. Indication of hazardous substances (only appli cable for MDR) For CMR substances, the Commission intends to explore the feasibility for EUDAMED to provide the list of official CMR1 substances (from CLP Regulation2) available in the ECHA3 database. The CAS number4, EC number and/or official chemical nam e could be used to identify those substances. With regard to endocrine disruptor substances, pending verification that an official database managed by the Commission containing these substances is available, a solution is currently being explored. Inform ation to be provided is known by the economic operator in charge of the submission as it shall be displayed on the device label (Annex I Section 23.2 (f) of the MDR). 1 CMR stands for carcinogenic, mutagenic, or toxic for reproduction 2 Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (the 'CLP Regulation') 3 The European Chemicals Agency 4 A CAS Registry Number, also referred to as CASRN or CAS Number, is a unique numerical identifier assigned by the Chemical Abstracts Service (CAS) to every chemical substance described in the open scientific literature

mdcg_2018_6_art16_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -6 Page 1 of 2 MDCG 2018 -6 Clarifications of UDI related responsibilities in relation to Article 16 of the Medical Device Regulation (EU) 2017/745 and the In-Vitro Diagnostic Medical Device Regulation (EU) 2017/746 October 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -6 Page 2 of 2 Relevant obligations arising from Article 16(1) Any distributor, importer or other natural or legal person that assumes the obligations incumbent on manufacturers in accordance with Article 16(1), assumes all the relevant responsibilities related to UDI, including UDI labelling. This means that those e conomic operators must also apply for registration as Manufacturers, receive a Single Registration Number (SRN), apply for the appropriate conformity assessment procedure and feed and provide UDI -product registration. However, in accordance with the provis ion of Article 16(1)a, when a distributor or importer enters into an agreement with a manufacturer whereby the manufacturer is identified as such on the label, the manufacturer is responsible for meeting the requirements placed on manufacturers in this Reg ulation, including the relevant UDI obligations. Relevant obligations arising from Article 16(2) to 16(4) The distributor or importer carrying out the operations in Article 16(2) shall ensure that: - the activities mentioned in points (a) and (b) of par agraph 2 are performed by means and under conditions that in no way compromise the readability of the UDI carrier and its information identifying the actual device. - the specific procedures are part of the distributor's or importer’s quality management sy stem.

mdcg_2018_2_nomenclature_en.pdf.txt

This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 1 MDCG 2018 -2 Future EU medical device nomenclature Description of requirements Introduction According to Article 26 of the Regulation 745/2017 on medical devices and Article 23 of Regulation 746/2017 on in-vitro diagnostic medical device , the Commission is required to make available a medical device nomenclature to support the functioning of the future EUDAMED . This document intends to provide a detailed description of requirements and criteria that the future nomenclature is expected to fulfil. This is expected to serve as a reference basis throughout the decision process and will also ensure th at all legal and technical issues associated with the future EU medical device nomenclature are properly mapped. 1. Description of legal requirements It arises from the text of the new Regulations (namely Article 26 of Regulation 745/2017 and Article 23 of Regulation 746/2017) that t he future EU medical device nomenclature will have to comply with certain defined requirements . First of all, t he future nomenclature shall be available free of charge to manufacturers and other natural o r legal persons required by the Regulation to use that nomenclature, this meaning that no manufacturer or natural/legal person should be subject to fee or suffer from any discrimination, compared to other operators, in relation to the use of the nomenclature under the new Medical Device Regulations. It shall be therefore ensured that relevant names and codes are accessible (in full) in EUDAMED to all operators that are requested to provide the relevant UDI submissions. Provisions in Chapter III and Annex VI of the new Regulations, and in particular the combination of Article 28( 3) of the Regulation 745/2017 on medical devices and point 8 of part B of Annex VI , provide that moreover names and codes are publicly availabl e in the UDI database (in EUDAMED ). By virtue of Article 26, t he Commission shall a lso endeavour to ensure that the nomenclature is available to other stakeholders free of charg e, where reasonably This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 practicable. The public availability of terms and codes in EUDAMED is in itself an ideal vehicle to provide sufficient access of all stakeholders . Finally the nomenclature shall be internationally recognised at the time of the date of application of the Regulations. In this context, global harmonisation principles and orientations followed and adopted by the International Medical Device Regulators Forum (IMDRF) and the World Health Organisation , are taken into particular account . Without prejudice to the fulfilment of requirements d escribed in previous paragraphs, the European Commission and the Competent Authorities from EU Member States shall benefit from the full access to the most up to date nomenclature system and its hierarchies free of charge . They shall not be charged for any service received from the nomenclature provider, which is necessary for them to exert their supervisory role over the nomenclature and the fulfilment of their obligations under the new Regulations. 2. Description of other relevant criteria In order for the system to leverage further the potential of the future EU nomenclature, some other essential requirements that the nomenclature shall fulfil have been identified . While those requirements are not explicitly mentioned in the texts of the two Regulation s, they are essential to guarantee the good functioning of the future EUDAMED and to the fulfilment of some of the regulatory objectives set in the new Regulation s, namely facilitating effective market surveillance operations and facilitating device traceability throughout the supply chain. Policies/rules for update, removal and creation of names and descriptions in the nomenclature are to be sound and must reflect regulators ’ and the wider healthcare economy needs . An EU regulatory team on no menclature composed of regulators , to be established possibly as an MDCG sub -group , will review, determine (preferably within a global perspective) and validate those rules prior to designation decision and will continue to hold an advisory role on these matters . On a periodic basis, in accordance with a pre -defined procedure, and in consultation with the nomenclature provider, that group shall also provide feedback and advice on the governance of terms and descriptions, based, inter alia, on the requests received from economic operators and other stakeholders. In the context of activities mentioned in the previous paragraph, it shall be aimed to ensure that the terminology structure used for it should not be unnecessarily granular and should not contain names that are only used by only a few economic operators This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commi ssion. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 3 or stakeholders , unless it is proven to be advantageous to regulators or the wider healthcare economy. The structure and design of the future nomenclature should facilitate the establishment of lin ks with the codes defining N otified Bodies competence (designation scope) , the scope of medical device s QMS (Quality Management System)/QA (Quality Assurance) certificates , and product portfolio s in the mandate of Authorised Representatives . The nomenclature should have hierarch ies by which terms and codes could be meaningfully grouped into categories and subcategories The future nomenclature system shall adequately support the functioning of the EUDAMED database and the functioning of the new Regulations as a whole. In this context, EUDAMED shall make available the most updated names/codes related information, to the be nefit of operators and general public. Therefore, the nomenclature provider will need to have procedures and services in place that shall allow E UDAMED to be kept up -to-date at any time. When setting the procedure, in particular the frequency, related to the periodic review of nomenclature terms and descriptions , this shall be taken into account. For enforcement purposes , in relation to its obligations vis -à-vis the Commission and the EU economic operators, the nomenclature provider shall have a legal entity in either one of the EEA countries or Switzerland or Turkey1 with an exception being foreseen for international organisations in which the EU is one of the members . System/processes shall be in place to periodically review the terminology structure and content to incorporate learning from ongoing experience with real -world use of device nomenclature (ex. EUDAMED, GUDID, registries) as well as from technological innovation . Availability of names and descriptions in all the official EU langu ages is recognised as of being of high importance. All copyright s associated with the nomenclature shall be secured. 1 Indication of these countries is based on current situation with the applicable directives on medical devices as a result of the combination of the legal text of those Directives and relevant currently applicable international agreements . this list of countries might be subject to change in the context of the new m edical device framework.

12 MDCG 2020-12 Guidance on transitional provisions for consultations of authorities on devices.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 1 of 6 MDCG 2020-12 Guidance on transition al provisions for consultations of authorities on devices incorporating a substance which may be considered a medicinal product and which has action ancillary to that of the device, as well as on devices manufactured using TSE suscep tible animal tissues June 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 2 of 6 Guidance on transitional provisions for consultations of author ities on devices incorporating a substa nce which may be considered a medicinal product and which has action ancillary to that of the device, as well as on devices manufacture d using TSE susceptible animal tissues I. Consultations for a substance which may be considered a medicin al product and which has action ancillary to that of the device (including human blood derivatives) Consultation procedure under the MDD and AIMDD According to Annex I section 7.4 of Directive 93/42/EEC on medical devices (the MDD), and Annex I section 10 of Directive 90/385/EEC on active im plantable medical devices (the AIMDD), for devices containing a substance which, if used separately, would be considered to be a medicinal product and which is liable to act upon the body with an action ancillary to that of the device, the notified body is required, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, to seek a scientific opinion from one of the competent authorities designated by the Member St ates or the European Medicines Agency (EMA) on the quality and safety of the substance in the medical device, including the clinical benefit/risk profile of the incorporation of the substance into the device. Similarly, where changes are made to that substance, particularly relating to its manufacturing process, the notified body is required to consult with the same authority in order to confirm that the quality and safety of that substance are maintained and to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical device. This consultation on changes is referred to as supplementary consultation in this guidance document. There is an equivalent consultation requirement for medical devices containing a human blood derivative with ancillary action. In this case the notified body is required to consult the EMA only. Transitioning from MDD and AIMDD to MDR Regulation (EU) 2017/745 on medical devices (the MDR) establishes a similar requirement in Article 52 (9) (Annex IX section 5.2 and Annex X Section 6): fo r devices incorporating, as an integral part, a substance which, if used separately, may be considered to be a medicinal product 1 and which has an action ancillary to that of the device (hereafter referred to in this document as the ancillary substance), the notified body is required, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, to consult a medicinal products authority designated by a Member State or the EMA2 on the quality and safety of the substance, including the benefit or risk of the incorporation of the substance into the device. The notified body is 1 including a medicinal product derived from human blood or human plasma 2 only the EMA in the case of medicinal products derived from human blood or human plasma, or those falling exclusively within the scope of Regulation (EC) 726/2004 Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 3 of 6 required to do so both for the initial conformity assessment of the device (this consultation is referred to as initial in this guidance document) and for an y subsequent changes to the ancillary substance, in particular in relation to its manufacturing process (the consultation on changes is referred to as a supplementary consultation, by analogy to the M DD/AIMDD). A competent auth ority designated by a Member State in accordance with Directive 2001/83/EC or the EMA (hereafter referred as medicinal products authority in this document) consulted has 210 days since the receipt of all the necessary documentation to provide its opinion in the case of an initial consultation, or 60 days for a supplementary consultation. Unlike the MDD and AIMDD, the MDR also states that the notified body may not deliver the certificate if the opinion is unfavourable (Annex IX 5.2 (e) and (f)). This document provides guidance on fulfilling th is requirement for the first time under the MDR for devices which already underwent a consultation with a medicinal products authority according to Annex I 7.4 of the MDD or Annex I 10 of the AIMDD. Consultation for ancillary substances under the MDR for devices which have undergone the consultation under the MDD or AIMDD In order for the notified body to issue the first certificate for a given device under the MDR, a full conformity assessment covering all requirements has to be carried out even if the device has been certified under the MDD (Q&A IV.1 MDCG 2019-6). For devices containing ancillary substances, this includes the consultation of the medicinal products authority as per Article 52 (9) of the MDR. For some devices, there may be no change to the device, the ancillary substance and its manufacturing process since the last consultation of the me dicinal products authority under the MDD/AIMDD. Nevertheless, there may be changes in the documentation of the device due to the new requirements of the MDR, for example in clinical evaluation, which have a bearing on the quality, safety or usefulness of the ancillary substance. There may also be changes in the assessment of the device and its documentation by the notified body under the MDR. Lastly, the medicinal products authority may have new information on the substance, leading to a modified or different opinion. For the first consultation under the MDR, the notified body is required to submit the full documentation package to the medicinal products authority as described in dedicated guidance. The notified body is free to approach any medicinal products authority at its discretion, not necessarily the one consulted under the MDD/AIMDD. This should in clude the last opinion of the medicinal products authority under the MDD/AIMDD (whether initial or supplementary), as well as a consolidated list of changes, if any, in the following:  the ancillary substance,  its manufacturing process,  the way the substance is incorporated into the device,  design, manufacturing of the device which could influence the quality, safety or usefulness of the ancillary substance, and/or  the parts of the technical documentation related to the above aspects. If there were no changes to some or any of the above, the package may be accompanied by a declaration by the notified body to this effect, stating the elements that have remained identical. If there have also been no changes to the assessment of this documentation by the notified body, this may be included in the declaration. Should there be only administrative changes to the above (e.g. changes of names or addresses, changes in document layout, etc.), these should be clearly detailed in the declaration. The medicinal products authority may consider the depth of its review given the extent of the changes since the previous consultation under the MDD/AIMDD. It is at the discretion of the medicinal Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 4 of 6 products authority to issue its opinion in less than 210 days. If many elements concerning the substance remain identical, the medicinal products authority is highly recommended to expedite its review. The medicinal products authority may contact the authority consulted on this device under the MDD/AIMDD, who may, at its discretion, confirm the opinion provided in the previous consultation and/or share any additional information. The final opinion for the consultation under the MDR and its issuance according to the stipulated timeline remains the responsibility of the medicinal products authority to which the notified body submitted the request under the MDR. Note on “liability to act upon the body” It should be noted that Annex I 7.4 of the MDD refers to devices in which the substance is liable to act upon the body . In the MDR (Article 52(9), referring to Article 1(8), and Section 5.2 of Annex IX), this is no longer the case. Therefore, for al l those devices where the "liability to act upon the body" was used by the manufacturer as a justification not to follow the consultation, the consultation must take place under the MDR. In those cases where there are doubts on the applicability of the consultation, independently of any considerations concerning the classification of the device, the notified body should seek the scientific opinion as described in Annex IX Section 5.2 (b) of the MDR. Relevant text from MDD and MDR MDD – Annex I Section 7.4 [emphasis added] Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive 2001/83/EC and which is liable to act upon the body with action ancillary to that of the device, the quality, safety and usefulness of the substance must be verified by an alogy with the methods specified in Annex I to Directive 2001/83/EC. For the substances referred to in the first paragraph, t he notified body shall, having verified the usefulness of the substance as part of the medical device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States or the European Medicines Agency (EMEA) acting particularly through its committee in accordance with Regulation (EC) No 726/2004 (1) on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the substance into the device . When issuing its opinion, the competent authority or the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the notified body. Where a device incorporates, as an integral part, a human blood derivative, the notified body shall, having verified the usefulness of the substance as part of the medical device and taking into account the intended purpose of the device, seek a scientific opinion from the EMEA , acting particularly through its committee, on the quality and safety of the substance including the clinical benefit/risk profile of the incorporation of the human blood derivative into the device . When issuing its opinion, the EMEA shall take into account the manufacturing process and the data related to the usefulness of incorporation of the substance into the device as determined by the notified body. Where changes are made to an ancillary substance incorporated in a device, in particular related to its manufacturing process, the notified body shall be informed of the changes and shall consult the relevant medicines competent authority (i.e. the one involved in the initial consultation), in order to confirm that the quality and safety of the ancillary substance are maintained. The competent authority Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 5 of 6 shall take into account the data related to the usef ulness of incorporation of the substance into the device as determined by the notified body, in order to ensure that the changes have no negative impact on the established benefit/risk profile of the addition of the substance in the medical device. MDR – Annex IX 5.2 b (a) Where a device incorporates, as an integral part, a substance which, if used separately, may be considered to be a medicinal product within the meaning of point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derive d from human blood or human plasma and that has an action ancillary to that of the device, the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (b) Before issuing an EU technical documentation assessment certificate, the notified body shall, having verified the usefulness of the substance as part of the device and taking account of the intended purpose of the device, seek a scientific opinion from one of the competent authorities designated by the Member States in accor dance with Directive 2001/83/EC or from the EMA , either of which to be referred to in this Section as ‘the medicinal products authority consulted’ depending on which has been consulted under this point, on the quality and safety of the substance including the benefit or risk of the incorporation of the substance into the device . Where the device incorporates a human blood or plasma derivative or a substance that, if used separately, may be considered to be a medicinal product falling exclusively within the scope of the Annex to Regulation (EC) No 726/2004, the notified body shall seek the opinion of the EMA. (c) When issuing its opinion, the medicinal products authority consulted shall take into account the manufacturing process and the data relating to the usefulness of incorporation of the substance into the device as determined by the notified body. II. Consultations for medical device s containing TSE susceptible an imal tissue under the MDR, where such a consultation took place under the M DD or AIMDD Article 5(4) of Regulation (EU) 722/2012 requires that for all medical devices, including active implantable medical devices, manufactured utilising tissues of animal origin which are susceptible to transmissible spongiform encephalopathy (TSE), the notified body must, through their competent authority, carry out a consultation of the other competent authorities and the Commission. Under the MDR, this requirement rema ins unchanged (Annex IX Section 5.3.2). In order to fulfil the requirements of the MDR, during the first certification under the MDR, the notified body is required to submit the full summary evaluation report as stated in Regulation (EU) 722/2012 to the competent authorities. If there have been no changes to the documentation required from the manufacturer as per Regulation (EU) 722/2012, the summary evaluation report may be accompanied by a declaration by the notified body to this effect, stating the elements that have remained identical. If there have also been no changes to the assessment of this documentation by the notified body, this may also be included in th e declaration. Should there be only administrative changes to the above (e.g. changes of names or addresses, changes in document layout, etc.), these should be clearly detailed in the declaration. Medical Device Medical Device Coordination Group Document MDCG 2020-12 Page 6 of 6 As stated in Article 5(5) of Regulation (EU) 722/2012, the competent authorities and the Commission may agree on shortening the time periods for the consultation. If many elements of the summary evaluation report remain identical, it is highly recommended to expedite the review. Relevant text from Regulation (EU) 722/2012 Article 5 (4) and (5) 4. Before issuing an EC design-examination certificate or an EC type-examination certificate, the notified bodies shall, through their competent authority, hereinafter ‘coordinating competent authority’, inform the competent authorities of th e other Member States and the Commission of their assessment carried out pursuant to paragraph 2 by means of a summary evaluation report in accordance with Annex II to this Regulation. 5. The competent authorities of the Member States may submit comments on the summary evaluation report referred to in paragraph 4 within the following deadlines: (a) in relation to medical devices using starting materials for which a TSE certificate of suitability as referred to in paragraph 3 has been submitted, within four weeks from the date on which the notified body informed the coordinating competent authority pursuant to paragraph 4; (b) in relation to medical devices using starting materials for which a TSE certificate of suitability has not been submitted, within 12 weeks from the date on which the notified body informed the coordinating competent authority pursuant to paragraph 4. The competent authorities of the Member States and the Commission may agree on shortening the time periods set out in points (a) and (b).

mdcg_2018_8_crf_transfer_en.pdf.txt

Medical Devices Medical Devices Coordination Group Document MDCG 2018 -8 Page 1 of 2 MDCG 2018 -8 Guidance on c ontent of the certificates, voluntary certificate transfers November 2018 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commissi on document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Devices Coordination Group Document MDCG 2018 -8 Page 2 of 2 In the meeting of 30 November 2018, MDCG endorsed the below positions. These positions will be part of a more comprehensive guideline related to notified bodies, currently under development. Content of the certificate under MDR / IVDR Annex XII, Chapter II, section 10 Certificates do not need to include reference to relevant common specifications or harmonised standards as long as such information on all examinations and tests performed is traceable and available from e.g. report(s) which are ment ioned in the certificate. Voluntary certificate transfer under MDR Article 58 / IVDR Article 53 While MDR Article 58(1) / IVDR Article 53(1) sets out the requirements for a transfer agreement, it does not specify the conformity assessment activities to be performed by the incoming NB. The incoming NB may decide not to carry out full conformity assessment activities according to Article 52 MDR / Article 48 IVDR, as long as it does have sufficient information in respect to the conformity activities performed by the outgoing NB. For quality management system certificates, the incoming NB needs to perform appropriate on -site audit(s) and assessments to ensure that the manufacturer in question applies the approved QMS and the post -market surveillance plan prior to the issue of any certificate. In respect to the assessment of technical documentations on a sampling basis, the oncoming NB shall review the previous assessment results together with a sample of a technical documentation and draw up or amend a sampling plan. For product certificates (Annex IX Chapter II/Annex X), new certificates without a comprehensive (initial) review may be issued as long as the documentation received does not identify ongoing existing or other concerns. The incoming NB assumes full responsibility for the new certificates issued following the transfer.

mdcg_2019_14_MDR_codes.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2019-14 MDCG 2019-14 Explanatory note on MDR codes December 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Explanatory note on MDR codes 1 Introduction Commission Implementing Regulation 2017/2185 establishes the codes for the designation of notified bodies in medical devices under Regulation (EU) 2017/745 and in vitro diagnostic medical devices under Regulation (EU) 2017/746. These codes are primarily used by designating authorities to define the notified body scope of designation but they are also used by the notified body to: 1) describe the individual qualification of the NBs staff members 2) describe the qualification required for assessing a device These codes may be very broad and, furthermore, unequivocal authorisation of personnel to codes and the assignment of codes to a device is not always straightforward. However, the notified body’s system needs to ensure, in all cases, that the authorisation of personnel and team allocation for the conformity assessment of a device ensures adequate knowledge and expertise. 2 Scope The lists of codes and corresponding types of devices established by the above mentioned Regulation takes into account various device types which can be characterised by design and intended purpose, manufacturing processes and technologies used, such as sterilisation and the use of nanomaterials. These lists of codes should be used in a way that provides for a multi-dimensional application to all typology of devices. This will ensure that notified bodies as well as the staff assigned to conformity assessment are fully competent for the devices they are required to assess. This guidance is intended to explain the different level of codes and how they should be used, including the use of conditions with a view to ensure a harmonised use of the codes especially for the allocation of resources to conformity assessment activities. 3 3 Assignment of codes to devices within the conformity assessment procedure When a manufacturer lodges an application with a notified body, the type of devices and technologies subject to conformity assessment activities are to be indicated. Usually, at the application review stage (as defined in section 4.3 of Annex VII MDR), notified bodies will verify the assignment of codes provided by the manufacturer or will assign these codes to the devices themselves. This verification is carried out in order to ensure that the notified body is able to assess the application based on its designation, and that it has available resources to carry out the relevant conformity assessment activities (feasibility evaluation). The final assignment is made by the NB. After this application review, and signing of the contract, the notified body will allocate appropriately qualified and authorised personnel to carry out audit activities or product reviews. The following table presents an overview of the different types of codes and a summary of the main characteristics of each of them for the assignment to specific devices and the allocation of resources. Type Code Assignment of codes to the device Relevance for allocation of conformity assessment team MDA / MDN Codes reflect design and intended purpose of device Exactly 1 code per device. The codes should be selected according to their hierarchical order in Regulation 2017/2185. If more than 1 MDA/ MDN code is applicable, the one that is highest in the list should be selected. Allocation of personnel involved in the review of technical documentation (e.g. product reviewers) or in audits concerning product related aspects. MDS Horizontal codes that reflect the specific characteristics of the device 0 to several per device Assign all codes applicable to the device. Select once an MDN/MDA code has been assigned. Allocation of personnel involved in the review of technical documentation (e.g. product reviewers of sterilisation validation). May also be applicable to staff performing audits concerning certain special processes (e.g. sterilization).* MDT Horizontal codes that describe technologies or processes 1 to several per device Assign the codes which describe the main production technologies or processes. Select once an MDN/MDA code has been assigned. Allocation of personnel involved in audits (e.g. site auditors involved in the auditing of metal processing). * Note: Assessment of these codes could be performed by Product reviewers or Site auditors depending on their competence 3.1 MDN / MDA-codes MDA / MDN-codes reflect the design and intended purpose of the device and hence are mostly relevant for the allocation of personnel involved in the review of technical documentation. In some specific cases, the NB may assign product reviewers to assess product performance and safety aspects during an audit. This means that if there are product related issues to be audited and the auditors do not possess the required qualification, product reviewers who are qualified for the device in question should be part of the audit team. The NB needs to ensure that the personnel allocated to the project are competent to assess for the devices and technologies under assessment . Special attention should be paid in situations such as the one described in example 4 of this section. 4 The MDA / MDN codes may either specify a field of medical application (e.g. MDA 0309 Active non- implantable ophthalmologic devices) or the physical or technological principle of the device (e.g. MDA 0302 Active non-implantable devices utilising non-ionizing radiation or MDA 0315 Software). Therefore, there are cases where more than one specific code might apply to a device (e.g. surgical laser for refractive surgery of the eye ). Also, where there is a broad intended purpose, several codes may apply. Having these issues in mind, when drafting the Regulation 2017/2185, the codes were put in order such that the MDA/MDN codes that require very specific technological knowledge and experience are highest in the code lists. Therefore, in cases where more than one MDA/MDN code apply, the code highest in the list is to be selected. This approach ensures consistent assignment of codes (and therefore consistent assignment of suitably qualified staff) to devices. Example 1: A surgical laser for refractive surgery of the eye is assigned to MDA 0302 Active non-implantable devices utilising non-ionizing radiation and not to MDA 0309 Active non- implantable ophthalmologic devices because, even though both codes are specific for the device, since MDA 0302 is higher in the list. Example 2: A screw for orthopaedic surgery is assigned to MDN 1102 Non-active osteo- and orthopaedic implants and not to 1104 Non-active soft tissue and other implants, because MDN 1102 is higher in the list. Devices may be composed of different “components” which, if they were products on their own, would belong to different MDA/MDN codes (1). In such cases, the intended purpose or the main physical or technological principle of the device should be considered (Example 3). Nonetheless, the notified body needs to ensure that the assigned staff is qualified to assess all components of the device. Example 3: A medical devices is composed of a suture anchor (a bone screw attached to a surgical suture to reattach ruptured tendons) as well as a single use deployment instrument and a single use bone drill. The components are provided sterile in a blister, are covered by the same technical documentation and are not available individually (e.g. are not medical devices on their own). This product is assigned to MDN 1102 Non-active osteo- and orthopaedic implants and not to MDN 1208 Non-active non-implantable instruments because the implanted component of the device is associated with the intended purpose rather than the deployment instrument and the drill. Note that, given the complexity and the diversity of medical devices, in exceptional cases deviations from the guidance given above may be necessary when assigning codes to devices in order to ensure suitably qualified staff in the conformity assessment. In such cases, a brief rationale shall be documented (see Example 4). Example 4: A heater-cooler unit (HCU) for cardiac surgery is a device through which blood circulates, and which changes the circulating blood’s temperature in order to achieve hypo- or hyperthermia. Both the codes MDA 0303 Active non-implantable devices utilising hyperthermia/hypothermia and MDA 0306 Active non-implantable devices for extra-corporal circulation, administration or removal of substances and haemapheresis are specific to the device. Since MDA 0303 Active non-implantable devices utilising hyperthermia/hypothermia is a code that describes physical or technological characteristics higher in the list, according to the rule explained above MDA 0303 should be chosen. Nonetheless, the notified body assigns the device to the code MDA 0306 Active non-implantable devices for extra-corporal circulation, administration or removal of substances and haemapheresis and documents that the risks associated with the HCU are such that the staff having experience in this code is more suitable to assess the device. It is important to note that Stand-alone software (i.e. software that is not part of a physical medical device) should be assigned to MDA 0315 since assessment of software requires very specific knowledge (see annex VII 3.2.2 5 th indent MDR) and also that non-implantable cardiovascular 1 This description does NOT refer to procedure packs or systems according to MDR Article 2 (10) and (11) since those are combinations of individual CE-marked products that have been subjected to separate conformity assessments. 5 catheters, guidewires, introducers, filters and related tools shall fall under MDN 1203 (instead of MDN 1201 or MDN 1202). 3.2 MDS codes MDS codes are horizontal codes that are applicable to devices with specific characteristics. All codes that are applicable need to be assigned to a device in order to ensure that the review team possesses the full set of qualifications necessary for the conformity assessment. The MDS-codes are mainly relevant for the allocation of personnel involved in the review of technical documentation. This is because, generally, the auditing aspects linked to MDS codes have their corresponding MDT code for the relevant technology (e.g. MDS 1001 Devices incorporating medicinal substances vs MDT 2007 Devices which require knowledge regarding the production of pha rmaceuticals ). However, MDS codes may also be applicable to staff performing audits concerning certain special processes (for example MDS 1005 for staff auditing ethylene oxide sterilization processes). Example 1: A partially resorbable, sterile surgical implant that contains an antibiotic to prevent post-surgical infection will need to be assigned to the following MDS codes: 1) MDS 1005 - Devices in sterile condition: because it is provided sterile, 2) MDS 1008 - Devices utilising [...] being wholly or mainly absorbed or locally dispersed in the human body […]: because it is absorbed, and 3) MDS 1001 - Devices incorporating medicinal substances: because it contains an antibiotic. Example 2: An infusion pump should be assigned to MDS 1009 - Devices incorporating software/utilising software/controlled by software […] because the infusion pump is controlled by software. 3.3 MDT codes MDT codes relate to the technologies and processes that are used in the manufacturing and making available of the devices. MDT codes are relevant for the allocation of site auditors. Assignment of MDT codes should be done taking into consideration production of the device itself as well as for critical upstream production steps. This means that, even though many codes could be applicable when taking into consideration the processes involved in the entire supply chain of a medical device, these should not be considered for the use of MDT codes (e.g. for an electronic medical thermometer, at one point, metal processing, plastic processing, non-metal mineral processing, chemical processing, manufacture in clean rooms, manufacturing using electronic components, labelling and packaging are necessary to assemble the device from raw materials). Example 1: An electronic medical thermometer for layman’s use should be assigned to the following MDT codes: 1) MDT 2010 Devices manufactured using electronic components including communication devices because the product is assembled from electronic components and 2) MDT 2011 Devices which require packaging, including labelling because the device is packed and labelled. Example 2: A sterile animal derived bone graft substitute is manufactured using several steps. In the first step, the raw animal bone undergoes a sequence of chemical treatments to remove organic components. In a second step, the remaining mineral bone component is subjected to a heat treatment, then ground and sieved to obtain particles of defined sizes. The material is packed, labelled and sterilized. Therefore the following MDT codes should be assigned: 6 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant after the heat treatment is conducted in clean rooms, 2) MDT 2009 Devices manufactured using processing of materials of human, animal, or microbial origin because the implant is made from animal bone 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Note: MDT 2006 Devices manufactured using chemical processing and MDT 2003 Devices manufactured using non-metal mineral processing (e.g. glass, ceramics) were not applied since the chemical treatment and (bone) mineral processing are already considered within the scope of processing of animal materials. Example 3: A calcium phosphate bone cement is provided as a sterile powder composed of a mixture of calcium salts and a vial with sterile saline. The following MDT codes should be assigned: 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant is in a controlled environment, 2) MDT 2006 Devices manufactured using chemical processing, because the main risks in manufacturing are related to the testing and mixing of the components, 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Example 4: A manufacturer of cross-linked hyaluronic acid implants has no in-house manufacturing. The finished, labelled implant is bought from a supplier. The implant raw material (hyaluronic acid) is produced by fermentation using bacteria. The following MDT codes should be assigned: 1) MDT 2008 Devices manufactured in clean rooms and associated controlled environments, because the manufacturing of the implant is in a controlled environment, 2) MDT 2005 Devices manufactured using bi otechnology, because the main risks in manufacturing are related to the production and cross-linking of the hyaluronic acid. 3) MDT 2011 Devices which require packaging, including labelling because the implant is packed and labelled. Note that, despite the fact that the manufacturer itself does not physically manufacture the device, the MDT codes concerning the manufacturing steps are assigned to the device since they are relevant when auditing suppliers / subcontractors. 4 Competence description: conditions (including limitations) Conditions should be established by the notified body for individual codes in cases where the qualification of the staff authorised to a certain code is not sufficient to cover the entire spectrum of the devices within this code. The designating authority could also apply conditions to the notified body's designation where the notified body does not have sufficient competence to cover a given code or could seek designation for conformity assessment of only certain devices within a code. Conditions, including limitations, should be formulated in an unambiguous way (see example 1). Furthermore, since the technical codes basically mirror the competence system of the notified body, the conditions and limitations should concern device characteristics (see example 2). Example 1: “MDN 1101 Non-active cardiovascular, vascular and neurovascular implants. Condition: heart valves”. This condition is unsuitable since it is not clear whether the notified body is restricted to assessment of heart valves or whether those products are excluded from 7 the scope of designation. Therefore, the condition should be “excluding heart valves” or “including only heart valves”. Example 2: “MDN 1102 Non-active osteo- and orthopaedic implants. Condition: excluding class III devices”. The scope of designation is intimately linked to the qualification of the staff that the notified body needs to have available. Conditions serve to exclude the devices for which the notified body does not have competent staff and/or suitable procedures; therefore, they need to be expressed in a way that they relate to knowledge and experience of staff and/or procedures. The condition “excluding class III devices” does not allow this and therefore it is unsuitable. In this case, the designating authority has to determine, based on the qualification of the notified body’s staff, which devices are included in the scope. This might result, for example, in the following condition: “including only orthopaedic plates and screws; excluding implants that are applied in or on the spine”. Further examples of conditions are illustrated in the final column of the table below. Considerations of the conditions should be based on the demonstrated competence of the applicant body . 8 5 Specific clarifications linked to individual codes The devices included in the third and fourth columns are only a few examples of the devices covered in the relevant code. The t hird column is not intended to provide an exhaustive list of devices included in each code. MDA CODE Active implantable devices Devices covered and Specific Considerations1 Examples of conditions MDA 0101 Active implantable devices for stimulation / inhibition / monitoring Implanted defibrillator Spinal cord stimulator Implantable cardiac pacemakers Implantable bladder stimulators Excluding brain stimulation MDA 0102 Active implantable devices delivering drugs or other substances Implanted drug delivery pump MDA 0103 Active implantable devices supporting or replacing organ functions Artificial heart Cochlear implants MDA 0104 Active implantable devices utilising radiation and other active implantable devices Prostate radioactive seed implant 1 The assessment also should consider Section 5.1 of Annex IX applies as well as Validation of SSCP acc. Article 32 . 9 MDA CODE Active non-implantable devices for imaging, monitoring and / or diagnosis Devices covered and Specific Considerations Examples of conditions MDA 0201 Active non-implantable imaging devices utilising ionizing radiation X-ray computer tomography equipment Gamma cameras Fluoroscopy equipment PET scanner Restricted to X-ray and gamma cameras MDA 0202 Active non-implantable imaging devices utilising non-ionizing radiation MRI computer tomograph MDA 0203 Active non-implantable devices for monitoring of vital physiological parameters Blood pressure monitor Medical thermometer Pulse oximeter Apnoea monitors Intensive care patient monitoring system Spirometers Electrocardiographs Electroencephalographs MDA 0204 Other active non-implantable devices for monitoring and / or diagnosis Ocular tonometer Audiometers Retinal cameras 10 MDA CODE Active non-implantable therapeutic devices and general active non-implantable devices Devices covered and Specific Considerations Examples of conditions MDA 0301 Active non-implantable devices utilising ionizing radiation Radioactive sources for cancer after loading therapy Therapeutic cyclotrons and linear accelerators MDA 0302 Active non-implantable devices utilising non-ionizing radiation Surgical laser for refractive surgery of the eye Laser for pain treatment Including only microwave and magnetotherapy medical devices MDA 0303 Active non-implantable devices utilising hyperthermia / hypothermia Medical heating blanket Warming and cooling blankets Blood warmers Paraffin bath MDA 0304 Active non-implantable devices for shock-wave therapy (lithotripsy) Extracorporeal shock wave lithotripsy device MDA 0305 Active non-implantable devices for stimulation or inhibition Automated external defibrillator Device for the transcranial magnetic brain stimulation Device for transcutaneous electrical nerve stimulation (TENS) Muscle stimulators Electrical acupuncture External bone growth stimulators 11 MDA 0306 Active non-implantable devices for extra- corporal circulation, administration or removal of substances and haemapheresis Haemodialysis machine and equipment Cardiopulmonary bypass pump Infusion pumps Feeding pumps Jet injectors for vaccination Blood pumps for heart-lung machines Anaesthesia machines MDA 0307 Active non-implantable respiratory devices Medical ventilator Hyperbaric chambers Nebulisers MDA 0308 Active non-implantable devices for wound and skin care Water jet for wound debridement MDA 0309 Active non-implantable ophthalmologic devices Aspiration pump for opthalmological use (removal of crystalline residue) MDA 0310 Active non-implantable devices for ear, nose and throat Hearing aids MDA 0311 Active non-implantable dental devices Powered dental surgical unit and hand pieces Surgical suction device for dental use Ultrasonic scalers Chairs with equipment MDA 0312 Other active non-implantable surgical devices RF electrosurgical generator Electrosurgical instrument Cauterization devices. Powered surgical drills and saws 12 MDA 0313 Active non-implantable prostheses, devices for rehabilitation and devices for patient positioning and transport Hospital beds Patient hoists Electric Wheelchairs Active limb prostheses Exoskeletons MDA 0314 Active non-implantable devices for processing and preservation of human cells, tissues or organs including in vitro fertilisation (IVF) and assisted reproductive technologies (ART) IVF cryopreservation systems blood bank refrigerator MDA 0315 Software Radiotherapy planning system. MDA 0316 Medical gas supply systems and parts thereof Medical gas supply system in a hospital Gas manifold and line pressure regulator for medical regulators Medical gas supply pipeline systems MDA 0317 Active non-implantable devices for cleaning, disinfection and sterilisation Sterilizers like autoclaves etc Washer disinfector for medical devices. MDA 0318 Other active non-implantable devices 13 MDN CODE Non-active implants and long term surgically invasive devices Devices covered and Specific Considerations Examples of conditions MDN 1101 Non-active cardiovascular, vascular and neurovascular implants Cardiac vascular stent Peripheral vascular stent Artificial heart valve Cardiac Valve Prostheses, Vascular and neurovascular grafts, shunts, vascular stents, cardiovascular patches Sutures for cardiovascular surgery For biological heart valves MDS 1003 should be applied. For drug eluting stents - MDS 1001 should be appliedIncluding only cardiac stents MDN 1102 Non-active osteo- and orthopaedic implants Artificial spinal disc Spinal cage Bone graft substitute for orthopaedic indications Prosthetic joint replacements (i.e knee, hip implants) Bone cement Hyaluronic acid implant for intra-articular use Orthopaedic nails, screws,plates Bone graft substitute for maxillofacial indications sutures, suture anchors, staples for orthopedic surgery spacers, ligament reconstruction products For antibiotic bone cements- MDS 1001 should be applied For absorbable substances MDS 1008 should be applied 14 MDN 1103 Non-active dental implants and dental materials Dental implant Dental fillers Root canal filler Abutments 15 MDN 1104 Non-active soft tissue and other implants Hyaluronic acid dermal fillers Intraocular lenses Intrauterine dispositive- IUD Breast implant Hernia mesh Urethral stent implants Sutures (not falling within the above codes) Eyelid implants Bariatric surgery devices: Intragastric Balloons, Gastric Bands, Anti-Reflux implants. Lung Volume Reduction devices: Coils, Valves, Sealants. Biliary and Pancreatic stents For contraceptive intrauterine devices containing copper or silver – MDS 1001 should be applied Excluding breast implants MDN CODE Non-active non-implantable devices Devices covered and specific conditions Examples of conditions MDN 1201 Non-active non-implantable devices for anaesthesia, emergency and intensive care Device for pleural drainage Masks, tubes for the administration of gases. Endotracheal tube Tracheostomy tubes Endotracheal tube introducers 16 MDN 1202 Non-active non-implantable devices for administration, channelling and removal of substances, including devices for dialysis Intravenous line Hypodermic needle Syringe tubing, bags for injection or transfusion Dialysis filter Dialysis solution Epidural catheters, Urinary Catheter Amnioscopic needles MDN 1203 Non-active non-implantable guide catheters, balloon catheters, guidewires, introducers, filters, and related tools Vascular filter catheter Embolectomy catheter Cardiovascular guidewires and catheters Neurovascular catheters central venous catheter. MDN 1204 Non-active non-implantable devices for wound and skin care Wound dressing Cotton wool Gauze dressings Bandages Sutures for dermal wound closure (of less than 30 days) Surgical gloves For dressings incorporating an antimicrobial agent - MDS 1001 should be applied MDN 1205 Non-active non-implantable orthopaedic and rehabilitation devices Orthoses Crutches Wheelchairs 17 MDN 1206 Non-active non-implantable ophthalmologic devices Contact lenses Eye drops Instrument for ophthalmologic surgery Solutions for contact lenses. MDN 1207 Non-active non-implantable diagnostic devices Thermal expansion thermometer MDN 1208 Non-active non-implantable instruments Instruments for general use in surgery: Forceps, clamps, scalpels, dental instruments MDN 1209 Non-active non-implantable dental materials Etching solution for dental use Braces Dental cements (when not considered long term surgically invasive) Dental impression materials MDN 1210 Non-active non-implantable devices used for contraception or prevention of the transmission of sexually transmitted diseases Condom Contraceptive diaphragms MDN 1211 Non-active non-implantable devices for disinfecting, cleaning and rinsing Solutions for disinfecting medical devices Contact lens care, catheter lock solutions MDN 1212 Non-active non-implantable devices for processing and preservation of human cells, tissue or organs including in vitro fertilisation (IVF) and assisted reproductive technologies (ART) Freezing solution for egg cells Embryo transfer catheters Artificial insemination probes Media, substances or mixture of substances intended for washing, separating, sperm immobilizing, cryoprotecting solutions. 18 MDN 1213 Non-active non-implantable devices composed of substances to be introduced into the human body via a body orifice or the dermal route MDN 1214 General non-active non-implantable devices used in health care and other non- active non-implantable devices Ultrasound gels 19 MDS CODE Devices with specific characteristics Devices covered and specific conditions Examples of conditions MDS 1001 Devices incorporating medicinal substances Devices incorporating medicinal products including herbal substances and human blood derivatives are included in this code. MDS 1002 Devices manufactured utilising tissues or cells of human origin, or their derivatives Section 5.3.1 of Annex IX applies MDS 1003 Devices manufactured utilising tissues or cells of animal origin, or their derivatives Section 5.3.2 of Annex IX applies Devices manufactured utilising tissues or cells of animal origin, or their derivatives, which are non- viable or rendered non- viable, unless such devices are intended to come into contact with intact skin only MDS 1004 Devices which are also machinery as defined in point (a) of the second paragraph of Article 2 of Directive 2006/42/EC of the European Parliament and of the Council1 MDS 1005 Devices in sterile condition Including aseptic processing, ethylene oxide gas sterilisation (EOG), low temperature steam, formaldehyde sterilisation, moist heat sterilisation, radiation (gamma, x-ray, electron beam), sterilisation with hydrogen peroxide, sterilisation with liquid chemical sterilising agents, thermic sterilisation with dry heat 1 Directive 2006/42/EC of the European Parliament and of the Council of 17 May 2006 on machinery, and amending Directive 95/16/E C (recast) (OJ L 157 9.6.2006, p. 24). 20 MDS 1006 Reusable surgical instruments Reusable surgical instruments according to art. 52 (7) c) MDR MDS 1007 Devices incorporating or consisting of nanomaterial MDS CODE Devices with specific characteristics Devices covered and specific conditions Examples of conditions MDS 1008 Devices utilising biologically active coatings and / or materials or being wholly or mainly absorbed or locally dispersed in the human body or are intended to undergo a chemical change in the body Section 5.4 of Annex IX applies for devices intended to be introduced into the human body via a body orifice or applied to the skin and devices at are systemically absorbed by the human body in order to achieve their intended purpose MDS 1009 Devices incorporating software / utilising software / controlled by software, including devices intended for controlling, monitoring or directly influencing the performance of active or active implantable devices MDS 1010 Devices with a measuring function MDS 1011 Devices in systems or procedure packs MDS 1012 Products without an intended medical purpose listed in Annex XVI to Regulation (EU) 2017/745 21 MDS 1013 Class III custom-made implantable devices MDS 1014 Devices incorporating as an integral part an in vitro diagnostic device 22 MDT CODE Devices for which specific technologies or processes are used Examples of device manufacturing technologies MDT 2001 Devices manufactured using metal processing 3 d printing, Casting, Welding 3d printing (metal), turning (metal), anodization, passivation, polishing, surface modification, laser tube cutting, honing MDT 2002 Devices manufactured using plastic processing Injection molding, Extrusion, Bonding polymer compounding, 3d printing (plastics), thermoforming, blow moulding, turning (plastics) MDT 2003 Devices manufactured using non-metal mineral processing (e.g. glass, ceramics) Ceramic sintering, ceramic compounding, MDT 2004 Devices manufactured using non-metal non-mineral processing (e.g. textiles, rubber, leather, paper) Weaving, knitting MDT 2005 Devices manufactured using biotechnology Fermentation using cell cultures, enzymatic production processes, purification and modification of biomolecules MDT 2006 Devices manufactured using chemical processing Compounding, buffering MDT 2007 Devices which require knowledge regarding the production of pharmaceuticals production, handling and incorporation into a device of substances which, if used separately, can be considered to be a medicinal product MDT 2008 Devices manufactured in clean rooms and associated controlled environments MDT 2009 Devices manufactured using processing of materials of human, animal, or microbial origin Handling, dissection, storage, processing, inactivation and sterilization of human and animal tissues MDT 2010 Devices manufactured using electronic components including communication devices MDT 2011 Devices which require packaging, including labelling 23 MDT 2012 Devices which require installation, refurbishment Installation of devices at the point of use by or under the manufacturer’s responsibility MDT 2013 Devices which have undergone reprocessing

QA requirements for notified bodies V2 01102019.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 1 of 14 MDCG 2019-6 v2 Questions and answers: Requirements relating to notified bodies Version 2 - October 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 2 of 14 Introduction This document presents questions and answers on requirements relating to notified bodies under Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). The issues covered by this document have been identified in the context of joint assessments, and the document may be updated from time to time as new issues are identified. I. ORGANISATIONAL AND GENERAL REQUIREMENTS I.1. Are CABs obliged to follow guidance endorsed by the Medical Devices Coordination Group (MDCG)? Guidance documents are by definition not compulsory. However, all guidance documents endorsed by the MDCG reflect the interpretation of the EU law jointly agreed by the authorities which are in charge of interpreting and applying the EU law. Hence notified bodies should be encour aged to apply these guidance documents (also taking into consideration Section 1.6.2 of Annex VII to the MDR/IVDR 1). Furthermore, it is to be noticed that the European Court of Justice often refers to guidance documents when developing its rulings. Hence Notified Bodies have an interest, also in terms of liabilit y risk, to follow that guidance. I.2. What is the meaning of “legal personality” under Section 1.1.1 of Annex VII 2? The CAB needs to have legal personality, meaning that it has to exist as a legal entity. To that end, it must be registered as legal entity, also called "legal person". The wording of the MDR/IVDR does not exclude that only a part of a legal entity undertakes conformity assessment activities in the field of medical devices. In this case, where the CAB is part of a wider legal entity, the documentation provided should be clear as to where the CAB sits within that legal entity. In case the entire legal entity is the CAB, the documentation to be provided refers to the legal entity as such. It is always this legal entity as such which is designated (and not its organisational part). I.3. What is the meaning of “organ isation” as described in 1.1.2 of Annex VII? The term of "organisation" as described in 1.1.2 refers to the whole organisation (e.g. corporate group) to which the CAB belongs including the CAB's legal entity. The concept of "organisation" should be based not only on ownership rights (e.g. shares), but also functional/hierarchical links, such as voting/management/other control rights. One typical example of organisation is a holding company owning different companies (i.e. separate legal entities), one of them being or containing the CAB. 1 1.6.2. The notified body shall take into consideration guidance and best practice documents. 2 Unless specified otherwise, a reference to Annex VII means a reference to both Annex VII of the MDR and Annex VII of the IVDR. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 3 of 14 I.4. Does the term “organisational structure” as per 1.1.5 refer only to hierarchical relationships? If a notified body is part of a larger organisation, both hierarchical (i.e. mother and daughter companies of the CAB) and horizontal relationships (e.g. sister companies where there is a common mother company) between the notified body and other entities belonging to that organisation are covered by the term "organisational structure". The organisational structur e of the CAB will vary depending on the complexity of the legal entity and the organisation to which it belongs. For instance, in the case of holding companies, the CAB could provide a matricial organisational chart with dual reporting relationships (i.e. functional and managerial). In this case, hierarchical and reporting lines should be clear and should match the information provided in job descriptions for the activities related to the MDR/ IVDR certification. I.5. Is a 3-year competitor clause for consultants covered in the MDR / IVDR requirements? The MDR/IVDR does no longer define the timelines for clearance of consultants that were defined in Section 1.3b of Annex I to the Implementing Regulation (EU) 920/2013, except in case that the person worked for the same company or the group (Section 1.2.4 of Annex VII). However, the requirements under the Implementing Regulation (EU) 920/2013 on the management of impartiality for consultants are included in sections 1.2.2, and 1.2.3 (c), (d) and (e) of Annex VII. Therefore, it is expected that CABs will have similar measures in place under both regimes. It is essential that competitors, authorised representatives and suppliers are also included in the identification, analysis and resolution of potential conflicts of interests. I.6. May CAB provide pre-certification services? Pre-certification services are not allowed before an application is lodged by the manufacturer (e.g. review of clinical data or assessment of the quality management system aside from regulatory standards such as ISO 13485) and therefore these services have to take place under the scope of the application. Every activity carried out once an application has been submitted will be considered part of the conformity assessment activities and therefore if the manufacturer withdraws its application after this process has started, the notified body has to inform the other notified bodies through Eudamed according to Article 53(2) of the MDR / 49(2) of the IVDR. Whenever these activities consist in providing solutions to the manufacturer, they fall under the definition of consultancy and therefore the notified body impartiality policy and procedure(s) will need to cover that these pre-certification activities could be seen as consultancy. The CAB has to implement in their policy and/or procedures how it prevents that pre-certification activities carried out as part of the conformity assessment activities are falling into consultancy. Services provided by the CAB that could fall under the definition of conformity assessment activities are not allowed outside of an application as they would be regarded as consultancy (e.g. gap analysis, check of MDR/IVDR readiness, use of mock-up files produced instead of “real” TD assessments). Nevertheless, general Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 4 of 14 training activities that are not client specific and that relate to regulation of devices or to related standards are allowed. I.7. Can the CAB accept applications prior to being notified? No, applications under the MDR / IVDR cannot be accepted before the designation of the CAB became valid, i.e. the day after the notification is published in NANDO. I.8. How are the conditions on remune ration to be assessed within the meaning of 1.2.5 of Annex VII? The MDR/IVDR establishes that remuneration cannot depend on the results of the assessments. Both direct and indirect correlations between results of the assessments and remuneration are prohibited. Hence an individual examination is needed. Special care has to be applied with regard to bonuses. Bonuses on the basis of general objectives, even when not directly linked to the result of the individual conformity assessments, might still be problematic if they indirectly correlate to the average result of assessments. In the context of a joint-assessment, sampling of contracts or agreements covering remuneration (sheets) should take place. The sampling should cover different grades of influence, e.g. project handlers, final reviewers/decision makers, or head of the CAB / medical devices' certification. I.9. Are declarations of absence of conflict of interests sufficient to ensure compliance with legal re quirements for impartiality? No, declarations are not sufficient in isolation to ensure compliance. CABs should define their own system to comply with the legal requirements for independence and impartiality, but a system based on analysis of risk and control measures should be generally in place. This system will usually include a comprehensive risk analysis of the CAB's activities, its staff (including top- level management) and the activities of its organisation or related bodi es. Risks posed to impartialit y from each individual should be assessed with regard to past employment, consultancy services and financial interests. For instance, shares in companies certified by the notified body or in competitors of these companies (investment funds can be seen differently) as well as relatives of the person under analysis. Also, the risks linked to subcontractors/suppliers (1.2.1) of the manufacturer need to be assessed. Section 2.4 of Annex VII also requires, as part of this system, a “multi-level” statement. Firstly, a general one, listing any existing or prior association with clients or devices or processes under assessment. This general one needs to be renewed from time to time (e.g. annually). In addition, there is a need for a written statement and verification by the notified body within each conformity assessment project. Any involvement in processes (e.g. design, risk management, manufacturing processes) being related with the devices and quality management systems for economic operators covered by the application/designation needs to be seen as consultancy. Other activities not specifically linked with the product will be also regarded as consultancy (e.g. internal audi ts to manufacturers or client specific training). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 5 of 14 I.10. Does a CAB that is part of a larger organisation need individual liability insurance? The CAB is responsible for taking out liability insurance and therefore there must be evidence that the legal entity is covered by a liability insurance that fulfils the legal requirements. The contract with the insurance company can be signed by other legal entity of a larger organisation (i.e. mother company) provided that the contract gives the CAB the individual right to be protected against liabilit y claims. The notified body must be able to invoke that right directly towards the insurance company, and not only indirectly via the company which has signed the contract (this is important e.g. in case of insolvency of the signing company or in case of unwillingness or inability of the signing company to effectively invo ke the insurance contract towards the insurance company). Furthermore, the signing legal entity must involve the notified body in any change of insurance conditions affecting the medical devices conformity assessment activities of the CAB so that the notified body has the possibility to react if it considers that the coverage is insufficient. Any change on the liability insurance which may affect the compliance of the notified body with the requirements set out in Annex VII should be communicated by the body to the authority responsible for notified bodies in accordance with articles 44 (1) of the MDR / 40(1) of the IVDR. II. QUALITY MANAGEMENT SYSTEM III. RESOURCES REQUIREMENTS III.1. Is a complete re-author ization of existing personnel necessary to document satisfaction of the new qualification criteria under section 3 of Annex VII? Yes, all personnel that will be used to per form conformity assessment tasks under the MDR/IVDR shall be authorized under the new criteria. For the satisfaction of the work experience criteria, the CAB can accept previous experience in a notified body but it cannot automatically grandfather authorisations (i.e. transfer authorisations) granted by other notified body or by the same notified body under the Directives. However, the experience in a notified body needs to be extensive and traceable and always specific to the tasks to be carried out and the specific technology or product (specific codes) in order to satisfy the MDR/IVDR qualification criteria. In addition, comprehensive and objective evidence of such previous experience in a notified body in the relevant scope shall be part of the personnel files. III.2. What is the meanin g of “permanent ava ilability of sufficient personnel” within Section 3.1.1 of Annex VII? In respect to the availability of personnel, MDR / IVDR Annex VII Section 3.1.1 do not establish the number of auditors / reviewers per code to ensure permanent availability of sufficient personnel. As a ve ry minimum, it is considered that notified body should have one person available and authorised per applied-for scope code Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 6 of 14 and role as per Section 3.2 of Annex VII at the time of the joint assessment. Nevertheless, it is recommended that the notified body has two product reviewers/auditors authorised per code to ensure a sufficient capacity to allow fulfilment of other related requirements such as rotation of personnel. When this is not the case, an observation may be raised at the joint assessment in order to flag that for certain codes the available resources are limited. The notified body is expected to have 2 auditors / reviewers available and authorised per applied-for scope in order to fulfil the legal requirements under Section 3.1.1 of Annex VII at the moment of its re-assessment joint assessment. III.3. What is the meaning of “possess or have access to all equipment and facilities” needed to perform its tasks within the meaning of Section 3.1.1 of Annex VII of the MDR? This question refers to the requirements in relation to possessing or having access to sufficient equipment and facilities to properly perform the conformity assessment activities within the CAB's applied-for scope. It is expected that the CAB would have internal testing facilities or access to testing subcontractor(s) (e.g. by a framework agreement) for device tests in support of the codes for which it seeks designation under Annex X and Annex XI(B). In order to be designated under Annex X and XI(B), the CAB's personnel needs to have the technical knowledge to identify and select all the tests needed; the CAB must have implemented detailed procedures ensuring the identification of the relevant tests; and have access to at least some of the tests to be performed within the scope of designation. In particular, for each MDA or MDN code for which the CAB applies under Annex X or XIB it should identify at least the basic tests to be performed and the corresponding testing fac ilities (internal or subcontracted). The CAB should be able to demonstrate how t he facilities available are linked to the codes the CAB applies for. Nevertheless, the CAB is not expected to hav e testing equipment and facilities (either in house or a framework agreement) covering all possible tests within a code under Annex X or XI(B) or as part of surveillanc e or unannounced audits as some of the tests are very specific or rarely used. For these purposes, the CAB should have procedures in place in order to find additional subcontractors whenever needed or to define under which circumstances the CAB will perform witness testing (i.e. when the test equipment needed is very specialised) III.4. What is the meaning of "two years' professional experience" in cases where the experience h as been gained within a CAB under section 3.2.5 of Annex VII? According to MDR/IVDR Annex VII 3.2.5 product reviewers have to demonstrate two years’ professional experience in the design, manufacture, testing or use of the device or technology to be assessed or related to the scientific aspects to be assessed. Experience related to the scientific aspects to be assessed could include, Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 7 of 14 but not be limited to, extensive experience in conformity assessment activities in a specific type of device or technology gained within a CAB3 . In such case, when professional experience – based on a relevant background education – is to be proven by activities only within a CAB, this experience should have been gained during at least two years. As a guideline if one individual has carried out at least five full technical documentation assessments of devices in the relevant code (or aspects to be assessed) or under the equivalent code under the Directives, during at least 2 years, this can be accepted as a valid work experience within the meaning of 3.2.5 of Annex VII. Nevertheless, based on the assessment of the educational background and specific work experience of the individual, the CAB has always to analyse if additional assessments must be performed (i.e. under supervision). In addition, in situations where the objective evidence for the experience gained during technical file reviews is insufficient (e.g. if the staff was authorised for the code in a different CAB without detailed supporting evidence), as a guideline, the technical documentation assessments on the code (or aspects to be assessed) to which the individual wishes to be authorised have to be carried out under close supervision of an experienced product reviewer (e.g. mirror review 4). At least five of these assessments should be related to a full assessment. In addition to technical documentation assessments or product tests, product-related audit activities can be considered as work experience as long as they are not used solely and they are adequately documented and assessed by the authorising personnel of [or within] the CAB. In all of the cases above, the CAB has to analyse individual training needs (e.g. on relevant standards) especially when the work experience was gained a few years ago in the past or when the individual has experience related to a very similar technology. Before authorisation, the authorising personnel needs to ensure that all the qualification criteria under 3.2.5 of Annex VII are fulfilled and their satisfaction fully documented (including an adequate justification in the exceptional cases where the criteria cannot be fully demonstrated as established in 3.3.1 of Annex VII) and that the knowledge is state-of-the-art. For codes (MDR/IVDR) comprising a broad range of devices, the CAB has to ensure that the individual has carried out technical documentation assessments in different devices covered by the code or the authorisation to the code is to be granted with appropriate limitations. III.5. Does the CAB need to defi ne qualification criteria for monitoring and maintenance of competences in accordance with Section 3.5 of Annex VII? 3 As defined in section 6.2.2. of NBOG BPG 2017-2 4 Mirror review is to be understood as a review carried out simultaneously by two product reviewers of the notified body, one being on training and the other one being an experienced product reviewer on that code. Once the review is finalised from the two reviewers, the most experienced will assess and document the quality of the review carried out by the person in training. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 8 of 14 Yes. The CAB’s personnel competence needs to be maintained and therefore reviewed at regular intervals. For this purpose, the authorising personnel5 (as per 3.2.3 of Annex VII) needs to define qualification criteria for monitoring and maintenance of competence of its entire staff (internal and external, as well as subcontractors), involved in conformity assessment activities. Such "re-qualification" or "maintenance" criteria will be used as a basis for re-authorisation of personnel to codes and roles. In respect of monitoring of competence, such criteria should be defined for personnel involved in conformity assessment activities, at least for personnel with relevant clinical expertise, product reviewers, site auditors and final reviewer / decision-maker, and authorising personnel. III.6. What is the meaning of the term “employed” in MDR Article 36(1) / IVDR Article 32(1)? The personnel referred to in Article 36(1) MDR / Article 32(1) IVDR carries out the key functions within the notified body, and therefore the Regulations expressly require that this personnel is employed by the notified body. This requirement is estimated to be complied with when the contractual relationship between the notified body and the individual meets at the minimum the following criteria:  direct employment contract between the notified body and the employee setting out the rights and obligations of the latter;  control and supervision over the activities of the employee by the notified body  direct reporting obligations of the employee towards the notified body; and  a direct paid remuneration by the notified body to the employee for the work carried out, accompanied by the payment of any relevant taxes and social security contributions. Any reference to “internal activities” sha ll be intended as activities being carried out by personnel employed by the Notified Body. N.B. Whenever needed and appropriate, any action from the Notified Bodies aimed at ensuring compliance with those requirements should be taken throughout the designation period as soon as possible and completed at the latest by the time of their first re-assessment. III.7. What is the meaning of “pe rmanent availability of personnel with relevant clinical expertise” in accordance with sections 3.2.4 and 3.1.1 of Annex VII? With regard to “personnel with relevant clinical expertise”, in order to fulfil the tasks covered in Section 3.2.4 of Annex VII it is expected that the CAB has at least one "internal clinician" who, where possible, has to be employed by the CAB. This does 5 Short term used in NBOG BPG 2017-2 to refer to "personnel responsible for establishing qualification criteria and for authorising other personnel to perform specific conformity assessment activities" according to Section 3.2.3 of Annex VII. Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 9 of 14 not preclude the possibility to subcontract su ch a role, provided that the notified body produces a justification as to why it is not possible to employ the person(s). In any case, when the CAB does not have the possi bility of employing that person(s), it should at least ensure that she/he is fully integrated throughout the conformity assessment and the decision-making process, which means that the person is involved in the CABs assessment and decision-making process in the same way as an employed staff. However, it should be noted that when the internal clinician is a subcontractor even if this person will suppo rt the final review and decision making process as indicated in 3.2.4 (e.g. in case an external clinical expert has been involved making a recommendation to the final reviewer or decision maker) they cannot be authorised as final reviewer or decision maker as these personnel should be employed by the notified body itself as required in Art. 36 of the MDR and Art. 32 of the IVDR. Accordingly, all “internal clinicians” are integrated, whereas some internal clinicians are not employed. Given that the term "internal clinician" is widely spread and it has been used to defined personnel carrying out tasks established in Section 3.2.4 of Annex VII it is assumed that when the term "internal clinician" is used, it could refer either to an employee of the CAB or not. IV. PROCESS REQUIREMENTS IV.1. Do devices certified under the Directives need to be subject to a full conformity assessment under the new Regulations if the manufacturer applies for certifi cation under the MDR / IVDR? The conformity assessment activities described under Article 52 / Article 48 apply to any certificate issued under the new regulations. As no exceptions were established under the regulations for the migration or transfer of MDD/AIMDD/IVDD certificates to the MDR / IVDR the general provisions should apply. Therefore, all devices to be certified under the MDR / IVDR should be subject to an initial certification according to the applicable annex. The notified body should ensure that all requirements under the MDR / IVDR are fulfilled. It may not restrict its procedures to gap audits or gap file reviews. It should be noted that MDD/AIMDD/IVDD certificates will remain valid until their expiration date and at the latest on 27 May 2024 as long as conditions laid down in Article 120(3) of the MDR and 110 (3) of the IVDR are complied with. IV.2. What should be the criter ia for auditing suppliers and subcontractors? The MDR/IVDR established that the audit of the manufacturer pr emises must include an audit on the premises of subcontractors and/or suppliers if appropriate. Therefore, the notified body should have criteria for auditing these actors on the basis of their criticality. At the very least, the criteria defined in Section 4.5.2(b) of Annex VII should Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 10 of 14 be applied (i.e. the control over the supplier/subcontractor and its influence on the conformity of the device is essential whereas the sole existence of a certificate against ISO 13485 is not sufficient). IV.3. What is the meaning of "examinations and tests" to be included in a certificate in accordance with Section 10 of Annex XII of the MDR / IVDR? 6 Certificates do not need to include reference to relevant common specifications or harmonised standards as long as such information on all examinations and tests performed is traceable and available from e.g. report(s) which are mentioned in the certificate. IV.4. What are the applicable requirements for voluntary certificate transfer under MDR Article 58 / IVDR Article 53? While MDR Article 58(1) / IVDR Article 53(1) sets out the requirements for a transfer agreement, it does not specify the conformity assessment activities to be performed by the incoming NB. he incoming NB may decide not to carry out full conformity assessment activities according to Article 52 MDR / Article 48 IVDR, as long as it does have sufficient information in respect to the conformity ac tivities performed by the outgoing NB. For quality management system certificates, the incoming NB needs to perform appropriate on-site audit(s) and assessments to ensure that the manufacturer in question applies the approved QMS and the post-market surveillance plan prior to the issue of any certificate. In respect to the assessment of technical documentations on a sampling basis, the oncoming NB shall review the previous assessment results together with a sample of a technical documentation and draw up or amend a sampling plan. For product certificates (Annex IX Chapter II/Annex X), new certificates without a comprehensive (initial) review may be issued as long as the documentation received does not identify ongoing existing or other concerns. The incoming NB assumes full responsibility for the new certificates issued following the transfer. IV.5. What are the applicable requirements for OBL manufacturers? The MDR / IVDR does not distinguish between OBL 7 and other manufacturers. There are just "manufacturers" and therefore OBL manufacturers must comply with the legal requirements, as any other manufacturer 8. 6 See also Q&A IV.8 7 OBL” (own brand label manufacturer) is a term used in the fiel d that describes manufacturer that are supplied with the finish ed medical device by their supplier, who often is called “OEM” (original e quipment manufacturer). Neither of both are defined in the MDR (or ever were defined in the Directives). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 11 of 14 IV.6. What is the role of the intern al or integrated clinician in the notified body´s assessment and decision-making process? The internal or otherwise integrated clinici an is responsible to identify when specialist input is required for the assessment of the clinical evaluation as defined in Section 3.2.4 of Annex VII of the MDR and IVDR. This decision will be made by the internal or integrated clinician on a case-by-case basis, based on the products covered by the applications lodged by the manufacturer and the clinical expertise available. The internal clinician or integrat ed clinician will be responsible fo r this process in all cases where the conformity of the device to the requirements of annex I is achieved also by clinical data. In cases where demonstration of conformity to requirements of Annex I based on clinical data is not deemed appropriate (in accordance with Article 61(10)) the internal or integrated clin ician will also examine the ju stification provided in order to assess its adequacy. The internal or otherwise integrated clinicians will decide if the review of clinical evaluation is to be carried out by themselves, to be delegated to other qualified staff or if it necessitates the input of external clinical experts. This process is also defined in Section 4.3 of Annex IX of the MDR and Section 5.4 of NBOG’s best practice guide 2017-2 as endorsed by the MDCG. Section 3.2.4 of Annex VII defines that there must be a clinician who is either internal (= employee) or otherwise integrated into the CAB's assessment and decision-making process. To be regarded as integrated, a clinician (who is not an employee) must have access to all the information, required to perform its activities, circulating in the CAB and must be involved in the internal processes in the same way as an employee, the only difference to an employee being that there is no employment contract, but a service contract and therefore this person should not be considered final reviewer or decision-maker as per 3.2.7 of Annex VII. In addition to this, the internal or otherwise integrated clinician will clinically judge the opinion provided by any external expert (including verificati on of comparability and consistency of the assessments of clinical evaluations conducted by clinical experts) and will be responsible to make a recommendation to the decision maker on the adequacy of the clinical evaluation. IV.7. What is the meaning of allocation of resources under Section 4.4 of Annex VII? Allocation of resources is to be understood as the allocation of appropriately authorised and qualified perso nnel and means (including eq uipment and facilities) for a given project (application), as stated in second paragraph of Section 4.4 of Annex VII "appropriate resources including personnel". Section 4.4 of Annex VII describes the assignment of tasks within a project to “individuals”, starting with the individual responsible for ensuring that the assessment of that application is conducted in accordance with the relevant procedures and for ensuring that the appropriate resources including personnel are utilised for each of the tasks of the assessment 8 Including but not limited to having: full and permanent access to the technical documentation; (ability for) post-market surv eillance including post market clinical follow-up; sufficient technical competence; and control of the quality system (control of the d esign, manufacture and/or final verificat ion and testing of the device s). Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 12 of 14 (often referred to as project leader) and following with the identification of individual personnel that will carry out each task of a given project. The assessment of the resources needed for each application is a key function that has to be fulfilled as part of the internal activities of the CAB as indicated in Section 4.1 of Annex VII and any changes on such allocation should be documented. IV.8. How can a CAB ensure that information on "examinations and tests" in accordance with Section 10 of Annex XII of the MDR / IVDR is available to all interested parties (as referred to in Section IV.3 of this document)? According to Annex XII information on tests and examinations performed as part of the conformity assessment activities need to be included on the certificates issued by notified bodies. This information might be of interest for competent authorities and third parties. If the certificates do not include explicitly references to relevant common specifications, harmonised standards or other standards or referential but include a reference to the relevant report(s), the CAB should ensure that competent authorities and interested parties can have access this information on request. For example, the certificate may include a sentence like "information on examinations and tests as per Annex XII, section 10 is available on reques t" and possibly provide a contact (e.g. e- mail). IV.9. Which changes need prior approval by the CAB? The Regulations - in Annex VII and in the specific conformity assessment annexes (i.e. Annex IX, X and XI) -establish the need for the manufacturer to notify certain planned changes. Section 4.9 of Annex VII contains general requirements for notified bodies in respect to changes. For manufacturers, the specific conformity assessment annexes (i.e. Annex IX, X and XI) detail such requirements e.g. asking for plans for “any” changes (e.g. MDR Annex IX, 5.2 f), 5.3.1 d) or Annex X 5.2), for changes could affect the safety and performance of the device or the conditions prescribed for use of the device (e.g. MDR Annex IX 4.10) or for “substantial” changes only (e.g. MDR / IVDR Annex IX 2.4). With regard to the latter, the CAB needs to make clear in its communication to the manufacturer (e.g. in the terms and conditions) what it considers as “substantial changes” to the quality management system or the device-range covered. In order to fully comply with all the relevant requirements the CAB must have documented procedures defining how different changes need to be notified and assessed prior to their implementation and how the assessment will be documented. In particular, the CAB will define in its procedures when the approval of such changes will take the form of a supplement of the previously issued certificate. IV.10. What is the frequency of surveillance audits according to the Regulations? According to the Regulations (Section 3.3 of Annex IX and Section 7 of Annex XI), surveillance audits have to be carried out at least every 12 months. This means that Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 13 of 14 the audit planning defined in Section 4.5.2 and 4.10 of Annex VII will need to take into consideration that surveillance audits have to be scheduled on at least an annual basis with a maximum of 12 months after the previous surveillance audit was carried out The first surveillance audit should be scheduled taking as a reference the certification decision date. IV.11. What is the meaning of the last sentence in Section 4.5.1 of Annex VII with regard to the need for notified bodies to take into consideration standards and guidance even if the manufacturer does not claim compliance? CABs need to consider all the availabl e guidance, common specifications and harmonised standards to carry out its assessments. This means, that CABs will have to consider this documentation when developing its own procedures and processes (including checklists and report templates) and when assessing the manufacturers QMS (e.g. by taking into consideration EN ISO 13485) and technical documentation. For instance, in order to assess if the solutions adopted by the manufacturer are state of the art and in line with expectations, the CAB need to use the available guidance documents and standards. It should be noted that non-conformities will not be raised against standards or guidance but need to be phrased against legal requirements. For instance, Annex I Chapter I Section 1 of the Regulation which states that “devices shall be safe and effective […] taking into account the generally acknowledged state of the art” can be used when the technical documentation does not follow standards or guidance. IV.12. What are the applicable requirements for re-certification? Conformity assessment activities to be carried out in case of renewal of certificates/re-certification are laid down in Article 56(2) of the MDR / Article 51(2) of the IVDR, where the Regulations establish that the notified body can extend the validity of the certificate for further periods based on a re-assessment in accordance with the applicable conformity assessment procedures (i.e. as described in annexes IX-XI). In addition, Section 4.11 of Annex VII states that the notified body must use the same methods and principles for the decision on re-certification as for the initial certification decision. While for EU Technical documentation assessment certificates and EU type examination, Section 4.11 of Annex VII establishes a targeted conformity assessment (i.e. focusing in certain elements of the technical documentation review), this is not the case for the quality management system certificates. The notified body will ensure that all relevant Regulation requirements for conducting audits (i.e. those covered in Section 4.5.2 of Annex VII, and sections 2.2 and 2.3 of Annex IX) are assessed in its entirety at le ast once after issuin g the certificate and before its expiry date. In addition, prior to the renewal of a QMS certificate, it is required that the notified body will assess the results of the surveillance audits carried Medical Devices Medical Device Coordination Group Document MDCG 2019-6 v2 (01/10/2019) Page 14 of 14 out during the period of validity of the certificate in accordance with section 4.10 of Annex VII, also including any unannounced audits and all audits carried out at subcontractors and suppliers. This review must include the manufacturer´s system for vigilance, post-market surveillance, PMCF and risk management as well as all open non-conformities Furthermore, re sults of the notified body´s ev aluation of additio nal scientific and clinical data and clinical evaluations and post-market information as well as the outcome of latest technical documentation assessments on sampling basis and product tests have to be considered. V. OTHER REQUIREMENTS V.1. Are activities described under arti cles 16 and 17 of the Medical devices Regulation (MDR) and Article 16 of the in vitro medical devices Regulation (IVDR) will be covered during joint assessments? Conformity assessment bodies (CABs) can i ssue certificates following the process described in articles 16 and 17 of the MDR and Article 16 of the IVDR but these are not considered conformity assessment activities covered by Chapter IV and Annex VII of the Regulations and therefore w ill not be part of joint assessments. V.2. What is the meaning of “publicly available” as regards the list of standard fees of a notified body under Article 50 MDR / Article 46 IVDR? Whenever the Regulations require certain information to be made “publicly available”, that implies that a member of the public can access this information at any point in time, without the need for additional steps. In view of the public functions carried out by notified bodies, this requirement supports transparency of their activities. Not only Article 111 MDR / Article 104 IVDR re fer to different type of fees (i.e. fees levied by Member States), but also it uses different wording. It cannot therefore be used to support the interpretation of Article 50 MDR / Article 46 IVDR. Moreover, public availability of fees levied by Member States will usually result from the official publication of national laws setting out such fees (therefore, there will be no need to request information on such fees).

mdcg_2020_4_nb_audits_covid-19_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 1 of 6 MDCG 20 20-4 Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID -19 quarantine orders and travel restrictions April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 2 of 6 1. Introduction In the context of the current COVID -19 global outbreak as well as the rapid spread of the virus across various regions of the globe, the resulting travel and quarantine restrictions have significantly affected the ability of notified bodies to conduct mandatory on -site audits under the medical devices legislation. Theref ore, in the interest of public health, this document has been developed to outline temporary extraordinary measures for notified bodies to follow in this interim period in order to allow continued availability of safe medical devices to the market and as sist in the prevention of the risk of medical device shortages. In this context, it is considered that alternative solutions to carrying out on -site audits by notified bodies under the medical devices Directives1 should be allowed under specific circumst ances, including the possibility to perform remote audits under certain conditions. This guidance takes immediate effect and is valid for the whole period of duration of the pandemic COVID -19 as declared by the World Health Organisation. 2. Scope This guida nce is intended to cover the following audits notified bodies are requested to carry out as part of medical devices conformity assessments:  surveillance audits under the medical devices Directives,  audits conducted for re -certification purposes under the medical devices Directives,  in cases where a manufacturer submits a change notification to a notified body that would typically require on -site audit or verification,  in cases where a manufacturer terminates (voluntarily or involuntarily) its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device(s). Although this guidance applies to the medical device Directives only, for Regulations (EU) 2017/745 (MDR) and 2017/746 (IVDR) in the event that the availability of devices is affected by COVID -19 restrictions the principles in this guidance may apply. 1Directive 90/385/EEC, the AIMDD; Directive 93/42/EEC, the MDD; Directive 98/79/EC, the IVDD. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 3 of 6 The temporary extraordinary measures proposed in this guidance should not apply to unannounced audits, or, to special a udits which require on -site assessment (such as the verification of implementation of specific corrective actions which can only be assesed on -site). This does not prevent the use of the alternative measures for these types of audits in cases where doubt has been raised on the conformity / safety of a device and it is not in the interest of public safety to wait until the end of the restrictions put in place due to the COVID -19 pandemic. In general, initial certification audits or audits to extend the s cope of certification under the Directives should not be performed using these temporary extraordinary measures. However, notified bodies may apply these extraordinary measures on a case -by-case basis for such audits in cases where devices are considered r elevant to ensure medical care, especially if clinically necessary during the period of COVID -19 restrictions. 3. Proposed temporary alternative extraordinary measures and arrangements to on -site audits Notified bodies may introduce temporary alternative extraordinary measures in place of on -site conformity assessment audits that have been impacted by COVID -19 restrictions and that are within the scope of section 2 above. Notified bodies should have documented procedures detailing the alternative temporary measures to be utilised and should define the criteria for implementing such measures (e.g. procedure for “force majeure”). The relevant procedures should also take into account the technologies to be used during such audits and also address the impact of the alternative measures on the audit duration. These temporary alternative extraordinary measures may include the following principles and arrangements:  Postponement of on-site surveillance audits under the Directives in line with documented procedures of the notified body for force majeure.  On-site audits may be replaced by remote audits using the most advanced available Information and Communication Technologies as ap propriate in accordance with legislation on information security and data protection.  Assessment of all relevant and required documents/records off -site by the notified body.  To take into account existing recent results from MDSAP audits (or other approp riate audits) in lieu of Directive audits, where available  To consider published international guidance such as those issued by the International Accreditation Forum (IAF) e.g. on how to use information and Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 4 of 6 communication technologies2 and for alternat ive auditing methods in extraordinary circumstances3. 4. Eligibility criteria and procedural aspects To be eligible for these temporary alternative extraordinary measures the audits must be covered within the scope of section 2 above. The possibility to make use of temporary alternative extraordinary measures to on - site audits should be carefully assessed and documented by notified bodies on a case -by-case basis and performed using a risk -based approach. In particular, when determining the possibility to use t hese alternative measures, the risk assessment should take into account the experience gained with a manufacturer. For example, manufacturers who have a history of a high number and/or critical non -compliances related to production/operational control ma y have an impact on the appropriateness to conduct such temporary measures. However, in these cases an alternative measure could be performed as a temporary measure to assess the progress of the manufacturer and should be be supplemented by an on -site audi t once travel restrictions are lifted. In order to assess which alternative extraordinary measure (as outlined in section 3 above) is most appropriate, the notified body should review their files relating to the status and operations of the manufacturer re lated to the audit in question, for example the activities conducted at the site to be audited, its quality management system, and its level of compliance from previous audits. Following this review, a risk analysis should be made as to whether or not the audit could be performed with alternative measures. Where a postponement cannot be justified, the notified body should assess which alternative extraordinary measure should be performed (e.g. remote audit; off -site document review; conference calls with r elevant personnel of the manufacturer). For remote audits, both the notified body and the manufacturer must have the required information and communication technologies or tools available and established (e.g. web conferences with document sharing, use of web cams for audits of production lines). Confidentiality of intellectual property aspects shall be safeguarded. Notified bodies should clearly document and communicate any such requirements for their audits with their auditees, along with the required documentation to be shared before and within such audits, including the necessary data protection and cybersecurity measures . The technological capability of the manufacturer to ensure that such an audit can be accomplished should be verified by the notified body in advance of the audit. 2 Requirements on how to use information and communication technologies to support and maintain the integrity of the audit/assessment process may be found in International Accreditation Forum document IAF MD 4 (Mandatory Document for the Use of Information and Communication Technology (ICT) for Auditing/Assessment Purposes). 3 ID3:2011 (IAF Informative Document For Management of Extraordinary Events or Circumstances Affecting ABs, CABs and Certified Organizations) Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 5 of 6 Designating Authorities may request to observe/witness such remote audits via information and communication technologies or to ols available and established. When establishing the audit plan, the notified body should adjust the duration for review of the areas on the audit plan, along with the overall duration of the audit, in coordination with the manufacturer in order to make ef fective use of these alternative extraordinary measures. The audit plan should also clearly indicate which alternative extraordinary measures will be used and what will be conducted remotely. When issuing their audit reports the notified body should also c learly indicate that the audit was conducted remotely and the method(s) used for such audits should also be specified. Remote surveillance audits should cover all of the surveillance tasks that can be verified remotely, including an off -site review of all documents that would normally be assessed on -site. Following such an alternative extraordinary measure the notified body should review and adjust the audit programme for each manufacturer to ensure that all required elements are assessed during the certi fication cycle. 5. Decisions taken on certification Remote audits undertaken for re -certification purposes should cover all of the mandatory re -certification tasks that can be verified remotely. Subsequent to a succcessful remote audit a notified body may r e-issue the certification with the condition that such audits should be followed up by an on -site verification audit at the next available opportunity to verify the elements that could not be assessed remotely (the timeline for the on -site verification aud it should be justified by the notified body). At the request of the notified body, the manufacturer may provide the notified body with records (e.g. product release documentation) on an ongoing or regular basis,. If the re -certification remote audit is uns uccessful, the certification should be suspended or should expire as appropriate. Remote audits conducted by the incoming notified body in the context of cases where a manufacturer terminates its contract with a notified body and enters into a contract with another notified body in respect of the conformity assessment of the same device (s), should also cover all of the tasks that can be verified remotely to allow the incoming notified body to ensure a proper assessment of the conformity of the device. If the remote audit is unsuccessful (as per the notified body’s procedures for unsucces sful audits), the incoming notified body should not issue the certification. In the exceptional circumstance of the issuance of an initial or extended scope certificate under these alternative extraordinary measures (as per section 2 Scope above), the no tified body should consider the clinical risk / benefit of their decision and should clearly document their rationale for these decisions. At the request of the designating authority the notified body should inform the national authority of any such decisi ons and provide any supporting documentation. Medical Device Medical Device Coordination Group Document MDCG 20 20-4 Page 6 of 6 Note: A task force established in March 2020 under the MDCG NBO working group is tasked with the development of guidance to define the operational implementation details of this guidance document.

Guidance on significant changes &amp; annexes.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2020 - 3 MDCG 2020 -3 Guidance on significant changes regarding the transitional provision under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD March 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it ca nnot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on significant changes regarding the transitional provision under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD1 1 Introduction Article 120( 2) and 120( 3) of the Medical Device Regulation (EU) 2017/745 (MDR) states that devices which have a valid certif icate issued by a notified body under the Active Implantable Medical Devices Directive 90/385/EEC (AIMDD) or the Medical Devices Directive 9 3/42/EEC (MDD) may be placed on the market or put into service after th e date of application of the MDR under certain conditions and no later than 26 May 2024. Questions 8 and 9 of the CAMD Transition Sub Group guidance : “FAQ – MDR Transitional provisions, V1.0 of 17. January 2018”2 state that the certificates covered by MDR Article 120(3) include “all certificates which are commonly issued by notified bodies with reference to the Council Directives MDD and AIMDD” . Conditions referred to in the first paragraph require that no significant change s in design or intended purpose of a device be performed after the date of application of the MDR . Therefore, it is important for manufacturers and notified bodies to get clarity on the significant changes to be considered under MDR Art icle 120(3). It is also important that the AIMDD and MDD certificates remain valid following changes that are not significant with regard to design or intended purpose , provided that the required surveillance is carried out by the notified body that issued the certificate. See also Question 17 of the above mentioned CAMD guidance2. 2 Scope This guidance document is intended to provide clarification on the changes to a device that should be considered a “significant change in design or a significant change in the intended purpose” under MDR Art icle 120(3). Assessment s should be made on a case -by-case basis. 1 The principles outlined in this guidance can be applied also for class I devices requiring the involvement of a notified body for the first time. 2 https://www.camd -europe.eu/wp -content/uploads/2018/05/FAQ_MDR_180117_V1.0 -1.pdf 3 This guidance document does not elaborate on the process for manufacturers’ submission and notified bodies’ assessment of such changes as these should be part of the conformity assessment process and surveillance defined by the relevant notified body under the MDD or AIMDD. It is expected that manufacturers adjust their change not ification procedures, i.e. their provisions to inform their notified body on changes, in accordance with the principles outlined in this guidance until the date of application of the MDR. The adjusted procedures will be subject to notified body assessment within their surveillance activities according to MDR Art. 120(3). 3 Changes to Directive certificate s It is important to highlight that no issuing of new MDD/AIMDD certificates, including modified, amended or supplemented certificates , is allowed under MDR Article 120(3). In particular, i f the manufacturer wishes to make a “significant chang e in design or intended purpose” under MDR Article 120(3), the implementation of such a change would prevent the manufacturer from continuing to place that device on the market under the Directives . 4 Assessment of changes' significance in accordance with MDR Article 120(3) In line with agreed arrangements for notification of changes between the manufacturer and the notified body according to the AIMDD/MDD (e.g. contractual relationships, approved procedures) changes and their implementation will be verified by the notified body as part of the surveillance activities, or following a manufacturer’s submission for prior approval . The outcome of this verification will determine whether a certificate in accordance with AIMDD/MDD remains valid according to Article 120 MDR. To use this derogation from Article 5 MDR manufacturers are not allowed to make s ignificant change s in design or a significant changes in the intended purpose. In case of doubt whether a change is significant they should ask their notified body . For instance, administrative changes of organisations are considered in principle as non - significant. This includes changes of the manufacturer’s name , address or legal form (legal entity remains) or changes of the authorised representative. Furthermore, all changes not having an impact on the design or the intended purpose of the device can be regarded as not significant in the meaning of MDR Article 120(3) . This is the case for example of relocation or addition of new manufacturing sites, including when it affects subcontractors or suppliers , or of certain changes of the quality management system, provided that the conditions for which the conformity assessment certification was granted are maintained. Nevertheless, such changes continue to be subject to the agreed notification procedure identified in the first paragraph of the current secti on. T he manufacturer should always remain responsible for providing evidence that all the above -mentioned changes do indeed neither affect the design nor the intended purpose. 4 On the other hand, when the change is likely to affect the design or the inten ded purpose of the device, the significance of such a change must be assessed on a case -by-case basis. To facilitate a harmonised judgement of the significance of changes flowcharts (see Annex) have been developed. If a change is not a significant chang e in design or intended purpose under MDR Article 120(3), the implementation of such a change is therefore allowed during the transitional period. Acc. to section 3 the certificate should not be amended. The notified body that issued the AIMDD or MDD certif icate may confirm in writing (after having reviewed manufacturer’s description of the (proposed ) change) that the implementation of the change does not represent a significant change in design or intended purpose under MDR Article 120(3) and that the relat ed AIMDD or MDD certificate remains valid after the date of application of the MDR, but no longer than its expiry date or 26 May 2024, whichever comes first. Such written confirmation corrects or complements information on an existing certificate but does not represent the issuance of a “supp lemented certificate” as this is prohibited as mentioned in Section 3 . In case of requests from authorities the manufacturer should number such letters received from the notified body and submit them together with the certificate. In relation to class I medical devices requiring the involvement of a notified body for the first time, manufacturers of such devices must be able to justify their decision when the changes are considered to be non -significant. The justificat ion shall be documented and made available when requested. This guidance document provides in its Annex several flowcharts based on NBOG’s Best Practice Guide 2014 -3: “Guidance for manufacturers and Notified Bodies on reporting of Design Changes and Change s of the Quality System” . In particular, Chart C , which is specific to software, draws inspiration from Annex VI, Part C, section 6.5 of the MDR to identify modifications that are considered as significant change in (software) design. The assessment of a proposed change by using the main flowchart and any of the applicable sub-charts in the Annex, is intended to assist manufacturers and notified bodies in deciding whether or not a change is to be considered significant in the design or intended purpose of the device under MDR Art icle 120(3). The flowcharts are divided into a main chart and five sub -charts (A to E) . There are six categorical questions in the main chart that are linked to one or more sub -charts with more detailed questions . The change is considered a non -significant change of design or intended purpose per MDR Art icle 120(3) if the answer to every question in a sub -chart leads to “ non- significant change ” also when returnin g to the main chart. On the contrary, if any sub-chart 5 delivers the result “significant change” , the change being assessed is a “ significant chang e in design or intended purpose” of a device according to the MDR Article 120(3). 6 Annex Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Main Chart Change of an existing Medical Device certified under MDD or AIMDD Change of the Intended Purpose? Software change? Chart A Chart B Chart C Yes Yes Yes No No If non -significant If non -significant If non -significant A B C Change of the design or performance specification? No No X Design change related to corrective actions*? *assessed and accepted by the relevant Competent Authority acc. to CAMD FAQ no 17 Yes 7 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Main Chart (ctd.) Change of a Material*? Change of terminal sterilization method of device or packaging design with impact to the sterilisation? Chart D Chart E The change is considered a non - significant change per MDR Art. 120(3) Yes Yes No No No If non -significant D E *The termmaterial includesany substance ( synthetic, natural, biological, chemical, physical, medicinal, ...) that is used to make or compose the device 8 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart A FromMain Chart: Change of the IntendedPurpose* The changeisconsidered significantper MDR Art. 120(3) Extension or change of the Intended Purpose? New user or patient population? Change of clinical use**? Yes Yes Yes No No No Limitation of the Intended Purpose? Return toMain Chart QuestionX Yes No A1 A2 A3 A4 ** Example: - Change in the anatomical site; - Change in the access site or deployment methods; * Labellingchangesshouldbe assessedtoensuretheyarenot potentiallysignificantwhen linkedtothe intendeduse(e.g. contraindicationsandwarnings). Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart B FromMain Chart: Change of theDesignorPerformance Specification* Yes No No B1 Change of built -in control mechanism, operating principles, source of energyor alarms ? Yes No Return toMain Chart QuestionC (or move directly to E if Chart D was previously used) Yes B3 The changeisconsidered significantper MDR Art. 120(3) betakeninto not * Itshall accounthowthe changeis achieved. A changein specification maybetriggeredby, but isnot limited to, changeof hardwareor software, includingchangeof a component. Does the change require further clinical or usability data to support safety and perfor - mance? ** Do new risks require control measures or are existing risks negatively affected? B2 ** Compare MEDDEV 2.7/1 rev.4 forfurtherguidance Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart C FromMain Chart: Software Change New or modified architecture or database structure, change of an algorithm? Required user input replaced by closed loop algorithm ? Yes Yes No No New or major change of operating system or any component? No Yes C1 C2 C3 New diagnostic or therapeutic feature, or new channel of inter-operability ? Yes C4 No Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart C (ctd.) The changeisconsidered significantper MDR Art. 120(3) Yes No Return toMain Chart QuestionD C5 No New user interface or presentation of data*? *“Presentationof data“ goesbeyondthe appearanceof theuser - interface whichmayinclude newlanguages, layoutsor graphicsandisconsidered a minor change. Itisconnectedtomedical datawhicharepresentedin a newformatorby a new dimensionormeasuring unit. Yes *Minor changeswithout impacttodiagnosisor treatmentdeliveredmay include: - correctionof an error whichdoesnot posea safetyrisk(bugfixes), - Security update (e.g. cyber -security enhancements, longevitycalculations), - appearanceof the user interface, - operatingeffeciencies. - Changestoenhancethe userinterfacewithout changesin performance Minor Change*? C6 Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart D FromMain Chart: Change of a Material* Change to a material of human/animal origin including addition of new materials? No Yes Change to a material containing a MS** ortothe MS itselfor, a change which may impact the quality, safety or efficacy of a MS *** ? Yes No D1 D2 **MS: Substancewhich, if used separately, would be considered to be a medicinal substance ***Including a change in its manufacturing process, which result in changes to the existing specification of the medicinal substance. * These relate to changes involving existing ingredients and materials. Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart D (ctd.) Ingredient new ormaterial from uppliermeetsexisting s specification? The changeisconsidered significantper MDR Art. 120(3) No Yes Yes Changed ingredientor material fromexisting suppliermeetsexisting specification? No Return toMain Chart QuestionE D3 D4 Change tobeassessedin accwithChart B Design Changes and Changes of the Intended Purpose Which may be Considered “Significant“ When Interpreting the First Sentence of MDR Art. 120(3) Chart E FromMain Chart: Change of terminal sterilization method of device or packaging design with impact to the sterilization Design Change which affects or changes the sterility assurance**? Yes No No Yes Change in packaging design which affects functionality, safety, stability or seal integrity? E2 E3 Shelf-life change validated by protocols approved by the notified body ***? The changeisconsidered significantper MDR Art. 120(3) The change is considered a non-significant change per MDR Art. 120(3) No Yes E4 ** Guidance on assessing changes for their impact on the effectiveness of the sterilization process is provided in the respective sterilization standards such as:  EN ISO 11135 (Ethylene Oxide),  EN ISO 11137 -1 Radiation), (  EN ISO 17665 -1 (Moist Heat),  EN ISO 13408 -1 (Aseptic Process). Change* of terminal sterilization method? No Yes E1 * Includes change from non-sterile to sterile or a change to the sterilisation method. Changes of cycle parameters under the approved quality management system are not deemed as significant in the meaning of Art. 120(3) MDR ***In principle, an increase in shelf life can be considered non -significant ( e.g. the increase is made following the completion of a real time test whose method and end -point was validated and previously assessed by the notified body).

md_application-transitional-provisions-certificates_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-10 rev.1 Page 1 of 2 MDCG 201 9-10 rev. 1 Application of transitional provisions concerning validity of certificates issued in accordance to Directives 90/385/EEC and 93/42/EEC October 2019 July 2020 rev. 1 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-10 rev.1 Page 2 of 2 MDCG 2019 -10 revision 1 changes MDR postponement dates: from 2020 to 2021 Application of transitional provisions concerning validity of certificates issued in accordance to Directives 90/385/EEC and 93/42/EEC1 According to Article 120(2) of Regulation (EU) 2017/475 on Medical Devices (the MDR), certificates issued in accordance with Directives 90/385/EEC and 93/42/EEC (the Directives ) will remain valid until 26 May 2024 at the latest. However, Article 120(3) establishes specific conditions that such certificates, and the related devices thereof, have to comply with. In particular, it is required that the notified body that issued the certificate – under a valid designation – continues to be responsible for the appropriate surveillance activities with respect to all of the applicable requirements related to the devices it has certified and that it has the possibility to take any necessary measure in relation to those. It has to be noted that, as reported in FAQ n.17 of the MDR transitional provision document published by the CAMD Transition Sub Group, the contract between the manufacturer and the notified body who issued the certificate under the relevant Directive shall include provisions allowing the appropriate performance of such surveillance activities. In order to allow manufacturers to take advantage of Art. 120( 2) and Art. 120(3) of the MDR, it needs to be ensured that Authorities responsible for notified bo dies have the right to and do monitor those notified body’s activities to the extent appropriate and necessary. For this purpose, Article 120(3) and Article 122(1) of the MDR provide the necessary legal basis for Member States to establish the necessary le gal empowerments2 by means of National law to carry out the needed monitoring activities in relation to Notified Bodies. All this is regardless of whether the Notified Body has applied or not to be designated under the MDR and/or it has a still valid desig nation under the Directives during the validity of certificates issued in accordance to the Directives . Concerning information published in the NANDO database, in accordance to Article 120(1) of the MDR, any publication of a notification in respect of a no tified body in accordance with the Directives will become void as from 26 May 2021 . Therefore, NANDO will only be used in relation to the Directives for information purposes after 25 May 2021 . NANDO will therefore list those notified bodies that have bee n designated under the Directives with a clear message that they are not able to issue new certificates but only allowed to carry out surveillance activities for valid certificates in the transitional period, as established in Article 120 of the MDR. 1 This document specifically refers to transitional provisions laid down in Regulation (EU) 2017/745 but can be applied by analogy to Regulation (EU) 2017/746. 2 It should be noted that relevant legal empowerments might be already available by means of National law which build on different EU pieces of legislation.

md_2020-14-guidance-mdsap_en.pdf.txt

1 Medical Devices Medical Device Coordination Group Document MDCG 2020-14 MDCG 2020-14 Guidance for notified bodies on the use of MDSAP audit reports in the context of surveillance audits carried out under the Medical Devices Regulation (MDR)/ In Vitro Diagnostic medical devices Regulation (IVDR) August 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and a representative of the European Commission chairs it. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance for notified bodies on the use of MDSAP audit reports in the context of surveillance audits carried out under the Medical Devices Regulation (MDR)/ In Vitro Diagnostic medical devices Regulation (IVDR) Background In fulfilling the EU’s commitment to encourage notifi ed bodies to make use of audit reports from the Medical Device Single Audit Program (MDSAP) in a manner that is compatible with EU legislative requirements, the Medical Device Coordination Group (MDCG) endorsed this guidance which has been developed by a group of experts comprised of interested Member State representatives, notified body associations and stakeholders. Scope The purpose of this document is to provide guidance to notified bodies on how to take into account MDSAP Medical Device Regulatory Audit Reports 1 (from hereafter “MDSAP audit reports”) issued by MDSAP auditing organisations2 when performing surveillance audits under Regulation (EU) 2017/745 – Medical Devices Regulation (MDR) and Regulation (EU) 2017/746 – In Vitro Diagnostic medical devices Regulation (IVDR). This is of particular use when a manufacturer has undergone an MDSAP audit and wishes to present this audit report (including the associated attachments) in context of the regular surveillance audits performed in accordance to the MDR or IVDR. General regulatory considerations Under the MDR/IVDR, most conformity assessme nt procedures consist of both the quality management system audit and the assessment of a device’s safety and performance. Notified body’s conformity assessment activities, which are a prerequisite for the manufacturer’s declaration of conformity, when concluded successfully result in a conformity assessment certificate, a pre-market requirement for most classes of medical devices and IVDs. In that regard, notified bodies designated under the MDR/IVDR fulfil roles, which correspond to combined functions of both MDSAP auditing organisations and MDSAP participating regulatory authorities. 3 Therefore, the roles performed by notified bodies and MDSAP auditing organisations differ as the latter solely perform quality management system audits which are then utilised by regulatory authorities in their evaluation of a product’s safety and performance for the purpose of issuing a marketing authorisation. 1 MDSAP audits are recorded using the Medical Device Regulatory Audit Report form (MDSAP AU F0019.1). Final MDSAP audit reports are signed in section 18 of the form. 2 Auditing Organization: An organization that audits a medical device manufacturer for conformity with quality management system requirements and other medical device regulatory re quirements. Auditing Organizati ons may be an independent organization or a Regulatory Authority which perform regulatory audits. (IMDRF/MDSAP WG/N3 FINAL:2016) 3 Regulatory Authority: A government body or other entity that exercises a legal right to control the use or sale of medical devices within its jurisdiction, and that may take enforcemen t action to ensure that medical products marketed within its jurisdiction comply with legal requirements. (GHTF/SG1/N78:2012, cited from IMDRF/MDSAP WG/N3 FINAL:2016) 3 Requirements of the MDR/IVDR The MDR/IVDR clearly state that all manufacturers need to have a quality management system in place so as to ensure that devices manufactured in se ries are in conformity with the requirements of the respective regulation and that experience from the use of devices is taken into account in the production process (MDR Recital 32/IVDR Recital 31). This becomes an explicit requirement for manufacturers to establish, document, maintain, keep up to date and continually improve quality management systems so that to ensure compliance with the Regulations (MDR Article 10 (9)/IVDR Article 10(8)). Notified bodies are charged with the assessment of quality management systems of devices in accordance with MDR Article 52 and IVDR Article 48. Specifically, notified bodies are responsible for auditing and certifying manufacturers’ quality management systems (MDR/IVDR Annexes IX and XI and Annex VII section 4.5 ), following up with appropriate surveillance audits (MDR/IVDR Annex IX section 3 and Annex VII section 4.5.1, 4.10) as well as conducting unannounced audits (MDR/IVDR Annex VII section 4.5.1). Notified bodies are also responsible for the development of their appropriate procedures for conformity assessments according to the MDR /IVDR. The MDR/IVDR specifically state that notified bodie s’ audit programmes should clearly identify the number and sequence of activities required to demonstrate complete coverage of a manufacturer’s quality management system (MDR/IVDR Annex VII 4.5.2) and that surveillance audits need to be carried out on at least an annual basis (MDR/IVDR Annex VII section 4.10 and Annex IX section 3.3). For each surveillance audit identified in the audit programme, the objectives, criteria and scope of the surveillance audit are defined in an audit plan which adequately addresses and takes into account specific requirements for the devices, technolog ies and processes involved (MDR/IVDR Annex VII section 4.5.2(a) – third bullet point). Surveillance audits are expected to gather sufficient information to verify the proper implementation of the quality management system and ensure that it continues to comply with the requirements of the MDR/IVDR. When and how to take MDSAP audit reports into account It is important to stress that the MDR/IVDR remain applicable in their entirety. The use of MDSAP audit reports within the EU legislative framework is possible only where the MDSAP audit covers similar or equivalent MDR/IVDR requirements. Designated notified bodies maintain the full authority over their judgement, conclusion and final decision about the conformity of quality management systems to the relevant provisions of the MDR/IVDR and the safety and performance of medical devices and IVDs intended to be placed on the market in the EU. Given that surveillance audits, their periodicity and EU auditors’ competencies are mandated by law, yearly surveillance audits need to be maintained. Ho wever, it could be possible to take into account the scope and outputs of manufacturers’ recent MDSAP audit reports as an input for developing surveillance audit programmes. The taking into account of MDSAP audit reports could define in a more precise manner the activities to be performed during a surveillance audit. For example, the positive quality management system conformity appraisal through MDSAP might lead to a reduction 4 of the focus on aspects already covered by MDSAP audit reports. The notified body may then focus their surveillance audit on specific MDR/IVDR requirements which are either not covered or only partially covered by the MDSAP audit report. Non-exhaustive list of examples (alphabetical order): - clinical evaluation/performance evaluation process (including post-market clinical/performance follow-up), - EU authorised representative contractual provisions, - EU UDI assignments within the quality management system, - manufacturer financial coverage in respect of potential liability, - person responsible for regulatory compliance qualification and role, - records control, - system for risk management, - vigilance and post market surveillance activities, including the associated corrective actions and preventive actions. Similarly, non-conformities identified in recent MDSAP audit reports can trigger the notified body to pay particular attention to those aspects in the MDR/IVDR planned surveillance audit. It is important to highlight the following details: - The taking into account of MDSAP audit reports is not applicable to initial quality management system audits required for the issuing of EU QMS certificates. Notified bodies designated under the MDR/IVDR would always need to conduct these audits in their entirety. - The taking into account of MDSAP audit reports is not applicable to MDR/IVDR unannounced audits. - Reports of MDSAP unannounced audits or special audits should not be taken into account in the narrowing of focus in MD R/IVDR surveillance audits. - Regular surveillance audits would still take place on a yearly basis. However, the positive QMS conformity appraisal through an MDSAP audit may lead to a limitation of the surveillance focus from aspects already covered by the MDSAP audit reports. - When MDSAP audit reports are considered as input to the planning of an MDR/IVDR surveillance audit, these reports should be taken into account in their complete form, including all associated attachments. Both positive and negative statements about the conformity of the manufacturer should be incorporated in the planning of the MDR/IVDR audit. If there is concern about the functioning of the quality management system, for instance due to information gathered through the assessment of vigilance cases or post market activities, previous surveillance audits or technical documentation assessments, a complete surveillance audit should be carried out. Notified bodies may wish to determine and establish additional guidance in order to support their procedures for evaluating MDSAP audit reports. Such guidance could for example specify the content details of MDSAP audit reports considered acceptable (i.e. may be taken into consideration) in the notified body assessment programme and what modifications may be done to the notified body assessment programme after the taking into consider ation of the MDSAP audit report (to ensure that 5 any specific assessment items that are not covered in the MDSAP audit reports are performed by the notified body). The notified body shall remain fully responsible for its decision, to whether or not, and to what extent, an MDSAP audit report can be taken into account. The Annex to this guidance identifies and analyses aspects within MDSAP audit reports that are relevant in relation to the EU requirements. Part I focuses on providing an explanation of where to find relevant information in MDSAP audit reports that could be used to a greater or lesser extent as supporting evidence for MDR/IVDR quality management system requirements. Part II provides examples on how correlations between MDR requirem ents to sections of MDSAP audit reports may be established in the notified bodies’ additional guidance or procedures. Although the examples in Part II focus on MDR requirements, the same methodology could be applied for the IVDR. 6 Annex Part I – Explanation of relevant information in MDSAP audit report The following table shows where information with relevance for MDR/ IVDR quality management system audits can be found in MDSAP audit reports and highlights specifics that should be understood by notified bodies when taking into account such information. A comprehensive description of MDSAP audit report content can be found in MDSAP AU P0019 MDSAP Me dical Device Regulatory Audit Reports and MDSAP AU G0019 Medical Device Regulatory Audit Report Form Guidelines 4 Sections of MDSAP audit report Relevant information Section 1 – Audit Information Name of MDSAP auditin g organisation, audit dates and duration, audit team Section 2 – Audited Facility Audited facility name and address. In case of a multi-site audited organization, a separate audit report is generally required for each audited facility. This means, the audited facility described in Section 2 is not necessarily the manufacturer responsible for the overall product. Also see Section 4. Section 3 – Certification Schemes, Scopes & Criteria, Audit Types Certification schemes with scope of certification, audit type and audit criteria. In some cases, a list of medical devices covered in the scope is attached to the audit report. The “CE marking” scheme may be referenced, but this is not mandatory. For unannounced audits, it is important to understand that they are commonly performed to verify effectiveness of corrective actions on non-conformities, and their content is not the same as that of unannounced audits under MDR/IVDR. 4 Both documents are available in the “MDSAP Documents” / “MDSAP Audit Procedures and Forms” section of the MDSAP program homepag e (https://www.fda.gov/medical-devices/cdrh- international-programs/medical-device-single-audit-program-mdsap , accessed on 2020-03-25). 7 Sections of MDSAP audit report Relevant information Section 4 – Certification Holder and Multi- site Organization Relationship between audited facilities and reference to other audited facilities included in the audit. Certification Holder is the main facility shown on the title page of the certificate. Campus is a group of facilities that can be described in one audit report by derogation from general requirement of separate audit reports for each facility. Related sites are other audited facilities that are described in separate audit reports. Corporate Information describes the use of multiple names and identities by the organization and its significant relationships of the manufacturer with related companies in the context of the audited QMS and its associated activities and devices. Section 5 – Audit Objectives Additional audit objectives applying to schemes other than MDSAP may be included, but this is not mandatory. Section 6 – Audited Facility Description Regulatory Roles of th e audited facility are indicated separately for each MDSAP parti cipating country. It may additionally include the roles in other countries, such as Europe, but this is not mandatory. Activities at the Audited Facility describe what is actually done at the audited site. Activities not included in the Scope of Certification are activities performed at the facility which are not required to be listed in the MDSAP certificate. Section 7 – Critical Suppliers Critical suppliers of the audited facility that are relevant to the scope of audit, including pr oducts or services obtained from them and indication whether this audit extended to visit a supplier. Instead of a detailed description in this section, the list may be attached to the report. Section 8 – Audit History Outcomes of previ ous audits that have been taken into consideration in preparation for this audit. Section 9 – Exclusion and Non- Applications of requirements in the QMS Exclusion and non-application of ISO 13485 requir ements in the QMS of the audited facility. Section 10 – Outcome of Pre-Audit Activities Outcome of the preceding documentation review and/or stage 1 audit, if applicable. Instead of detailed description in this section, additional records may be attached to the report. 8 Sections of MDSAP audit report Relevant information Section 11 – Audit Findings Sections 11.1-11.7 describe audit findings and ev idence related to ISO 13485 and country-specific requirements. Please refer to MDSAP Audit Model and details of requirements5 for more information. Section 11.7A is only included, if the critical suppliers we re visited as part of the audit, to describe the audit findings made at the visited supplier locations. Section 11.8 may include findings according to scheme s other than MDSAP, but this is not mandatory. Section 12 – Non-conformities List of non-conformities, references to which are made in Section 11. Grade is a numeric classification of significance of non-conformity between 1 and 5 according to GHTF/SG3/N19:2012 - Quality Management System - Medical Devices – Non-conformity Grading System for Regulatory Purposes and Information Exchange Section 13 – Significant Deviations from the Audit Plan Circumstances that lead to deviations from the audit plan and obstacles experienced by the audit team during the audit. Section 14 – Follow-up of Past Non-conformities Results of audit team’s evaluation of effectiveness of ac tions taken in response to non-conformities identified in prior audits with the possible status Closed, Superseded of Left Open. A record with the details of this evaluation may be attached to the report. Section 15 – Summary of Major Changes to the Audited Facility Summary description of major changes since previous audit, especially those changes not described in Section 11. Section 16 – Conclusions Extensive conclusion of the audit, including the statement on the conformity of the QMS with the audit criteria and recommendations of the audit team. Section 17 – Attachments List of records th at are considered as part of the audit report, including those referenced in Section 6 (list of medical devices), Section 7 (list of critical suppliers), Section 10 (outcome of pre-audit activities), Section 11.2 (review of sampled technical documentation), Section 14 (updated non-conformity report relative to past non- conformities). Section 18 – Audit Report Approval Date and signature of review and approval of the final audit report. 5 The MDSAP Audit Model can be found in the “MDSAP Documents” / “MDSAP Audit Procedures and Forms” section of the MDSAP program homepage ( https://www.fda.gov/medical- devices/cdrh-international-programs/medical-device-single-audit-program-mdsap , accessed on 2020-03-25). 9 Part II – Examples on how correlations between MDR requirements to sections of MDSAP audit reports may be established The following examples of established correlations between MDR qua lity management system requirements and the MDSAP Audit Model show how certain overlapping requirements may be covered in MDSAP audit reports, and what specific MDR requirements are not covered. The referen ces direct to MDSAP audit processes and tasks that overlap with MDR requirements and are linked to same or similar ISO 13485 requirements. It is recommended that notified bodies develop more detailed gu idance for determining the extent in which MDR/IVDR quality mana gement system requirements correlate to those covered in MDSAP audit reports. Any such fully developed correlation should be revised in the event of a pub lication of changes to any basic criteria document including EN ISO 13485, MDSA P Audit Model and MDR/IVDR, or any documen t utilised to establish correlation, su ch as CEN/TR 172236. The examples provided in the below table cover only the following three blocks of MDR requirements: Clinical evaluation, Suppli er controls, and Post-market surveillance. MDR requirement Sections of MDSAP audit report addressing this topic(s) Particular MDR requirements not covered in an MDSAP audit Clinical evaluation MDR Article 10, paragraph 3 MDR Annex IX, Chapter I, 2.1, indents 10-11 MDR Annex XI, Part A, 6.1 indent 17 Section 11.5 – Design and Development, Task 11 Specifics of Article 61 and Annex XIV Part A Clinical evaluation plan and procedures to keep up to date the clinical evaluation plan Supplier controls MDR Article 10, paragraph 9 (d) MDR Annex IX, Chapter I, 2.2 paragraph 2 b) indent 3 Section 11.1 – Management, Task 5 Section 11.3 – Measurement, Analysis and Improvement, Tasks 2, 7, 13 Section 11.5 – Design and Development, Tasks 1, 7, 8, 16 Section 11.6 – Production and Service Controls, Tasks 7, 14, 19, 21, 22 Section 11.7 – Purchasing, all tasks Annex II 3. (c) 6 CEN/TR 17223:2018 Guidance on the relationship between EN ISO 13485: 2016 (Medical devices – Quality management systems – Requ irements for regulatory purposes) and European Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation. 7 MDR Annex XI, Part A, 6.1 indent 1 refers back to MDR Annex IX, Chapter I, 2.1 10 MDR requirement Sections of MDSAP audit report addressing this topic(s) Particular MDR requirements not covered in an MDSAP audit Post-market surveillance MDR Article 10, paragraph 10 MDR Annex IX, Chapter I, 2.1 indent 8-9 MDR Annex XI, Part A, 6.1 indent 1 8 MDR Annex XI, Part B, 13 Section 11.3 – Measurement, Analysis and Improvement, Task 12, 14, 15 Section 11.4 – Medical Device Adverse Events and Advisory Notices Reporting, Tasks 1, 2 Specific requirements on the PMS system incl. PMS plan, PMS report, PSURs, and PMCF plan (Articles 83-86 and Part B of Annex XIV as well as obligations resulting from the provisions on vigilance (Articles 87 to 92) 8 MDR Annex XI, Part A, 6.1 indent 1 refers back to MDR Annex IX, Chapter I, 2.1

mdcg_2019_13_sampling_MDR_IVDR.pdf.txt

1 Medical Device Medical Device Coordination Group Document MDCG 2019 -13 MDCG 2019 -13 Guidance on sampling of MDR Class IIa / Class IIb and IVDR Class B / Class C devices for the assessment of the technical documentation Decem ber 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. 2 Guidance on s ampling of MDR Class IIa / Class IIb and IVDR Class B / Class C devices for the assessment of the technical documentation 1 Introduction Regulation (EU) 2017/745 on medical devices (MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) establish the requirements for sampling of Class IIa / Class IIb and Class B / Class C devices for the assessment of the technical documentation. Article 52(4) and (6) of the MDR and Article 48( 7) and ( 9) of the IVDR est ablish the need to assess the technical documentation of at least one representative device per generic device group (for Class IIb and Class C) and for each category of devices (for Class IIa and Class B) prior to issuing the certificate. Section 2.3 and 3.4 of Annex IX of both Regulations (and section 10 of Annex XI of the MDR ) defines that the quality management system assessment has to be accompanied by the assessment of technical documentation for devices selected on a representative basis . Section 4.5.2(a) of Annex VII of both Regulations1 requires the notified body to draw up and keep up to date, a sampling plan for the assessment of technical documentation as referred to in Annexes II and III prior to the audit . Section 4.5.2(b) of Annex VII requires the notified body to assess t he technical documentation as preparation for the audit (s). This assessment is expected to be finalised in due time of such audit (s). 2 Scope This guidance is intended to define the requirements of sampling for Class IIa and Class IIb devices under the MDR and Class B and Class C devices under the IVDR for the purpose of assessing the technical documentation . This guidance defines and further elaborates on the sampling criteria and use of such criteria for drawing up and maintaining a sampling plan. In addition, th is guidance clarifies th e tasks to be performed by the notified body including the applicability of Chapter II of Annex IX of both Regulations and the extent of the technical documentation assessment. See Section 5.3 for exemptions for specific types of devices. 1 Hereafter referred to as “Annex VII” for both, the MDR and the IVDR. 3 3 Definitions The Regulations do not contain definitions of certain terms applicable to sampling , and in some instances certain definitions given cannot be used on an operational level. Therefore , only for th e purpose of this guidance the following definitions apply : 3.1. Category of devices : category of devices should be understood as the relevant M DA/MDN codes (MDR) or IV R code s (IVDR) according to Regulation (EU) 2017/2185 on the codes for the designation of notified bodies . 3.2. Generic device group2: is to be understood :  in respect of the MDR3,4 as the 4th level of the European Nomenclature on Medical Devices (EMD N) 5, 6 (i.e. combination of one letter plus 6 digits ), and  in respect of the IVDR as the 3rd level of the EMD N (i.e. combination of one letter plus 4 digits respectively) in combination with the most appropriate IVP code. 3.3. Device range: device range is to be understood as all “device categories" for Class IIa and Class B devices and all “generic device groups ” for Class IIb and Class C devices covered in a certificate . 3.4. Device : device should be understood as the device(s) associated with one Basic UDI -DI7. 3.5. QMS certificates: QMS certificates are EU q uality management system certificates (MDR and IVDR) , EU quality assurance certificates (MDR) and EU production quality assurance certificates (IVDR) issued by notified bodies as a result of conformity assessments . 2 "A set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics" (Art. 2 (7) MDR and Art. 2(8) IVDR). 3 In cases, where the 4th level for the MDR do es not exist the notified body should use the next higher level . 4 If the notified body considers that for a particular device level 4 for the MDR/level 3 for the IVDR is not sufficiently specific to define a generic device group, it can use the next lower level if available. 5EMDN nomenclature can be found currently at : http://www.salute.gov.it/imgs/C_17_pagineAree_328_listaFile_itemName_15_file. pdf 6 In case where more than one EMDN code applies to one device, only the most appropriate one of these EMD N codes will be assigned for sampling purposes. The technical documentation related to that particular device will be assessed in its entirety. 7 As defined in MDCG 2018 -1 v2 Guidance on BASIC UDI-DI and changes to UDI -DI. 4 4 Sampling criteria The Regulation s establish minimum requirements for sampling prior to issuing the certificate and during its validity. The notified body will ensure that these requirements will be complied with when drawing up a sampling plan. In addition, other considerations have to be observed in order to ensure an adequate coverage of devices on a representative basis. 4.1. Quantitative Sampling Criteria 4.1.1. Sampling prior to issuing a QMS certificate The Regulations establish the need for the notified body to assess technical documentation for a number of devices prior to issu ing the QMS certificate : - For Class IIb and Class C the technical documentation of at least one representative device per generi c device group (as per Article 52(4) of the MDR and Article 48( 7) of the IVDR ). This means that the notified body shou ld asses s how many generic device groups as per 3.2 are covered in the application (how many nomenclature's 4th levels for MDR / 3rd levels in combination with applicable IVP codes for the IVDR8), select per group at least one representative device covered by a Basic UDI -DI and assess the technical documentation for the device(s) selected . - For Class IIa and Class B the technical documentation of at least one representative device per category of devices (as per Article 52(6) of the MDR and Article 48( 9) of the IVDR ). This means that the notified body should asses how many categories of devices as per section 3.1, (how many MDA/M DN or IVR codes ), are covered by the ma nufacturer’s application, select per category at least one representative device covered by a Basic UDI -DI (MDA/MDN or IVR code ) and assess the technical documentation for the device(s) selected . The outcome of these assessments is an essential input for the final review according t o Annex VII section 4.7 of the R egulations prior to issuing of the certificate . 4.1.2. Sampling during surveillance After issuing the certificate, the notified body will continue to assess technical documentation in line with the sampling plan. Section 3.5 of Annex IX of both Regulations indicates that surveillance assessment shall also include an 8 Generic device groups for Class C devices will consist on an EMDN + an IVP code. Therefore, when different products are covered under the same EMDN but corresponds to different IVP codes, the notified body will assign the most appropriate IVDP code to each device. 5 assessment of the tech nical documentation9 which means that at least one technical documentation must be reviewed each year . In addition, notified bodies will ensure that the entire device range is covered during the period of validity of the certificates as required by Section 4.5.2 (a) of Annex VII . This means that at least one device per each category, in case of Class IIa and Class B devices , and at least one device per each generic device group, in case of Class IIb and Class C devices, should be samp led and the relevant technical documentation assessed between the issue of a certificate and its expiry date. Furthermore, in addition to the above -mentioned criteria , the number of samples to be assessed need to be selected on a representative basis ( as per Annex VII 4.5.1 9th indent MDR, An nex IX 2.3 3rd paragraph MDR / IVDR, and An nex VII 4.5.1 8th indent IVDR). Therefore, in developing the sampling plan (see section 6), the notified body should also ensure that the number of devices sampled is proportionate to the total number of devices contained in the certificate. For this purpose, it is expected that 15%10 of devices from each category and from each generic device group covered in the certificate will be sampled during its validity – taking into account the maximum validity of 5 years . In cases where the certificate contains very few devices and the technical documentation s of these have been already reviewed, it is expected that during surveillance audit s the notified body will focus on the review of the technical documentation related to post -market surveillance in accordance with Annex III . Normally, the devices to be sampled after the certificate has been issued would be spread evenly during the validity of the certificate. However, the notified body might decide to perform different number s of reviews in a given year for different reasons (e.g. workload , vigilance concern ) as long as throughout the surveillance period all initially determined assessments are performed . Such an approach is acceptable as long as the minimum requirements mentioned in the first paragraph of this section are complied with. 4.2. Qualitative Sampling Criteria Section 2.3 of Annex IX of both Regulations establishes qualitative criteria to be used when drawing up sampling plans. While s ome of these criteria such as similarities in design, technology and manufacturing and sterilisation methods may be covered already by the fact that devices belong to the same category or generic device group , all the criteria defined in Section 2.3 of Annex IX including novelty of the technology intended purpose or the results of any previous relevant assessments such as with regard to physical, chemi cal, biological or clinical properties must be individually considered when prioritising the review of one device over another. This prioritisation should take into account the inherent risk of the different devices included in the relevant category of devices / generic 9 The follow -up of change notifications according to Section 4.9 of Annex VII (e.g. “the device range covered” in Annex IX section 2.4), and other surveillance activities as laid down in Section 4.10 of Annex VII are to be carried out in addition to sampling during surveillance . 10 For the first certification cycle under the MDR/IVDR the 15% may be decreased to a minimum of 5%. 6 device group which means that , for instance, novel devices, will usually be prioritised over well -known technologies (unless there are specific concerns over the latter). Additional criteria may be also taken into consideration by the notified body11. As required by the Regulation, the notified body must document its rationale for the samples taken , in particular, mentioning what specific criteria have been taken into account. It should be noted, that as long as there are devices that have not been sampled , each device should only be sampled once during the period of validity of the certificate unless vigilance cases or other information which have been brought to the notified body ’s attention will require it . 5 Assessment of the technical documentation 5.1. Depth of the assessment The depth and extent of the technical documentation assessment of Class IIa / IIb and Class B / Class C devices will be the same as the depth of assessment carried out for Class III and Class IIb implantable and Class D devices . This means that the technical documentation of a device shall be assessed against all General Safety and Performance Requirements (Annex I) and requirements of Annex II and III. Records of the assessment shall be prepared which allow a third party to understand the functionality of the device and all aspects of the assessment including judgements made by the assessor . It should be taken into account that every device (i.e. Basic UDI -DI) might include different variants, models or sizes. In that case, the review of the technical documentation will also include the assessment of how the differences among these have been addressed in the technical documentation and whether all of them are in line with the relevant requirements. 5.2. Applicability of Chapter II, Section 4 of Annex IX Taking into account the wording of article s 52(4) and 52(6) of the MDR and Article 48(7) and 48(9) of the IVDR, as combined with annex es VII and IX, the tasks to be carried out by the notified body as part of the conformity assessment activities described in Chapter II , Section 4 of Annex IX comprise t he complete review of the technical documentation in accordance with Annexes II and III . In addition, the manufacturer will grant access to the technical documentation as referred to in Section 2.2 of Annex IX and the notified body will provide the manufacturer with a report on the technical documentation assessment. For Class IIa / IIb and Class B / Class C the notified body will neither require an application nor issue an EU technical documentation assessment certificate (see 5.3 for exceptions) . 11 For instance, where controls or calibrators are specifically intended to be used in conjunction with a specific IVD device, these controls or calibrators will preferably be assessed alongside that device 7 5.3. Additional requirements for s pecific types of devices under the MDR and the IVDR For class IIb implantable devices12, Article 52(4) second subparagraph of the MDR establish es the need to review the technical documentation in accordance with the complete Section 4 of Annex IX for every device, therefore an application as well as the issuance of an EU technical documentation assessment certificate are req uired . They are exempt from sampling. According to Article 54 , Class IIb active devices intended to administer and/or remove a medicinal product falling into rule 12 of Annex VIII are subject to the clinical evaluation consultation procedure prior to issuing of the certificate . These devices can be subject to sampling but according to Article s 54(3) and 55 the notified body must ensure that at least the clinical evaluation assessment report (CEAR) for each device is uploaded in Eudamed prior to issuing the QMS certificate. This means that the sampling will not apply to the clinical evaluation as it has to be assessed for every device. Article 48 (7, 8 and 9) and Section 5 of Annex IX of the IVDR establish that class B and C devices for self -testing, near-patient testing and companion diagnostics are exempt from sampling . The manufacturer will lodge an application as per sections 5.1 (a) and 5.2 (a) of Annex IX of the IVDR , and , as described in section 5.1 (c-e) and 5.2 ( a-e), the notified bod y will review the technical documentation of all the devices covered in the certificate and will issue an EU technical documentation assessment certificate. 5.4. Reporting The technical documentation assessment of Class IIa / IIb and Class B / Class C devices and its reporting should follow the principles established in Annex VII and the applicable provisions of the conformity assessment annexes and should use or be similar to those procedures and checklists developed by the notified body for the assessment of Class III / IIb implantable devices and Class D devices . In order to fulfil the legal requirements, the reporting requirements established in Section 4.6. of Annex VII will apply. 6 Drawing up and keeping up to date a sampling plan According to Section 4.5.2(a) of Annex VII the notified body shall draw up and keep up to date a sampling plan . This plan should contain at least the devices covered by the certificate, their Basic UDI -DI, the generic device group (in case of Class IIb ), the generic device group plus the IVP code (in case of Class C devices) or the category of devices (in case of Class IIa / Class B devices) , the identifier of the respective technical documentation , the (planned) assessment dates and the status of such asse ssments . 12 Except fo r sutures, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors, which are subject to sampling 8 The notified body should update the sampling plan whenever needed on the basis of the criteria defined in this guidance as well as on the basis of its post - certification activities laid down in Section 4.10 of Annex VII. In particular, the outco me of the screening of relevant sources of scientific and clinical data and post-market information relating to the scope of their designation , or the review of vigilance data should be taken into account. If the manufacturer makes a change in the product range during the period of validity of the certificate, the notified body should review the sampling plan accordingly. When a dding new devices to the scope of the certificate which do not fall into the alrea dy covered generic device groups / categories of devices , the initial sampling criteria (section 4.1) apply. If the manufacturer applies for re -certification, the notified body should update the sampling plan with the samples to be assessed during the upc oming certification period according to the principles laid down under section 4.1.2 Sampling during surveillance and keep the sampling plan up to date as described above.

11 MDCG 2020-11 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90385EEC and 9342EEC.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-11 1 MDCG 2020-11 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90/385/EEC and 93/42/EEC to be performed in accordance with Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 May 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-11 2 Guidance on the renewal of designation and monitoring of notified bodies under Directives 90/385/EEC and 93/42/EEC to be performed in accordance with Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 1. Introduction The COVID-19 pandemic has created extraordinary circumstances that demand substantial additional resources, as well as a continued availability of vitally important medical devices, that could not reasonably have been anticipated at the time of adoption of Medical Devices Regulation (EU) 2017/745 (hereafter referred to as ‘MDR’). In order to allow Member States, health institutions and economic operators to prioritise the fight against the COVID-19 pandemic it was considered necessary to defer the application of certain MDR provisions by one year (i.e. until 25 May 2021)1. To ensure the continuous presence of a functioning regulatory framework for medical devices it was necessary to also defer by one year the date of repeal of the Medical Devices Directives 90/385/EEC and 93/42/EEC (hereafter referred to as ‘the Directives’). The deferral of the date of repeal has a consequential impact on the designations of certain notified bodies under the Directives, including their ability to carry out their obligations and be operational until 25 May 2021. The current COVID-19 pandemic also affects the way in which designating authorities are able to perform the required appropriate surveillance and monitoring activities over notified bodies. To take account of these extraordinary circumstances, the Commission and the Member States, on 18 May 2020, adopted Commission Implementing Regulation (EU) 2020/666 amending Commission Implementing Regulation (EU) 920/2013 as regards the renewal of designations and the surveillance and monitoring of notified bodies (hereafter referred to as ‘the Implementing Regulation’)2. The amendment provides for a derogation from certain requirements on the renewal of designations of notified bodies and for alternative surveillance and monitoring activities that designating authorities should carry out. In particular, in the interest of health and patient safety, and, to ensure consistency among the activities performed by designating authorities, this guidance document has been developed to outline common criteria for the renewal of designations of notified bodies under the Directives until 25 May 2021. In addition, this document intends to provide clarification on the appropriate activities performed by designating authorities over notified bodies in order to ensure an adequate level of surveillance in accordance with Article 5 paragraph 1, third subparagraph, of the Implementing Regulation. 1 OJ L 130, 24.4.2020, p. 18–22. 2 OJ L 156, 19.5.2020, p. 2–5 Medical Device Medical Device Coordination Group Document MDCG 2020-11 3 2. Scope This guidance covers the following activities performed by designating authorities under exceptional circumstances, as referred to in Article 4(6) of the Implementing Regulation:  renewal of designation under the Directives of notified bodies whose designation expires in the period from 26 May 2020 to 25 May 2021;  surveillance activities to be performed by designating authorities in accordance with the Implementing Regulation under COVID-19 related restrictions, notably quarantine orders and travel restrictions. This guidance does not apply to the procedure for the initial designation of a notified body under the Directives nor to the procedures for extensions of the scope of a notified body nor the lifting of limitations to the scope of a notified body3. 3. Renewal of designation of a notified body until 25 May 2021 When deciding upon the renewal of the designation as a notified body in accordance with Article 4(6) of the Implementing Regulation, designating authorities should perform an appropriate assessment of the continuous competence of the notified body and its ability to accomplish the tasks for which it has been designated. Designating authorities should base their decision to renew a designation on a review of documents, resources and activities, which lay ground for the verification of the criteria for designation as set out in the Directives and in Annex I to the Implementing Regulation. This review should include in particular the following:  assessment of relevant quality management system procedures, forms and records, in particular qualification criteria, procedures for selection and authorisation of persons involved in conformity assessment activities, procedures to ensure independence, objectivity and impartiality of the notified body’s activities;  assessment of an appropriate number of the notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations;  assessment of an appropriate number of the notified body’s personnel files;  discussion of the results of the assessments of quality management documents and records with responsible personnel, including management responsible for the implementation and update of the quality management system as well as the notified body’s assessors responsible for product review, including clinical evaluation, final review and decision-making processes;  review of the outcome of the most recent on-site surveillance assessments and observed audits as well as of recent extraordinary assessment activities conducted by the designating authority 3 See Article 11 of Directive 90/385/EEC and Article 16 of Directive 93/42/EEC. Medical Device Medical Device Coordination Group Document MDCG 2020-11 4 When performing the above-mentioned review, the designating authority could also consider, if relevant, the outcome of the most recent joint assessment carried out in accordance with Article 3 of the Implementing Regulation as well as joint assessments recently carried out in accordance with the MDR. In order to ensure a sufficient assessment the selection of the appropriate number of manufacturer’s technical documentation reviews and personnel files to be reviewed should take into account the volume of the activities performed by the notified body, its scope of designation and any relevant vigilance data. The designating authority should be able to justify the number and type of files selected. The designating authority should ask the notified body to implement appropriate measures to correct any non-conformities found during the review Normally, the renewal should include an on-site assessment. However, when exceptional circumstances prevent a designating authority from carrying out such an on-site assessment, alternative assessment measures should be used. Principles and arrangements of alternative measures described in Section 5 of this document concerning surveillance activities may apply. The results of the assessment performed by the designating authority should be documented and the final decision on the renewal of a designation should be substantiated. 4. Notification and information to be provided to the Commission In accordance with Article 4(6) of the Implementing Regulation, any decision by a Member State on the renewal of a designation as a notified body should be notified to the Commission and the other Member States through the New Approach Notified and Designated Organisations information system (NANDO) on or before the date of designation expiry. In line with the ordinary procedure, this should take place by means of submitting an update of the existing notification under the relevant Directive. The Commission may request further information relating to a decision taken by a designating authority on the renewal of a designation. In particular, designating authorities should make available, upon request from the Commission, the reports describing the assessments performed in relation to the renewal of the designation and the relevant outcome as described in Section 3 of this guidance. This should clearly document the basis for the renewal decision detailing the elements reviewed by the designating authority to substantiate the decision, including the results of any surveillance and monitoring activities as described in Section 5 of this guidance. Relevant notified body’s documentation should also be made available to the Commission on request. 5. Surveillance activities to be performed under exceptional circumstances In the context of the current COVID-19 pandemic, the resulting travel and quarantine restrictions may significantly affect the ability of designating authorities to conduct their Medical Device Medical Device Coordination Group Document MDCG 2020-11 5 mandatory surveillance and monitoring activities such as on-site assessments and observed audits of their notified bodies. Therefore, in accordance with Article 5(1) of the Implementing Regulation, in order to ensure an adequate level of surveillance, designating authorities should at least assess an appropriate number of notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations, and of personnel files, in addition to carrying out alternative surveillance measures. These alternative measures may include the following principles and arrangements:  on-site surveillance assessments may be replaced by remote surveillance assessments using the most advanced available Information and Communication Technologies as deemed appropriate in accordance with Union legislation on information security and data protection;  assessment of all relevant and required documents/records off-site. In order to ensure a sufficient assessment, the selection of the appropriate number of notified body’s reviews of the manufacturer’s technical documentation, including clinical evaluations, and personnel files to be reviewed, should take into account the volume of the activities performed by the notified body, its scope of designation and any relevant vigilance data. The designating authority should be able to justify the number and type of files selected.

mdcg_2019_5_legacy_devices_registration_eudamed_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 1 of 4 MDCG 201 9-5 Registration of legacy devices in EUDAMED April 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regar ded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 2 of 4 This document deals with registration of devices, which can continue to be placed on the market under Directive certificates by virtue of Article 120(3) of Regulation 745/2017 (MDR), and Article 110(3) of Regulation 746/2017 (IVDR) after the relevant MDRs application dates. Those products are, for the purpose of this document, referred to as “legacy devices”1. All following considerations, which are made in relation to the MDR shall apply to the IVDR, mutatis mutandis. Art 120(3) of the MDR lays down that t he requirements of the MDR relating to post - market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply to legacy devices placed on the market after the application date of the MDR in place of the corr esponding requirements of the Directives. The MDR is not explicit in requiring that these “legacy devices” are subject to relevant UDI obligations. The MDR device registration requirements (Annex VI Part A Section 2 and Part B that are complementary) mak e the Basic UDI -DI and UDI -DI the access keys for device -related information in the future Eudamed, which is reflected in the database design. Therefore, any registration of a device is normally possible in Eudamed only if a proper Basic UDI -DI and UDI -DI are assigned to the device and registered in the database together with the other device -related data. In light of this, taking all views heard into account, and considering that Article 120(3): - Refers to legacy devices to be registered in line with MDR provisions, - Lacks any explicit reference to UDI obligations for legacy devices the MDCG considers it appropriate to adapt the Eudamed design to allow the registration of legacy devices in Eudamed in the absence of a (Basic) UDI -DI. This is intended to prevent any technical constraint to the applicability of Art 120(3) for legacy device registration in Eudamed. A comprehensive description of the technical implications is provided in the Annex. 1 It shall be noted that, in other contexts, the term “legacy devices” might be used with a different meaning. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 3 of 4 Annex Basic considerations related to functioning of future registration of legacy devices in Eudamed 1. Legacy devices – covered by a valid Directive certificate - that will continue to be placed on the market after the MDR date of application should be registere d in Eudamed without a Basic UDI -DI and UDI -DI. The registration deadlines for those devices is clearly the one referred to in Article 123(3)(e): 18 months after the date of application (provided that Eudamed is fully functional on time)2. 2. However, in ca se of serious incident or field safety corrective action to be reported during the 18 months referred to in point 1, where the legacy devices have not been registered in Eudamed yet, they must be registered at the moment of the serious incident/field safet y corrective action reporting. 3. Point 1 will be applicable only to the devices that are not already registered as MDR devices. NOTE: All the Directive -compliant devices which have been placed on the market ahead of the general application dates and will not continue to be placed on the market afterwards, should be registered in Eudamed (without a Basic UDI -DI and UDI-DI) only if a serious incident report and/or a field safety corrective action report (with the field safety notice) occurs after the applica tion date. Technical implementation in Eudamed 4. Legacy devices that will be registered in Eudamed will need two other unique access keys (IDs) to replace the Basic UDI -DI and UDI -DI for the sake of the workability of Eudamed . 5. For this purpose, a Eudamed DI will be assigned to the device instead of the Basic UDI -DI and a Eudamed ID will be assigned by Eudamed instead of the UDI-DI allowing the system to work and to keep the design of Eudamed as close as possible to the MDR design. These Eudamed DI and Eudamed ID will be unique for a given legacy device. 6. The Eudamed DI could be either entirely generated by Eudamed or the manufacturer could partly assign the DI code. On the other hand, the Eudamed ID will be always automatically and fully generated b y Eudamed 2 It should be noted that all class I devices that are not sterile and/or with a measuring function under the Directives, are not eligible for any grace period. When placed on the market after the MDR date of application, they will have to be MDR compliant and be registered in EUDAMED as MDR devices. Medical Device Medical Device Coordination Group Document MDCG 201 9-5 Page 4 of 4 from the Eudamed DI. The proposed rules for the assignment (still under discussion) are that Eudamed DI start with character "B", where Eudamed ID will start with character "D" (only difference between Eudamed DI and Eudamed ID). Beside this f irst character, the Eudamed DI/ID will include the SRN of the manufacturer, a number (assigned by the manufacturer or Eudamed) and a check digit. 7. The relationship between the Eudamed DI and a Eudamed ID will be one to one. 8. Furthermore, the registration o f the legacy devices will require the manufacturer to enter the directive certificate identification (NB number, certificate number, revision number and expiry date) since they will not be registered in Eudamed by the NBs. In case a legacy device has been already registered in Eudamed and that same device becomes at any point in time an MDR compliant device, that MDR device should be considered as a new device requiring a new registration (due to the change in the applicable legislation) with a Basic UDI -DI and UDI -DI in Eudamed. However, only a UDI -DI should be entered, if another device with the same Basic UDI-DI has already been registered. Eudamed should facilitate this (copy) process and allow the linking between the MDR device and the corresponding legacy device .

mdcg_2019_4_devices_registration_eudamed_en.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 201 9-4 Page 1 of 2 MDCG 201 9-4 Timelines for registration of device data elements in EUDAMED April 2019 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission docum ent and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 201 9-4 Page 2 of 2 “With regard to timelines for device registration, the text of the MDR presents an inconsistency. On the one hand, Article 123(3)(d) lists the full Article 29 as being applicable from the application dates or, if EUDAMED is not functional on time, six mont hs after the date of publication of the notice referred to in Article 34(3). On the other hand, Article 123(3)(e) grants an additional 18 -month transitional period for obligations contained in Article 29(4). Taking into account: - the declared will of the c o-legislator to grant an 18 -month additional transitional period for device registration and registration of certificates, - the logical correspondence and complementary character of device data elements in Part A (Section 2) and Part B of Annex VI, - the nee d to ensure that information on devices in EUDAMED is not displayed to public in a partial or misleading nature, the obligation for registration in EUDAMED of device data elements listed in both part A, Section 2, and Part B of Annex VI, shall be applicabl e as from the timelines indicated in Article 123(3)(e) (meaning from 18 months after the general application date or, if EUDAMED is not fully functional on time, from 24 months after the date of publication of the notice referred to in Article 34(3)). This is without prejudice to the fact that the obligation related to the operation of assignment of Basic UDI —DI and UDI -DI to devices remains applicable as from the general application dates. This is also without prejudice to the fact that at any time after the general application date, for MDR compliant devices, the full registration of devices (Article 29) remains a pre-condition for the possible registration of their relevant serious incident in EUDAMED These considerations apply mutatis mutandis to the IV DR”.

2020-15-position-paper-actor-registration-module_en.pdf.txt

Medical Devices Medical Device Coordination Group Document MDCG 2020-15 MDCG 2020-15 MDCG Position Paper on the use of the EUDAMED actor registration module and of the Single Registration Number (SRN) in the Member States August 2020 This document has been endorsed by the Medical Device Coordinat ion Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States an d a representative of the European Commission chairs it. The document is not a European C ommission document and it cannot be regarded as reflecting the official position of th e European Commission. Any views expressed in this document are not legally binding and on ly the Court of Justice of the European Union can give binding interpretations of Union law. Medical Devices Medical Device Coordination Group Document MDCG 2020-15 MDCG Position Paper on the use of the EUDAMED actor registratio n module and of the Single Registration Number (SRN) in the Member States Article 33 of Medical Devices Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 (her eafter: ‘MDR’) sets out that the Commission, after consulting the MDCG, shall set up, maintain and manage the European database on medical devices (EUDAMED). EUDAMED shall be composed of multiple electronic systems (so called ‘modules’), including an elect ronic system on registration of economic operators, also referred to as the actor registration module . In accordance with Article 30(1) MDR, the actor registration module shall allow for the creation of a unique single registration number (‘SRN’) referred to in Article 31(2) and to collate and process information that is necessary and proportionate to identify the manufacturer (including producer s of system/procedure packs) and, where applicable, the authorised representative and the importer. As such, the actor registra tion module forms a pre- requisite for the use of the other EUDAMED modules and facilitates a secure way of accessing EUDAMED. The responsibility to assign SRNs to economic operators lies with the Member States. To that end, Artic le 31(2) stipulates that, after having verified and validated the data entered by an economic operator, the competent authority of a Member State shall obtain an SRN from the actor registration m odule and approve the issuing of it to the requesting manufacturer, authorised representative or importer. On 30 October 2019, the Commission published a notice by which it concluded that the full functionality of EUDAMED require s the availability and full opera tion of all six modules in accordance with the technical specifications and confirmed by an audit as referred to in Article 34. The notice foresees the launch of a fully functional EUDAMED for May 2022. However, at its meeting of 12 March 2020 th e MDCG agreed that the Commission makes available to Member States each EUDAMED module on a gradual basis as soon as it is operational. In line with the MDCG decision referred to above, the Commissi on has confirmed its readiness to deploy the actor registration module as of 1 December 2020. The members of the MDCG strongly encourage the use of the actor registration module by all relevant actors on their territories, including the use of the single registration number by actors as stipulated in the MDR (e.g. indicating the SRN on certificates). The members of the MDCG agree that double registration requirements for actors should be avoided as much as possible . Therefore, actors that obtai n an SRN should be considered in compliance with the actor registration requirements (for manufacturers, authorised representatives, importers, system/procedure pack producers) to the extent that national laws accommodate for this. In such cases, thos e actors should follow the obligations and requirements of the MDR related to both the registration of relevant actors (via the actor registration module) and the us e of their SRN as required.

05 MDCG 2020-5 Guidance on Clinical Evaluation - Equivalence.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-5 MDCG 2020-5 Clinical Evaluation - Equivalence A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Page 2 of 20 Clinical Evaluation - Equivalence A guide for manufacturers and notified bodies Page 3 of 20 1 Table of contents 1. Introduction .......................................................................................................... 4 2. Scope ................................................................................................................... 5 3. Equivalence ......................................................................................................... 5 3.1 Technical characteristics ............................................................................... 5 3.2 Biological characteristics ............................................................................... 6 3.3 Clinical characteristics ................................................................................... 9 4. Demonstration of equivalence ............................................................................ 10 5. Use of data from similar devices ........................................................................ 14 6. Clinical data identification ................................................................................... 15 Annex I – Equivalence table ..................................................................................... 16 Page 4 of 20 1. Introduction This guidance document is not legally binding. It has been put together following contribution from national competent authorities, industry and relevant stakeholders and it should therefore be recognised as best practice. The Regulation (EU) 2017/745 on medical devices1, hereafter referred to as the MDR (medical device regulation), provides a possibility to use clinical data related to an equivalent device in the clinical evaluation required for a device under conformity assessment2. Whilst carrying out a clinical investigation is the most direct way to generate clinical data concerning the safety and performance of medical devices for the purpose of CE marking, clinical data can also be sourced from3  clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,  reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated Equivalence shall be demonstrated according to the MDR requirements4. The European Commission has published a guide on clinical evaluation under the directives 93/42/EEC and 90/385/EEC; MEDDEV 2.7/1 rev. 45. This MEDDEV guide should be used also during the process of demonstrating equivalence under the MDR. However, it has been recognised that some of the requirements set out in MEDDEV 2.7/1 rev. 4 are not fully aligned with the MDR and that further guidance to address the differences would be of benefit to industry and other stakeholders. Only the text of the MDR is legally binding. In cases of divergence between the MEDDEV 2.7/1 rev. 4, this MDCG guidance and the MDR, the MDR shall take precedence. This MDCG guidance does not introduce any new requirements. The demonstration of equivalence does not remove the requirement to always conduct a clinical evaluation in accordance with the MDR. It is the demonstration of equivalence6 that allows the manufacturer to let clinical data from an equivalent device enter the clinical evaluation process of the device in question for the purpose of confirmation of conformity with relevant general safety and performance 1 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2017:117:TOC 2 MDR, Article 61 and Annex XIV Part A. 3 MDR, Article 2 (48) 2nd and 3rd indent. 4 MDR, Annex XIV, Part A (3). 5 MEDDEV 2.7/1 revision 4, Guidelines on medical devices, clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC https://ec.europa.eu/growth/sectors/medical-devices/current-directives/guidance_en 6 MDR, Annex XIV, Part A (3). Page 5 of 20 requirements7. There may also be other sources of clinical data than from an equivalent device8 to include in the process of clinical evaluation. 2. Scope This MDCG guidance covers the demonstration of equivalence, based on data pertaining to an already existing device on the market9, for the purpose of CE-marking under the MDR. One of the purposes of this document is to highlight the differences between the MDR and the MEDDEV 2.7/1 rev.4 specifically with regards to equivalence. It is also intended to provide additional guidance and support a harmonised approach to the demonstration of equivalence across the EU. In addition, non-exhaustive guidance and references have been provided with respect to device considerations for medical devices incorporating an ancillary medicinal product. This MDCG guidance also covers products without an intended medical purpose listed in Annex XVI of the MDR. 3. Equivalence The MDR requires10 that technical, biological and clinical characteristics are considered when demonstrating equivalence to another device. Whilst these general characteristics are described in the MEDDEV 2.7/1 rev. 4 Appendix 1 and are aligned with the MDR requirement, there are differences in the criteria that are set out for each of the three characteristics. Differences in criteria between the MDR and the MEDDEV 2.7/1 rev. 4 are highlighted below and are accompanied by some explanatory text. 3.1 Technical characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev 4, Appendix A1 The device is of similar design; is used under similar conditions of use ; has similar specifications and properties including physicochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms ; uses similar deployment methods, where relevant; has similar principles of operation and critical performance requirements. - be of similar design, and - used under the same conditions of use , and - have similar specifications and properties (e.g. physicochemical properties such as type and intensity of energy, tensile strength, viscosity, surface characteristics, wavelength, surface texture, porosity, particle size, nanotechnology, specific mass, atomic inclusions such as nitrocarburising, oxidability), and - use similar deployment methods (if relevant), and - have similar principles of operation and critical performance requirements 7 MDR, Article 61 (1) and (3 (a)). 8 MDR, Article 2 (48) 1st and 4th indent. 9 Whether the ‘market’ is presumed to be the EU market or not is related to requirements in Article 61. See section 4 (d) and (e) in this document for further guidance. 10 MDR, Annex XIV Part A (3). Page 6 of 20 (a) The MDR requires that technical characteristics shall be taken into consideration for the demonstration of equivalence including that the device in question and the device presumed to be equivalent are “used under similar conditions of use”. MEDDEV 2.7/1 rev. 4, however, specifies use under the same conditions with regard to technical characteristics11. The conditions of use shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance between the device in question and the device presumed to be equivalent. For further guidance on the assessment of ‘similar’, see also section 4 of this document. (b) Different examples are given for specifications and properties of the device when considering technical characteristics across the two definitions. These are examples only and are to be considered as such. They must not be interpreted as an exhaustive list of specifications and properties of technical characteristics when considering equivalence to another device. Note however that the MDR specifically points out that software algorithms shall be similar in the device presumed to be equivalent. This includes software algorithms in software driving or influencing the use of a device, and in software intended to be used alone12. It is the functional principle of the software algorithm, as well as the clinical performance(s) and intended purpose(s) of the software algorithm, that shall be considered when demonstrating the equivalence of a software algorithm. It is not reasonable to demand that equivalence is demonstrated for the software code, provided it has been developed in line with international standards for safe design and validation13 of medical device software. Software solely intended for the configuration of a device (e.g. presentation on a graphical user interface etc), and not related to any medical purpose14 (e.g. diagnosis, treatment etc), does not need to be similar when considering equivalence as long as it can be justified to not negatively affect the usability, safety or clinical performance. 3.2 Biological characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev. 4, Appendix A1 The device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables Use the same materials or substances in contact with the same human tissues or body fluids. Exceptions can be foreseen for devices in contact with intact skin and minor components of devices; in these cases risk analysis results may allow the use of similar materials taking into account the role and nature of the similar material. 11 “Conditions of use” with regard to technical characteristics may e.g. be environmental factors such as magnetic fields, temperature, moisture, conditions during transport of device in use etc. See section 3.3 in this document regarding use for the same clinical condition or purpose. 12 See MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 - MDR and Regulation (EU) 2017/746 – IVDR. 13 E.g. IEC 62304 Medical device software – Software life cycle processes, and IEC 82304-1 Health software – Part 1: General requirements for product safety. 14 MDR, Article 2(1). Page 7 of 20 (a) Manufacturers must consider the additional text in the MDR and adequately specify all applicable characteristics. The exceptions, outlined in the MEDDEV 2.7/1 rev 4, to not use the same materials are NOT acceptable under the MDR. The MDR requires that biological characteristics shall be taken into consideration for the demonstration of equivalence, i.e. the device uses the same materials or substances in contact with the same human tissues or body fluids for a similar kind and duration of contact, and with similar release characteristics of substances, including degradation products and leachables, as the presumed equivalent device. The distinction between “same materials or substances” and “similar release characteristics of substances” is made to account for the fact that processing, design and the use environment may introduce small changes even when the raw materials are the same. Processing can make materials more susceptible to degradation by changing properties of the material and/or by inducing different stresses. For example, small changes in pH or oxidative stress can increase or decrease release characteristics. For this reason, it is the final device that shall be assessed. (b) The principles outlined in ISO 10993 series of standards for the biological evaluation of medical devices can be adopted, in particular the ISO 10993-1 for a risk-based approach to biological evaluation15 and also for material characterization. In addition, the ISO 10993-18 which covers chemical characterization of materials can be adopted to specify the identity of materials and to estimate the type and quantity of leachables from the final device. Annex C of this standard addresses biological equivalence. The ISO 10993-17 includes principles on the toxicological risk assessment of leachables. Leachables may include degradation products or other substances from the materials or substances that the device is made of, but also other constituents for example residuals from the manufacturing process or sterilisation, any contaminations etc. Therefore, for the consideration of equivalence, it is the properties and characteristics of the final device that shall be taken into account. For degradable materials, ISO 10993, Parts 13, 14 and 15 address the identification and quantification of degradation products. Note, that there may be further parts in the ISO 10993 series of standards that are relevant for the device in question. (c) The MDR has additional requirements16 for devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed 15 ISO 10993-1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process, and collateral standards in the 10993 series. 16 MDR, Annex I, (12.2). Page 8 of 20 in the human body. For the consideration of equivalence, the substances shall be the same. Those devices are not medicinal products, but for the conformity assessment they shall comply with the relevant requirements laid down in Annex I to Directive 2001/83/EC17 for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions. This means that for the demonstration of equivalence under the MDR, those aspects shall also be taken into consideration. Note that the requirement18 that the notified body shall seek a scientific opinion from a competent authority for medicinal products or the EMA, for the device or its products of metabolism, that are systemically absorbed by the human body in order to achieve their intended purpose, on the compliance with the relevant requirements laid down in Annex I to Directive 2001/83/EC, always applies for the device under evaluation even if equivalence has been demonstrated under the MDR. (d) The demonstration of equivalence may also concern medical devices with an ancillary medicinal substance , for example drug-eluting stents or heparin- bonded central venous catheters. The MDR requires19 that biological characteristics shall be taken into consideration for the demonstration of equivalence, including that the device in question and the device presumed to be equivalent, use “the same materials or substances in contact with the same human tissues or body fluids”. This applies also to the medicinal substance and any related excipients/coatings. Excipients/coatings may potentially have a significant effect for example on the release characteristics of the medicinal substance intended only for a local effect from a stent, and thereby a significant effect on the clinical performance. In all cases, concerning the device under evaluation, the notified body shall20  verify the usefulness of the substance as part of the device, taking account of the intended purpose of the device, and  seek a scientific opinion from a competent authority for medicinal products or the EMA to ensure that the quality, safety and benefit/risk of using the ancillary medicinal product, including whether the manufacturing process have been adequately assessed. 17 Directive 2001/83/EC relating to medicinal products for human use. 18 MDR, Annex IX, Chapter II, 5.4 (b). 19 MDR, Annex XIV Part A (3) second indent. 20 MDR, Annex IX, Chapter II, 5.2. (b) and (c). Page 9 of 20 Note that medical devices with an ancillary medicinal substance are class III devices21. In cases where a manufacturer intends to claim equivalence to a device not manufactured by him, the MDR requires that the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis22 . Manufacturers cannot claim equivalence of a device with an ancillary medicinal substance to a device without an ancillary medicinal substance and vice versa. For example, the manufacturer of a heparin coated catheter shall not claim equivalence to a drug-free catheter even if both catheters are otherwise identical23 . See also section 4 of this document. Similarly, manufacturers shall not claim equivalence of the ancillary medicinal substance to a ‘standalone’ medicinal substance. 3.3 Clinical characteristics MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev . 4, Appendix A1 The device is used for the same clinical condition or purpose , including similar severity and stage of disease, at the same site in the body, in a similar population, including as regards age, anatomy and physiology; has the same kind of user ; has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose. - used for the same clinical condition (including when applicable similar severity and stage of disease, same medical indication ), and - used for the same intended purpose, and - used at the same site in the body, and - used in a similar population (this may relate to age, gender, anatomy, physiology, possibly other aspects), and - not foreseen to deliver significantly different performances (in the relevant critical performances such as the expected clinical effect, the specific intended purpose, the duration of use , etc.) (a) The MDR additionally requires that, for manufacturers to compare clinical characteristics, the device shall have the same kind of user . The MDR clearly points out that a user means any healthcare professional or lay person who uses a device24, and that a lay person means an individual who does not have formal education in a relevant field of healthcare or medical discipline25. Manufacturers must therefore take into consideration whether the intended user’s competence or knowledge can have any implication for the safety, clinical performance and outcome when considering equivalence between the device in question and the presumed equivalent device. For example, a device intended for professional use and a device intended for home use, but for the same clinical condition or purpose, may have a different safety and performance profile due to the environment in which they are intended to be used. 21 MDR, Annex VIII, Rule 14. 22 MDR, Article 61 (5). 23 MDR, Annex XIV Part A (3). 24 MDR, Article 2 (37). 25 MDR, Article 2 (38). Page 10 of 20 (b) The MDR does not explicitly state that the medical device needs to be used for the same medical indication, gender and duration of use as the equivalent device. However, it is understood that in general, this is covered by the MDR requirement that both devices should be used for the same clinical condition or purpose including similar severity and stage of disease and also have similar relevant critical performance which is also outlined in the MEDDEV 2.7/1 rev. 4. This is supported by the definitions in the MDR of the ‘intended purpose’26, and the ability of the device to achieve its intended purpose by the ‘clinical performance’27 including measurable ‘clinical benefit’28. 4. Demonstration of equivalence MDR, Annex XIV Part A (3) MEDDEV 2.7/1 rev. 4, Appendix A1 The characteristics listed in the first paragraph shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Considerations of equivalence shall be based on proper scientific justification . For assuming equivalence, - all three characteristics (clinical, technical, biological) need to be fulfilled; - similar means that no clinically significant difference in the performance and safety of the device would be triggered by the differences between the device under evaluation and the device presumed to be equivalent. There are a number of prerequisites that shall be fulfilled for the demonstration of equivalence: (a) The overall considerations of equivalence shall conclude whether the listed technical, biological and clinical characteristics in the MDR29 are similar to the extent that there would be no clinically significant difference in the safety and clinical performance of the device. Note that some of the listed characteristics in the MDR shall be the same, not only similar. The corresponding wording from MEDDEV 2.7/1 rev. 4 is presented for information above. Consideration must be given to the characteristics mentioned above and a gap analysis should be conducted by the manufacturer to evaluate any clinically significant difference(s). Modifications30 of a device may be implemented for a variety of reasons. If the differences have been introduced to address specific safety and/or performance issues it shall be duly justified, that there would be no clinically significant difference in the safety and clinical performance other than the intended improvements related to the specific issue that triggered the modification / difference. For all modifications and concomitant claims of equivalence, there must be no additional risks or potential of negatively altered performance related to the introduced modifications. 26 MDR, Article 2 (12). 27 MDR, Article 2 (52). 28 MDR, Article 2 (53). 29 MDR, Annex XIV Part A (3). 30 MDR, Article 61 (4). Page 11 of 20 See a template example of an Equivalence table in the Annex I of this document. A manufacturer of a medical device shall not claim equivalence to a product without an intended medical purpose listed in the MDR Annex XVI. (b) Manufacturers may identify more than one equivalent device to the device under evaluation, but each device shall be equivalent to the device under evaluation in all the listed technical, biological and clinical characteristics31. Equivalence to each device shall be fully investigated, described and demonstrated in the clinical evaluation report. This means that manufacturers shall not use different parts of different devices to claim equivalence to the device under evaluation. The MEDDEV 2.7/1 rev. 4 is in line with this approach. In exceptional cases, a deviation from this principle may be considered. There may be device systems comprised of several more or less “stand alone” devices, where it may be justified to consider equivalence of a device in the system to a presumed equivalent device in a device system already on the market (by the same manufacturer) provided that all technical, biological and clinical characteristics are same/similar32, and that the devices in the system do not affect the safety and performance of each other. This should be duly investigated and documented both on the level of potential interference between the devices in the system, as well as on the overall safety and clinical performance of the device system. (c) Regarding the clinical evaluation, the MDR requires33 that the manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose34. In addition, considerations of equivalence shall be based on proper scientific justification35. This implies that technical, biological and clinical characteristics shall be duly investigated and documented. The manufacturer is expected to fully identify and disclose any differences between the two devices. Pre-clinical data for the consideration of equivalence should allow a scientifically sound evaluation of technical and biological characteristics. Examples of data sources: 31 MDR, Annex XIV Part A (3), the requirement refers to only “a device” and “the device”. 32 MDR, Annex XIV Part A (3). 33 MDR, Article 61 (1) second paragraph. 34 MDR, Article 61 (1) second paragraph It may under certain circumstances be justified to demonstrate conformity without support of clinical data, see MDR, Article 61 (10), but note that this is not applicable for implantable devices or class III devices. 35 MDR, Annex XIV Part A (3) For guidance see also MEDDEV 2.7/1 rev 4, Annex A6, Appraisal of clinical data - examples of studies that lack scientific validity for demonstration of adequate clinical performance and/or clinical safety. Page 12 of 20  data from the technical documentation of a manufacturer’s own presumed equivalent device (specifications, test-results, chemical/physical/biological analyses, data from pre-clinical investigations etc)  data published in the scientific literature, e.g. animal or other pre-clinical data The assessment of whether any differences in characteristics would result in clinically significant difference in safety and clinical performance shall also be duly substantiated and based on proper scientific justification. This assessment may be supported by e.g. clinical data from the scientific literature, common specifications (CS)36, harmonised standards or other established technical specifications. Furthermore, for the assessment of safety, a risk-based approach37 is expected, both for the identification of characteristics that may affect safety as well as for the final assessment of equivalence regarding safety. It is important for the consideration of equivalence that pre-clinical data and any clinical data relate to the actual device under evaluation, and to a defined generation/version of the actual device considered for equivalence, bearing in mind that there may be significant differences between different generations of the other device. If a manufacturer is not able to demonstrate sufficient levels of access to the data38 relating to the presumed equivalent device and needed for the consideration of equivalence, equivalence claims cannot be made for the purpose of conformity assessment. (d) The MDR notes specific requirements in addition to the demonstration of equivalence in order not to perform a clinical investigation which must be taken into account. A manufacturer of implantable devices and class III devices shall perform clinical investigations except if the device has been designed by modifications of a device already marketed by the same manufacturer and equivalence can be demonstrated according to the MDR39. In this context, a marketed device is considered to be a device already placed on the market and CE marked with respect to either the MDR or the directives 93/42/EEC or 90/385/EEC. The CE marking should still be valid, should be based on an updated clinical evaluation, and the benefit/risk ratio for this device should be favourable. 36 MDR, Article 2, (71) ‘common specifications’ (CS) means a set of technical and/or clinical requirements, other than a standard, that provides a means of complying with the legal obligations applicable to a device, process or system. 37 ISO 14971 Medical devices – Application of risk management to medical devices, and also other related standards as applicable e.g. ISO 10993-1 and ISO 10993-18. 38 MDR, Annex XIV Part A (3) last paragraph. 39 MDR, Article 61 (4), and Annex XIV (3). Page 13 of 20 For a manufacturer of implantable devices and class III devices claiming equivalence to an already marketed device not manufactured by him , in addition to the requirements in MDR Article 61(4), the manufacturer must have a contract in place that allows full access to the technical documentation on an ongoing basis40. Furthermore, the MDR also requires that the original clinical evaluation of the equivalent device has been performed in compliance with the requirements of the MDR. This implies that the presumed equivalent device is certified under the MDR. As such, it will not be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC. (e) For devices other than implantable devices and class III devices and where the manufacturer wants to claim equivalence, MDR Article 61 (3) is applicable. This requirement does not specify whether the device is presumed to be marketed within the EU. Therefore, it will be possible to claim equivalence to a device certified with respect to the Directives 93/42/EEC or 90/385/EEC or the MDR. However, exceptions can be considered, and equivalence claimed to a device that is not CE-marked, provided all relevant MDR requirements regarding equivalence and clinical evaluation can be met. This includes  that the manufacturer shall have sufficient levels of access to the data relating to devices with which they are claiming equivalence41 . In the circumstance that the presumed equivalent device is from another manufacturer, there is no MDR requirement of a contract between the manufacturers for regulating the access to the technical documentation.  that clinical investigations were conducted in accordance with international guidelines42  that the clinical data meet the requirements of the MDR, and a justification is provided whether the clinical data are transferrable to the European population. The regulatory status of the presumed equivalent device should be disclosed. See MEDDEV 2.7/1 rev. 4 Appendix A1 for further guidance. (f) In case of products without an intended medical purpose listed in MDR Annex XVI clinical investigations shall be performed for those products unless reliance on existing clinical data from an analogous medical device is duly justified43. An analogous device, in this context, is understood as a medical device which is similar in terms of functioning and risks profile and has a medical purpose44. To duly justify reliance on existing clinical data from an analogous 40 MDR, Article 61 (5). 41 MDR, Annex XIV Part A (3) the last sentence. 42 MDR, Recital (64) Clinical investigation of medical devices for human subjects – Good clinical practice (ISO 14155), and World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects. 43 MDR, Article 61 (9). 44 MDR, Recital (12). Page 14 of 20 medical device, the principles of demonstration of equivalence45 should be applied with the acceptance that the device under evaluation will only have an aesthetic or another non-medical purpose whereas the analogous device has a medical purpose. The general requirement to demonstrate a clinical benefit46 shall be understood as a requirement to demonstrate the performance of the device. In addition, since the common specifications (CS) for the products without an intended medical purpose may have requirements related to the clinical evaluation regarding safety47 these requirements must be taken into consideration when demonstrating equivalence and concluding whether there would be no clinically significant difference in the safety48. There shall be no significant difference in the safety and performance between the product and the presumed analogous medical device. 5. Use of data from similar devices The term ‘similar devices’ may be understood as devices belonging to the same generic device group. The MDR defines this49 as a set of devices having the same or similar intended purposes or a commonality of technology allowing them to be classified in a generic manner not reflecting specific characteristics. In cases where equivalence cannot be demonstrated under the MDR, the data from similar devices may be useful for a variety of other purposes, for example: 1. Ensuring that the risk management system is comprehensive by identifying relevant hazards and clinical risks. 2. Understanding the state of the art, the natural course of disease and alternative available treatment options. 3. Helping to define the scope of the clinical evaluation, by identifying any design features in similar devices that pose special performance or safety concerns. 4. Provide input for clinical investigation design or post-market clinical follow-up design, and the post-market surveillance system. 5. Identification of relevant and specified clinical outcome parameters for the intended clinical benefits, based on the published clinical data pertaining to the similar device(s). 6. To define minimum requirements for a quantified clinical benefit that is considered clinically relevant, and/or to identify acceptable occurrence rates of risks and adverse events. 45 MDR, Annex XIV Part A (3). 46 MDR, Article 61 and Annexes XIV and XV. 47 MDR, Article 1 (2). 48 MDR, Annex XIV Part A (3). 49 MDR, Article 2 (7). Page 15 of 20 6. Clinical data identification A clinical evaluation of the device under assessment shall be made according to the MDR50. All the clinical data, both favourable and unfavourable shall be identified. This applies to clinical data from both the device in question and the device for which equivalence can be demonstrated. If the data meet the definition of clinical data as defined in the MDR51, the data shall then progress to data appraisal and analysis in order to evaluate whether the clinical data are providing sufficient clinical evidence for the purpose of confirmation of conformity with the relevant general safety and performance requirements (GSPR)52. For identifying, appraising and analysing available clinical data from the scientific literature to establish clinical evidence53, manufacturers will find facilitative guidance in sections 8-10 of MEDDEV 2.7/1 rev. 4. In the event that the data do not meet the MDR definition of clinical data these are not clinical data and cannot be subject to data appraisal, analysis and evaluation for the purpose of providing clinical evidence for the confirmation of conformity with the relevant GSPR. 50 MDR, Annex XIV Part A. 51 MDR, Article 2 (48). 52 MDR, Annex I. 53 MDR, Article 2 (51). Page 16 of 20 Annex I – Equivalence table A table, such as the table below, may be used to clearly demonstrate equivalence and to identify the supporting data on a device by device basis. The items in the first column of the table are examples only and are to be considered as such. They must not be interpreted as an exhaustive list of specifications, properties, parameters and/or aspects for demonstrating equivalence to another device. The manufacturer should identify differences and place emphasis on the differences between the two devices rather than the similarities. Considerations shall include the potential additive effect of multiple small differences. For further considerations of equivalence, see sections 3 and 4 in this document. Scientific justifications shall be provided for the different characteristics when claiming no clinically significant difference in the safety and clinical performance of the device. Where more than one device is assessed for equivalence, the table should be completed separately for each presumed equivalent device. The documentation of the demonstration of equivalence shall be included in the clinical evaluation report. Medical Device Medical Device Coordination Group Document MDCG 2020-5 Equivalence table for the comparison of a device with a presumed equivalent marketed device for the purpose of demonstrating equivalence 1. Technical characteristics (add a separate row for each of the assessed characteristics) Device 1 (under clinical evaluation) Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Device is of similar design 1.1 Used under similar conditions of use 1.2 Similar specifications and properties including physiochemical properties such as intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and software algorithms 1.3 Uses similar deployment methods where relevant 1.4 Has similar principles of operation and 1.5 Page 18 of 20 critical performance requirements Scientific justification why there would be no clinically significant difference in the safety and clinical performance of th e device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No 1.1 1.2 1.3 1.4 1.5 2. Biological characteristics (add a separate row for each of the assessed characteristics) Device 1 Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Uses the same materials or substances in contact with the same human tissues or body fluids (The characteristic must be the same for the demonstration of equivalence) 2.1 Similar kind and duration of contact with the same human tissues or body fluids 2.2 Similar release characteristics of substances including degradation products and leachables 2.3 Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No Page 19 of 20 2.1 2.2 2.3 3. Clinical characteristics (add a separate row for each of the assessed characteristics) Device 1 Description of characteristics and reference to specifying documents Device 2 (marketed device) Description of characteristics and reference to specifying documents Identified differences or conclusion that there are no differences in the characteristic Same clinical condition or purpose, including similar severity and stage of disease 3.1 Same site in the body (The characteristic must be the same for the demonstration of equivalence) 3.2 Similar population, including as regards age, anatomy and physiology 3.3 Same kind of user (The characteristic must be the same for the demonstration of equivalence) 3.4 Similar relevant critical performance in view of the expected clinical effect for a specific intended purpose 3.5 Scientific justification why there would be no clinically significant difference in the safety and clinical performance of the device, OR a description of the impact on safety and or clinical performance (use one row for each of the identified differences in characteristics, and add references to documentation as applicable) Clinically significant difference Yes / No Page 20 of 20 3.1 3.2 3.3 3.4 3.5 Summary In the circumstance that more than one non-significant difference is identified, provide a justification whether the sum of differences may affect the safety and clinical performance of the device.

10-1 MDCG 2020-10-1 Guidance on safety reporting in clinical investigations.pdf.txt

Page 1 of 16 1 MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745 May 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission. The document is not a European Commission document and it cannot be regarded as reflecting the official position of the Europea n Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union ca n give binding interpretations of Union law. Page 2 of 16 MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745 May 2020 Table of contents 1 INTRODUCTION .................................................. ............................................................... ............................................................... ........................................................ 3 1.1 SAFETY REPORTING IN THE ABSENCE OF EUDAMED .............................................................. ............................................................... ............................................................... ..... 3 2 SCOPE ......................................................... ............................................................... ............................................................... ............................................................... . 4 2.1 CLINICAL INVESTIGATIONS OF MEDICAL DEVICES .............................................................. ............................................................... ............................................................... ......... 4 2.2 MEDICAL DEVICES USED IN CLINICAL TRIALS OF MEDICINAL PRODUCTS (DRUG TRIALS ) ............................................................. ............................................................... ........................ 4 3 DEFINITIONS ................................................... ............................................................... ............................................................... ............................................................ 5 3.1 INVESTIGATIONAL DEVICE .............................................................. ............................................................... ............................................................... ...................................... 5 3.2 ADVERSE EVENT (AE) .......................................................... ............................................................... ............................................................... ............................................... 5 3.3 SERIOUS ADVERSE EVENT (SAE).......................................................... ............................................................... ............................................................... ................................. 5 3.4 DEVICE DEFICIENCY .............................................................. ............................................................... ............................................................... .............................................. 5 4 REPORTING METHOD .............................................. ............................................................... ............................................................... ................................................... 6 4.1 TRANSITION TO REPORTING VIA EUDAMED .............................................................. ............................................................... ............................................................... ............... 6 4.2 OVERVIEW OF FORMATS TO BE USED BY SPONSORS WHEN REPORTING TO NCA S .............................................................. ............................................................... ............................. 6 4.3 COLLECTING REPORTS FROM INVESTIGATORS .............................................................. ............................................................... ............................................................... ............. 6 5 REPORTABLE EVENTS ............................................. ............................................................... ............................................................... .................................................... 7 5.1 EXCEPTIONS FOR PMCF INVESTIGATIONS ACCORDING TO MDR ARTICLE 74.1 .......................................................... ............................................................... ................................... 7 5.2 REPORTABLE EVENTS OCCURRING IN THIRD COUNTRIES .............................................................. ............................................................... .............................................................. 7 5.3 TRANSITION PERIOD FOR REPORTABLE EVENTS IN PRE -MARKET CLINICAL INVESTIGATIONS INITIATED UNDER DIRECTIVES LEGIS LATION .............................................................. ........................ 7 5.4 TRANSITION FOR REPORTABLE EVENTS IN PMCF CLINICAL INVESTIGATIONS INITIATED UNDER DIRECTIVES LEGISLATION .............................................................. .......................................... 8 6 REPORT BY WHOM ................................................ ............................................................... ............................................................... ..................................................... 8 7 REPORT TO WHOM ................................................ ............................................................... ............................................................... ..................................................... 8 8 REPORTING TIMELINES ........................................... ............................................................... ............................................................... .................................................... 8 8.1 REPORT BY SPONSOR TO NCA S............................................................... ............................................................... ............................................................... .............................. 8 8.2 REPORT BY THE INVESTIGATOR TO THE SPONSOR .............................................................. ............................................................... ............................................................... ........ 9 9 CAUSALITY ASSESSMENT .......................................... ............................................................... ............................................................... .................................................. 9 10 REPORTING FORM ................................................ ............................................................... ............................................................... .................................................... 11 10.1 COMPLETION GUIDELINES : FORM HEADER .............................................................. ............................................................... ............................................................... .............. 11 10.2 COMPLETION GUIDELINES : EVENT DETAILS .............................................................. ............................................................... ............................................................... .............. 13 11 REFERENCES .................................................... ............................................................... ............................................................... ......................................................... 16 12 APPENDIX – CLINICAL INVESTIGATION SUMMARY SAFETY REPORTING FORM .............................................................. ............................................................... .......... 16 Page 3 of 16 1 Introduction Safety reporting in clinical investigations of medical devices shall be performed in line with the requirements of the Regulat ion (EU) 2017/745 – Medical Device Regulation (MDR) Article 80(2): The sponsor shall report, without delay to all Member States in which the clinical investigation is being conducted, all of th e following by means of the electronic system referred to in MDR Article 73: a) any serious adverse event that has a causal relationship with t he investigational device, the comparator or the investigation procedure or where such causal relationshi p is reasonably possible; b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention ha d not occurred, or circumstances had been less fortunate; c) any new findings in relation to any event referred to in points a) and b). The period for reporting shall take account of the severity of the event. Where necessary to ensure timely reporting, the spon sor may submit an initial report t hat is incomplete followed up by a complete rep ort. Upon request by any Member State in which the clinical investig ation is being conducted, the sponsor shall provide all informa tion referred to in paragraph 1. For post-market clinical follow up (PMCF) investigations of CE- marked devices1 used within the intended use covered by the CE-marking, report ing requirements of MDR Article 80(5) and (6) apply. This means tha t the vigilance provisions laid down in Articles 87 to 90 and i n the acts adopted pursuant to Article 91 shall apply for PMCF clinical investigat ions. However, this guidance document is still relevant for PMC F clinical investigations as the reporting of serious adverse events where a causal relat ionship to the preceding investigational procedure has been est ablished shall follow the reporting procedures of clin ical investigations as outlined in Article 80. 1.1 Safety reporting in the absence of Eudamed Since the electronic system referred to in Article 73 (Eudamed) will not be available and fully functional at the Date of appl ication of the MDR this guidance outlines the procedures for safety reporting in clinic al investigations in the absence of Eudamed. This document defines Serious Ad verse Event (SAE) reporting mod alities and includes a summary tabulation reporting format. 1 The PMCF investigations referred to in MDR Article 74(1). Page 4 of 16 2 Scope 2.1 Clinical investigation s of medical devices The reporting modalities and format set out in this guidance ap ply to:  Pre-market clinical investigations covered by Articles 62 and 74(2) of the MDR conducted with: a) Non-CE marked devices, b) CE marked devices used outside the intended use(s) covered by t he CE-marking. c) The term pre-market clinical inv estigation may also include som e studies covered by MDR Article 82. As MDR Article 82 allows member states to define national requi rements for such clinical investigations, sponsors are encourag ed to check with the applicable NCA2 whether this guidance or other reporting procedures should be applied. In situations where a clinical investigation has started using a non-CE marked device, and the right to bear the CE marking ha s been obtained before the end of the clinical investigation, the SAE reporting continues until completion of the investigation, according to the clinical investigation plan and these guidelines apply throughout the SA E reporting period. For pre-market clinical investigations involving CE marked comp arator devices used within their intended purpose, SAEs occurri ng in or to subjects that are in the comparator arm of an investigation sha ll also be reported in accordance with these guidelines. Note: SAEs concerning CE marked devices which meet the vigilanc e reporting criteria also need to be handled under the post-mar ket surveillance/vigilance system.  Those Post-Market Clinical Follow Up (PMCF) investigations that involve procedures additional to those performed under th e normal conditions of use of the device, and where those additional pro cedures imposed by the clinical investigation plan are invasive o r burdensome, covered by MDR Article 74(1). For these clinical in vestigations the safety reporting for events pertaining to MDR Article 80(6) follow the Serious Adverse Event reporting process only, and ar e outlined in this guidance. Events pertaining to MDR Article 8 0(5) are reported following the vigilance process only and are outside t he scope of this guidance.  Note that other post-market clinical investigations may be subj ect to safety reporting requirements in line with this guidance due to national requirements following MDR Article 82, but there is no such general requirement. Sponsors are encouraged to check wit h the applicable NCA whether this guidance or other reporting procedu res should be applied.  Due to the transitional provisions in MDR Article 120(11) this guidance also covers clinical investigations which have started to be conducted in accordance with Article 10 of Directive 90/385/EEC (AIMDD) o r Article 15 of Directive 93/42/EEC (MDD) prior to 26 May 2021. These investigations may continue to be conducted after date of appli cation of the MDR, but the reporting of serious adverse events and device deficiencies shall be carried out in accordance with the MDR re quirements from 26 May 2021 and onwards. 2.2 Medical devices used in clinical trials of medicinal products ( drug trials)  A CE-marked device which is used outside its intended purpose, or a non-CE marked device in a clinical drug trial would implic itly have to be assessed for safety and performance and the study shall foll ow both MDR (Chapter VI) and the applicable legislation for cli nical drug trials. This guidance document is then relevant for compliance with the MDR regarding safety reporting. 2 For the purpose of this guidance," NCAs" encompasses the Natio nal Competent Authorities of the EEA, Switzerland and Turkey. Page 5 of 16  If a drug-device study (or a drug trial) is not undertaken to a ssess the safety or performance of a device used in the study, the reporting requirements of MDR Article 80 do not apply, as long as the dev ice is CE marked and used within its intended purpose. This gui dance is not applicable, but the vigilance re porting provisions of MDR apply in those situations, as for any commercially available device. Sponsors should make sure that the device manufacturer is notified about any incidents related to the device and the legal manufacturer of the device is responsible for the subsequent vigilance reporting. 3 Definitions 3.1 Investigational device A device that is assessed in a clinical investigation (MDR Article 2(46)) Note: An investigational device can be a non-CE marked device o r a CE marked device. The definition in MDR Article 2(46) does not differentiate between different regulatory statuses of devices. However, the reporting requirements are different depending on whether the c linical investigation is done for purposes described in Article 62, 74 or 82. The definition is understood to cover also the devices i nvestigated in PMCF investigations, even if they are not subject to notification pe r Art 74.1. 3.2 Adverse Event (AE) Any untoward medical occurrence, unintended disease or injury o r any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinic al investigation, whether or not related to the investigational device. (MDR Article 2(57)) Note: a. This definition includes events that are anticipated as well as unanticipated events b. This definition includes events occurring in the context of a c linical investigation related to the investigational device, th e comparator or the procedures3 involved. 3.3 Serious Adverse Event (SAE) Any adverse event that led to any of the following: a) death, b) serious deterioration in the health of the subject, that result ed in any of the following: i. life-threatening illness or injury, ii. permanent impairment of a body structure or a body function, iii. hospitalisation or prolongation of patient hospitalisation, iv. medical or surgical intervention to prevent life-threatening il lness or injury or permanent impairment to a body structure or a body function, v. chronic disease, c) foetal distress, foetal death or a congenital physical or menta l impairment or birth defect (MDR Article 2(58)) 3.4 Device deficiency Any inadequacy in the identity, quality, durability, reliabilit y, safety or performance of an i nvestigational device, includin g malfunction, use errors or inadequacy in information supplied by the manufacturer. 3 For the purpose of safety reporting all activities related to the use of a medical device may be considered procedures Page 6 of 16 (MDR Article 2(59)) 4 Reporting method A new template for the Summary Reporting Form should be used fo r all studies from 26 May 2021. The tabular format featured in the Appendix needs to be filled in/updated for each reportable event or for new findings/updates to already reported events. It shall be tr ansmitted to all NCAs where the clinical investigation is being performed. For more details on how to complete the form refer to section 10. Reporting form . 4.1 Transition to reporting via Eudamed Once Eudamed is available and fully functional the obligations and requirements that relate to performing safety reporting via Eudamed shall apply from the date corresponding to six months after the date of pub lication of the notice referred t o in Article 34(3) of the MDR. 4.1.1 Ongoing events at time of transition to Eudamed It is acknowledged that at the time of transition to reporting via Eudamed, there will be ongoing events for which initial rep orts have been made according to the procedures described in this document. For the se reportable events follow-up and final reports will be submit ted to the NCAs by the same procedure, but all new reportable events shall be ente red in Eudamed. Whether retrospective uploading of previous event reports to Eu damed will be possible is not clear at the time this guidance i s issued. 4.2 Overview of formats to be used b y sponsors when reporting to NC As Under directives legislation Until May 25th, 2021: The tabular format from MEDDEV 2.7/3 Appe ndix I should be used Transition period From May 26th, 2021 and until Eudamed is available The Tabular format of this guidance (Appendix- Summary Reporting Form) should be used. When Eudamed is available but not yet mandatory and until the timepoint when Eudamed becomes mandatory Either the Tabular format of this guidance (Appendix- Summary Reporting Form) or the Eudamed web form can be used. Note: Once the shift to Eudamed reporting has been made for a s pecific clinical investigation, Eudamed should continue to be used for reporting all new events and updates to those events throughout the remai nder of the clinical investigation. From the timepoint when Eudamed is mandatory* *From the date corresponding to six months after the date of publication of the notice referred to in Article 34(3) of the MDR. Web form via Eudamed shall be used for all new events, and upda tes to those events. The Tabular format of this guidance (Appendix- Summary Reporting Form) can be used only to transmit follow-up reports/final repo rts to the NCAs on events which were in itially reported in this format . 4.3 Collecting reports from investigators The format in which sponsors wish to receive single event repor ts from investigators will be up to the sponsor to design and t hey may be adapted to an individual clinical investigation. When sponsors design s uch reporting forms, they should consult this guidance document to e ns ure al l relevant details are captured in the reports from the investiga tor, so that the sponsors can fu lfil their reporting obligation s. Page 7 of 16 5 Reportable events For the purpose of this guidance and based on the definitions a bove, the following events are considered reportable events in accordance with MDR Art. 80(2): a) any serious adverse event that has a causal relationship with t he investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention ha d not occurred, or circumstances had been less fortunate; c) any new findings in relation to any event referred to in points a) and b). Serious adverse events related to a CE marked device which is p art of the investigation procedure (for example a CE-marked imp lanting tool used in combination with a non-CE marked investigational device) are reportable per MDR Article 80(2) if there is a causal, (or rea sonably possible) relationship to the device, the comparator or the investigation procedure. The reporting procedures described in this guide sh ould then be followed in addition to the normal vigilance reporting procedur es for CE marked devices. All causality assessments should be made using the guidance in section 9. Only causality level 1 (i.e. “not related”) is exclu ded from reporting. If either the sponsor or the investigator has assigned a higher ca usality level than "not related", the event should be reported. 5.1 Exceptions for PMCF investigatio ns according to MDR Article 74. 1 Following Article 74.1 the SAE reporting for these PMCF clinica l investigations is governed b y Articles 80(5) and 80(6). This means that the provisions o f vigilance laid down in Articl es 87-90 and acts adopted pursuant to Article 91 shall apply. H owever, the SAEs where a causal relationship between the serious adverse event a nd the preceding investigational procedure has been established shall follow the reporting procedures of clinical investigations as outlined in Article 80. For the purpose of this guidance reportable events in PMCF clin ical investigations are thus those serious adverse events where a causal relationship between the serious adverse event and a preceding investigation al procedure has been established. “Preceding investigational procedure” shall be understood as a procedure which is imposed by th e Clinical Investigation Plan a nd which has taken place before (or coincided in time) with the serious adverse ev ent. This includes but is not limited to the burdensome or inva sive procedure(s) which defines whether the study is subject to notification requ irements following MDR article 74(1). 5.2 Reportable events occurring in Third Countries Reportable events occurring in Third Countries4 in which a clinical investigation is performed under the same clinical investigation plan have to be reported in accordance with this guidance to the NCA (s) of the European countries in which the clinical investigati on is being conducted.  The NCA shall start receiving the reportable events occurring i n Third Countries as soon as the clinical investigation is auth orised to start in that Member State.  Events occurring in Third Countries after the participating Eur opean sites have closed shall continue to be reported. 5.3 Transition period for reportable events in pre-market clinical investigations initiated und er directives legislation It is acknowledged that the MDR implies changes to the reportin g requirements compared to the directives’ requirements where a ll SAEs should be reported regardless of relatedness. Under MDR sponsors are n o longer obliged to report SAEs that are “not related” to the c linical investigation 4 Countries other than Switzerland, Turkey and those belonging t o the EEA. Page 8 of 16 procedures or the investigational device. At the date of applic ation for MDR there will be ongoing events for clinical investi gations initiated under directives legislation. As from the 26th of May 2021 sponsors are no longer expected to submit follow-u p reports to NCAs for events that have been deemed “not related“ (see section 9 of this document for guidan ce on causality assessment). For ongoing events that have a cau sality assessment other than “not related” follow up reports will still have to b e provided. To facilitate the transition and give time for sponsors to upda te Clinical Investigation Plans and study procedures in clinica l investigations a sponsor may continue to report all SAEs t o NCAs until Eudamed reporting is mandatory (see section 4.1 Transition to reporting via Euda med). This applies only to studies which have started to be conducted5 in accordance with Article 10 of Directive 90/385/EEC or Artic le 15 of Directive 93/42/EEC prior to 26 May 2021. 5.4 Transition for reportable events in PMCF clinical investigation s initiated under dire ctives legislation In case of PMCF studies which required SAE reporting according to the Pre-MDR national legislations, MDR article 80 (5) and 80 (6) shall apply from May 26th, 2021. 6 Report by whom Reportable events have to be reported by the sponsor of the cli nical investigation, which could be the manufacturer, the legal representative or another person6 or entity,. 7 Report to whom Reportable events must be reported at the same time to all NCAs where the clinical investigation has commenced using the summary tabulation featured in the Appendix. A list of clinical investigation contact points within the NCAs is published at the Commission's homepage. For the purpose of this guidance, an investigation is considere d to have commenced in an individual Member State: • For investigations under the directives: When the sponsor is au thorized to start the investigation in accordance with the noti fication procedures in that Member State. • For investigations started under the MDR: When the sponsor is a uthorized to start the investigation in that Member State in ac cordance with the provisions laid out in the MDR. Member States may also require separate reporting to the Ethics Committee(s). 8 Reporting timelines 8.1 Report by sponsor to NCAs. The sponsor must report to all NCAs where the clinical investig ation is authorised to start: • For all reportable events as described in section 5 which indic ate an imminent risk of death, serious injury, or serious illne ss and that requires prompt remedial action for other patients/subjects, us ers or other persons or a new finding to it: Immediately, but not later 5 For the purpose of safety reporting this is defined as “Author ised to start in the individual Member State in line with appli cable directives legislati on, regardless of whether any subjects have been recruited in the Member State or not.” 6 Contact person established by the sponsor in line with Article 62(2) if accepted by Member State. Page 9 of 16 than 2 calendar days after awareness by sponsor of a new report able event or of new information in relation with an already re ported event. This includes events that are of significant and unexpected nat ure such that they become alarming as a potential public health hazard. It also includes the possibility of multiple deaths occurring at s hort intervals. These concerns may be identified by either the NCA or the manuf acturer. • Any other reportable events as described in section 5 or a new finding/update to it: Immediately, but not later than 7 calendar days following the date of awareness by the sponsor of the new repor table event or of new information in relation with an already r eported event. In some cases, a different periodicity or different modalities may be agreed between the participating NCAs and the sponsor ac cording to the investigation’s design and to the pathology under clinical inve stigation. This would allow implementation of adequate provisio n for clinical investigations in which SAE frequency is expected to be high du e to the natural progression of the disease (e.g. palliative on cology). 8.2 Report by the investigator to the sponsor The sponsor shall implement and maintain a system to ensure tha t the reporting of the reportable events as defined under chapt er 5 will be provided by the investigator to the sponsor immediately, but no t later than 3 calendar days after investigation site study per sonnel’s awareness of the event. 9 Causality assessment The relationshi p between the use of the medic al device7 (including the medical - surgical procedure) and the occurrence of each adverse event shall be assessed and categorized. D u r i n g c a u s a l i t y a s s e s s m e n t a c t i v i t y , c l i n i c a l j u d g e m e n t s h a l l be used and the relevant documents, such as the Investigator’s Brochure, the Clinical Investigation Plan or the Risk Analysis Report shall b e consulted, as all the foreseeable serious adverse events and the potential risks are listed and assessed there8. The presence of confounding factors, such as concomitant medi cation/treatment, the natural history of the underlying disease, other concurrent illness or risk factors shall also be c o n s i d e r e d . The above considerations apply also to the serious adverse even ts occurring in the comparison group. For the purpose of harmonizing reports, each SAE will be classi fied according to four different levels of causality: 1. Not related 2. Possible 3. Probable 4. Causal relationship The sponsor and the investigators will use the following defini tions to assess the relationship of the serious adverse event t o the investigational device, the comparator or the investigation procedure. 1. Not related: Relationship to the device, comparator or procedur es can be excluded when: - the event has no temporal relationship with the use of the inve stigational device, or the procedures related to application of the investigational device; 7 Intended as both investigational device and comparator. 8 For a comparator device, the Operator’s Manual could be a rele vant document. Page 10 of 16 - the serious adverse event does not follow a known response patt ern to the medical device (if the response pattern is previously known) and is biologically implausible; - the discontinuation of medical device application or the reduct ion of the level of activation/exposure - when clinically feasi ble - and reintroduction of its use (or increase of the level of acti vation/exposure), do not impact on the serious adverse event; - the event involves a body-site or an organ that cannot be affec ted by the device or procedure; - the serious adverse event can be attributed to another cause (e .g. an underlying or concurrent illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); - the event does not depend on a false result given by the invest igational device used for diagnosis9, when applicable; In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, depending on the t ype of device/procedures and the serious adverse event. 2. Possible: The relationship with the use of the investigational device or comparator, or the relationship with procedures, is w eak but cannot be ruled out completely. Alternative causes are also pos sible (e.g. an underlying or concurrent illness/ clinical condi tion or/and an effect of another device, drug or treatment). Cases where re latedness cannot be assessed, or no information has been obtain ed should also be classified as possible. 3. Probable: The relationship with the use of the investigational device or comparator, or the relationship with procedures, seem s relevant and/or the event cannot be reasonably explained by ano ther cause. 4. Causal relationship: the serious adverse event is associated with the investigational device, co mparator or with procedures beyond reasonable doubt when: - the event is a known side effect of the product category the de vice belongs to or of similar devices and procedures; - the event has a temporal relationship with investigational devi ce use/application or procedures; - the event involves a body-site or organ that o the investigational device or procedures are applied to; o the investigational device or procedures have an effect on; - the serious adverse event follows a known response pattern to t he medical device (if the response pattern is previously known) ; - the discontinuation of medical device application (or reduction of the level of activation/exposure) and reintroduction of its use (or increase of the level of activation/exposure), impact on th e serious adverse event (when clinically feasible); - other possible causes (e.g. an underlying or concurrent illness / clinical condition or/and an effect of another device, drug o r treatment) have been adequately ruled out; - harm to the subject is due to error in use; - the event depends on a false result given by the investigationa l device used for diagnosis10, when applicable; In order to establish the relatedness, not all the criteria lis ted above might be met at the same time, depending on the type of device/procedures and the serious adverse event. 9 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment a nd incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious dis ease. In other cases, the patient might not receive an effectiv e treatment (thereby missing out on the benefits that treatment would confer) or might not be diagnosed with the correct disease or condition. 10 If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary treatment a nd incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious dis ease. In other cases, the patient might not receive an effectiv e treatment (thereby missing out on the benefits that treatment would confer), or might not be diagnosed with th e correct disease or condition. Page 11 of 16 The sponsor and the investigators will distinguish between the serious adverse events related to the investigational device an d those related to the procedures (any procedure specific to the clinical investig ation). An adverse event can be related both to procedures and the investigational device. Complications caused by concomitant treatments not impo sed by the clinical investigation plan are considered not relat ed. Similarly, several routine diagnostic or patient management procedures are applied to patients regardless of the clinical investigation p lan. If routine procedures are not imposed by the clinical investigation plan, complications caused by them are also considered not related. In some particular cases the event may not be adequately assess ed because information is insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators will make the maximum effort to define and categorize the event a n d a v o i d these situations. Where an investigator assessment is not avail able and/or the sponsor remains uncertain about classifying the serious adverse event, the sponsor should not exclude the relatedness; the even t should be classified as “possible” and the reporting not be d elayed. Particular attention shall be given to the causality evaluation of unanticipated serious adverse events. The occurrence of una nticipated events related could suggest that the clinical investigation places su bjects at increased risk of harm than was to be expected before hand. 10 Reporting form The reporting form template for the summary SAE tabulation is g iven in the Appendix of this document. The reporting form is study specific and covers only a given cl inical investigation, defined by a distinct clinical investigat ion plan. English is the recommended language for the reporting form. The report form ca n be modified in any applicable software (not only Microsoft Ex cel) but the file needs to be compatible with Microsoft Excel when sent to the participating NCAs. The template form contains inserted filters and functionality t o facilitate use of preferred terminology in the reporting. The se are important for the analysis and should be maintained. Sponsors who generate the excel report file by automated proces ses may implement other technical features in their systems for e x c e l f i l e generation to ensure the preferred terms listed in metadata are used. The table gives a cumulative overview of the reportable events per clinical investigation and will be updated and transmitted to participating NCAs each time a new reportable event or a new finding to an al ready reported event is to be reported. More detailed informati on has to be provided on request of an NCA, if so requested by using the ind ividual study specific reporting form (see further section 4.3 Collecting reports from investigators ). 10.1 Completion guidelines: Form header 10.1.1 EUDAMED/CIV-ID The union-wide Single Identification Number mentioned in MDR Ar ticle 70(1) will not be possible to generate until Eudamed for MDR is fully functional. For the transition period, clinical investigations will get tracking numbers (CIV-ID) upon registration in the Eud amed2 database which is performed by the NCA upon receipt of an application. This CI V ID is provided to the sponsor during the NCA’s handling of th e initial application for the clinical investigation and should be entered on the saf ety reporting form. The CIV ID should already be available for a clinical investiga tion started under the directives’ legislation, where it should be indicated on the MEDDEV 2.7/3 reporting form etc. Sponsors who are not aware of the CIV ID of their clinical inv estigations are invited to cont act the concerned NCA to get this information. Page 12 of 16 10.1.2 Title of Clinical Investigation The identifying title of the Clinical Investigation. The title indicated here should be consistent with other title entries (s uch as in clinical investigation application form, clinical inves tigation plan cover page etc). 10.1.3 CIP number/code The unique identification code or short name assigned to the sp ecific clinical investigation pl an by the Sponsor (numeric, alp hanumeric or acronym) should be indicated. 10.1.4 Contact person Name, address, e-mail and telephone number should be provided f or the person who is sponsor’s point of contact in case NCA hav e follow up questions regarding submitted safety report forms. 10.1.5 MS+NCA Reference numbers For each participating Member State indicate the country code11 and the NCA’s national reference number for the clinical inves tigation. Example: SE 5.1-20YY-XXXXXX DK 20YYXXXXXX 10.1.6 No. of subjects enrolled to date total Indicate the total number of subjects who have been enrolled (p er date of report) in the clinical investigation globally. 10.1.7 No. of subjects enrolled to date per country List all countries where the clinical investigation has been au thorised by date of report and indicate the number of subjects who have been enrolled in the clinical investigation (per date of report) in each coun try. 10.1.8 Device type Indicate the type of device(s) assessed in the clinical investi gation (e.g. pacemaker, coronary stent, hip implant). 10.1.9 Reference Member State Indicate the name of the Member State which drew the unique EUD AMED/CIV ID (normally the first Member State receiving an appli cation for the clinical investigation). Once the coordinated assessment pr ocedure (per MDR Article 78) is up and running, the coordinatin g Member State should be indicated here. 10.1.10 No. of investigational devices used to date total Indicate the total number of investigational devices which have been used (per date of report) in the clinical investigation g lobally. 10.1.11 No. of investigational devic es used to date per country List all countries where the clinical investigation has been au thorised by date of report and indicate the number of investiga tional devices which have been used in the clinical investigation (per date of repor t) in each country. 10.1.12 Date of report Indicate the date when the report is compiled for transmission to NCAs. Format DD/MM/YYYY. 11 Use ISO-3166-1 alpha-2 codes, i.e.two-letter country codes as defined in ISO 3166-1 Page 13 of 16 10.2 Completion guidelines: Event details Each unique reportable event is presented in a separate line. U pdates to a previously reported event should be made by changin g the information in the same line, and clearly identified according to the princ iples described below. Any new information added in the form should be highlighted in bold and/or colour. This includes any new lines added and any c hanges made to the information in an already existing line. In the initial report, in any given line, no fields shall be le ft intentionally blank. To meet this requirement, preliminary i nformation should be filled in, despite the need of further updating. 10.2.1 Status The sponsor shall identify the new/updated information in the s tatus column as: A = added = new reportable event; M = modified = new finding/update to an already reported event; U = unchanged. 10.2.2 Date Sponsor received report of SAE/DD Indicate the date when the sponsor was first notified by the in vestigation site about the event. This date is checked for comp liance with reporting timelines as outlined in section 8 Reporting timelines . Format DD/MM/YYYY. 10.2.3 Country code Indicate the country code 11 for the country in which the subject associated with the event has been enrolled. 10.2.4 Investigation site Name identifying institution or site where the clinical investi gation is carried out. 10.2.5 Subject ID code The study specific subject ID code, i.e. the link between study data and the actual subject identity (which is not to be provi ded in this form). 10.2.6 SAE ID code The investigator, sponsor or manufacturer should assign a uniqu e ID to each SAE that has occurred, This number shall remain un changed throughout all other alterations of the particular SAE-reportin g due to ongoing assessment. 10.2.7 Date of procedure/First use Indicate the date of the relevant procedure or the date when th e subject was exposed to the dev ice for first use. Format DD/MM /YYYY. 10.2.8 Date of event onset The date when the first signs of an event were noticed may be d ifferent (earlier) than the date when the event fulfilled the s eriousness criteria (see further the definition in section 3.3 Serious Adverse Even t (SAE)). The date when the event became an SAE should be repor ted as Date of event onset. In case of Device Deficiencies which did not lead to an SAE, the date the DD was discovered should be indicated. Format DD/MM/YYYY. 10.2.9 SAE or DD Choose one option from SAE(Seriou s Adverse Event) or DD (Device Deficiency). Do not add other options. Page 14 of 16 10.2.10 Age The subject’s age at date of event onset should be indicated. In cases where exact date of birth is not available as a basis for age calculation, it is acknowledged that an approximate age at date of event onset could be calculated based on the age at enrollment. Normally the Age should be indicated in Years, although for pae diatric/neonatal populations it may be more relevant to indicat ed age in months, weeks or days. When a different unit than years is used, the un it should be indicated as appropriate. 10.2.11 Patient gender Choose one option from the following list (do not add other opt ions):  Female  Male  Other  Unknown 10.2.12 Location of device For this field, it is the location of the device at the time th e report is submitted to NCA is of interest (i.e not at the tim e of investigator or sponsor awareness of the event). Changed location of the device is in i tself not a reason to provide an updated report. However, whene ver an update/final report is provided for other reasons, it is relevant to update this field if the device for example has reached the sponsor by then. Choose one option from the following list (do not add other opt ions):  Investigational/study site  Sponsor  Subject  Manufacturer  Remains implanted  Discarded  Unknown  Other 10.2.13 Classification of event Choose one option from the following list of consequence charac teristics (do not add other options):  Death  Life-threatening illness or injury  Permanent impairment/ Chronic disease  Hospitalization  Medical or surgical intervention  Foetal distress, fœtal death or congenital physical or mental o r birth defect  Not applicable (Note that this option is only to be selected in case of reportable Device deficiencies that did not lead to an SAE) Page 15 of 16 It is acknowledged that for a specific event two or more option s may be equally applicable, e.g. ” Hospitalization” and “medica l intervention”. The highest-ranking classification should be indicated, using the f ollowing ranking order: 1) Death , 2) life threatening, 3) foeta l distress, 4) permanent impairment, 5) Medical or surgic al intervention 6) hospitalizat ion. 10.2.14 Description of event Provide a description of the event in free text. Below is a non -exhaustive list of items that could be relevant to cover:  Nature of the observed symptoms  Duration and severity of the symptoms  Date of onset of first signs of the event (before it became a S AE)  Medical background of the patient  Medical care of the patient  Comments on the event in relation to already known safety data Use of standardised terminology corresponding to relevant IMDRF codes is encouraged. 10.2.15 Action/treatment /outcome Provide information in free text on actions taken, treatment(s) administered and the outcome. 10.2.16 Relationship to procedure Choose one option from the foll owing list of causality levels ( for explanatory texts see sect ion 9 Causality assessment):  Not related  Possible  Probable  Causal Please report the assessments by sponsor and investigator in th e respective columns. 10.2.17 Relationship to device Choose one option from the foll owing list of causality levels ( for explanatory texts see sect ion 9 Causality assessment)  Not related  Possible  Probable  Causal Please report the assessments by sponsor and investigator in th e respective columns. 10.2.18 Unanticipated SADE Choose option Yes or No An Unanticipated Serious Adverse Device Effect12 is an effect which by its nature, incidence, severity or outco me has not been identified in the current risk assessment. Procedure s associated with the use of a device should be addressed in the risk assessment, which make s it possible to 12 An adverse device effect is an adverse event related to the us e of an investigational device. A serious adverse device effect is an adverse device effect that has resulted in any of the consequence characteristics of a serious adverse eve nt. Page 16 of 16 determine whether the procedure related SAEs are Unanticipated Serious Adverse Device Effect or not. SAEs related to procedure s imposed by the clinical investigation plan but not with the use of the dev ice should not be considered Serious Adverse Device Effects. 10.2.19 Investigation arm Choose one option from the following list:  Test group  Comparison group  Blinded  Not applicable Note: For some study designs it might be more relevant to add n ame of device; i.e. in a clinical investigation with several te st groups it might be useful to differentiate which investigational device that the s ubject has been exposed to. 10.2.20 Event status Choose one option from the following list (do not add other opt ions):  Resolved  Resolved with Sequelae  Ongoing  Death 10.2.21 Date of event resolution Add date in format DD/MM/YYYY. If event status is “Ongoing” ent er Not Applicable. 11 References 1. R e g u l a t i o n ( E U ) 2 0 1 7 / 7 4 5 o f t h e E u r o p e a n P a r l i a m e n t a n d o f t h e council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC No 178/2002 and Regulation (EC) No 1 223/2009 and repealing Council Directives 90/385/EEC and 93/42/ EEC. 2. Council Directive 90/385/EEC of 20 June 1990 on the approximati on of the laws of the Member States relating to active implantable medical devices, last amended by Directive 2007/47/EC. 3. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, last amended by Directive 2007/47/EC. 4. Codes for the representation of names of countries and their su bdivisions – Part 1: Country codes (ISO 3166-1) published by In ternational Organisation for Standardization (ISO). 12 Appendix – Clinical Investigation Sum mary Safety Reporting Form

08 MDCG 2020-8 Guidance on PMCF Evaluation Report Template.pdf.txt

Medical Device Medical Device Coordination Group Document MDCG 2020-8 1 MDCG 2020-8 Post-market clinical follow-up (PMCF) Evaluation Report Template A guide for manufacturers and notified bodies April 2020 This document has been endorsed by the Medical Device Coordination Group (MDCG) established by Article 103 of Regulation (EU) 2017/745. The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.The document is not a European Commission document and it cannot be regarded as reflecting the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give binding interpretations of Union law. Medical Device Medical Device Coordination Group Document MDCG 2020-8 2 Post-market clinical follow-up (PMCF) Evaluation Report Template A guide for manufacturers and notified bodies Medical Device Medical Device Coordination Group Document MDCG 2020-8 3 Contents Introduction ........................................................................................................................................................................................................................................... 4 Post-market clinical follow-up evaluation report Template ............................................................................................................................................................ 4 Section A. Manufacturer contact details ....................................................................................................................................................................................... 5 Section B. Medical Device description and specification .......................................................................................................................................................... 5 Section C. Activities undertaken related to PMCF: results ..................................................................................................................................................... 7 Section D. Evaluation of clinical data relating to equivalent or similar devices .................................................................................................................... 7 Section E. Impact of the results on the technical documentation ............................................................................................................................................ 7 Section F. Reference to any common specification(s), harmonized standard(s) or guidance document(s) applied ...................................................... 9 Section G. Conclusions .................................................................................................................................................................................................................. 9 Medical Device Medical Device Coordination Group Document MDCG 2020-8 4 Introduction The Medical Device Regulation (EU) 2017/745 (MDR) considers the post-market clinical follow-up (PMCF) as a continuous process that updates the clinical evaluation and that shall be addressed in the manufacturer’s post-market surveillance plan. The MDR reinforces the PMCF process by the manufacturer, devoting part B of Annex XIV to it and providing a set of requirements for developing a PMCF plan and its evaluation report, necessary to its implementation. The manufacturer shall analyse the findings coming from the activities foreseen in the PMCF plan and document the results in this PMCF evaluation report that shall be part of the clinical evaluation report and the technical documentation. The conclusions of the PMCF evaluation report shall be taken into account to update eventually the clinical evaluation, the risk management documentation, the post market surveillance plan and the SSCP, if applicable. The purpose of the present templates is to guide manufacturers in complying with the requirements of the MDR with respect to the compilation of the PMCF evaluation report. This would assist manufacturers in a harmonised and complete presentation of post market clinical data and facilitate the activity of notified bodies and competent authorities in finding the information in an organized format. Post-market clinical follow-up evaluation report Template Post-market clinical follow- up (PMCF) plan corresponding to the present evaluation report PMCF plan number and version: Post-market clinical follow- up (PMCF) Evaluation Report PMCF report number: PMCF report date: PMCF report version: Revision history Rev Revision date Description of change Revised by Medical Device Medical Device Coordination Group Document MDCG 2020-8 5 Section A. Manufacturer contact details Legal manufacturer name: Address: SRN: Person responsible for regulatory compliance: E-mail: Phone: Fax: Authorised representative (if applicable): Address: Contact person: E-mail: Phone: Fax: Section B. Medical Device description and specification Refer to section B from PMCF plan, if there are no changes. If there are changes from PMCF plan, please fill in the different requested fields highlighting those changes. Product or trade name: Model and type: General description of the device: Medical Device Medical Device Coordination Group Document MDCG 2020-8 6 Intended purpose1 Intended users Basic UDI-DI: Intended patient population: Medical condition(s)2: Indications: Contraindications: Warnings: List and description of any variants and/or configurations covered by this plan: List of any accessories covered by this plan: Certificate number (if available): CND code(s)3: Class: Classification rule: Expected lifetime4 Novel product ☐ yes ☐ no Novel related clinical procedure: ☐ yes ☐ no Explanation of any novel features: 1 Intended purpose means the use for which a device is intended according to the data supplied by the manufacturer on the label in the instructions for use or in promotional or sales materials or statements and as specified by the manufacturer in the clinical evaluation (MDR, Article 2(12)). 2 It refers to the clinical condition that is to be diagnosed, prevented, monitored, treated, alleviated, compensated for, replaced, modified or controlled by the medical device. 4 The expected lifetime is to be defined during the design input phase by considering the current state of the art for a specific intended use and indication of a device. Medical Device Medical Device Coordination Group Document MDCG 2020-8 7 Section C. Activities undertaken related to PMCF: results In this section the manufacturer shall report all the activities described in section C of the PMCF plan which have been performed, all the collected clinical data obtained from those completed activities, as well as any justification of deviations from the plan. The discussion shall include the analysis of the findings, whether positive or negative and also the potential impact on the different documents (clinical evaluation report, risk management file, SSCP, etc…) initially reviewed during the conformity assessment. It is expected for each activity performed, a description in different subsections, related to the type of activities (device registry, PMCF studies, real world evidence, surveys about the use of device, etc…), and for each subsection, a description about the quality of data collected.5 Section D. Evaluation of clinical data relating to equivalent or similar devices In this section the manufacturer shall report all the clinical data collected relating to an equivalent device or selected similar device(s), provide an analysis and conclusions, and whether changes of the state of the art, or newly identified hazards would have an impact on the devices benefit-risk determination, the clinical evaluation and/or the PMCF plan. Product name of equivalent / similar device Results discussed References used to get the results (publications, part of technical documentation from this equivalent / similar device) Section E. Impact of the results on the technical documentation 5 For the analysis and assessment of the clinical data collected, some parts of section 9.3.1 from Meddev 2.7/1 rev.4 could be used to assess the quality of data. Medical Device Medical Device Coordination Group Document MDCG 2020-8 8 In this section, the manufacturer shall discuss the aggregate results coming from each PMCF activity planned and performed, described in section C, but also results coming from equivalent and/or similar device, described in section D, which are considered to impact the technical documentation and at least the following documents shall be considered: 1. Clinical evaluation report - CER (date and version) ☐ No relevant information from the clinical evaluation report have been considered. If applicable, it is expected from manufacturer to describe why some information that might have an impact on the CER have not been considered. Relevant information analyzed and monitored: - - Analysis of the outcome is to be reported in the updated clinical evaluation report. 2. Risk management file (date and version) ☐ No relevant information from the risk management file have been considered If applicable, it is expected from manufacturer to describe why some information that might have an impact on the risk management file have not been considered. Relevant information analyzed and monitored: - - - Medical Device Medical Device Coordination Group Document MDCG 2020-8 9 Analysis outcome to be reported in the risk management file updated: - - Section F. Reference to any common specification(s), harmonized standard(s) or guidance document(s) applied In this section the manufacturer should point out whether the collected clinical data related the device in question still confirm adherence to applied common specifications and/or applied harmonized standards, and/or guidances listed in the PMCF plan. Common Specification(s) applied (Title, date and version) Harmonised standard(s) applied (Title, date and version) Guidance(s) followed (Title, date and version ) Section G. Conclusions In this section, it is expected that the manufacturer shall provide an overall conclusion of the findings and relate them to the aims of the PMCF plan. The conclusions shall be taken into account in the following clinical evaluation and in the risk management. Finally, this conclusion shall highlight if any need for preventive and/or corrective measures has been identified. The conclusion may also give input to the next PMCF plan. Medical Device Medical Device Coordination Group Document MDCG 2020-8 10