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European Commission Q&A on practical aspects related to the implementation of Regulation (EU) 2023/607 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices REV. 2 JULY 2024 EXTENSION OF THE MDR TRANSITIONAL PERIOD AND REMOVAL OF THE ‘SELL OFF’ PERIODS Health and Food Safety - 2 - Q&A on practical aspects related to the implementation of Regulation (EU) 2023/607 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices1. Disclaimer: This Q&A document is intended to facilitate the application of Regulation (EU) 2023/607 of the European Parliament and of the Council of 15 March 2023 amending Regulations (EU) 2017/745 (MDR) and (EU) 2017/746 (IVDR) as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices. This document has not been formally endorsed by the European Commission and is without prejudice to any interpretation of the relevant provisions by the Court of Justice of the European Union or national courts. The information in this Q&A document is of a general nature and not intended to address specific circumstances of any particular case; the document does not intend to provide professional or legal advice. The information is not necessarily comprehensive nor complete. If needed, this document will be updated in order to address additional questions that may arise. Q&A revision history Date Action March 2023 Initial issue July 2023 1st update (Rev. 1) - Q&A no 1: addition of last sentence - Q&A no 2: addition of footnote 3 - Q&A no 7: addition of last sentence in the 4th paragraph; addition of footnotes 7, 8 and 9 - Q&A no 8: addition of footnote 11 - Q&A no 17: addition of 2nd paragraph - Q&A no. 6.1, 6.2, 9.1, 9.2, 11.1: new July 2024 2nd update (Rev. 2) – changes concern the alignment of the text with the Q&A on the extension of the IVDR transitional periods and the correction of editorial mistakes. - Q&A no 2: clarification regarding legacy devices that require certification for the first time under the MDR - Q&A no 3: addition of the word ‘certification' in the question’s heading and in the 1st sentence - Q&A no 7: addition of the word ‘down' in the 1st paragraph (3rd line), of the word ‘optional’ in the 5th paragraph (1st line) and of ‘/or’ in the 5th paragraph (5th line) - Q&A no 8: editorial change in the 3rd paragraph and addition of the text “The timing ....period.” in the 5th paragraph - Q&A no 9.2: clarification regarding legacy devices that require certification for the first time under the MDR - Q&A no 11.1: new - Q&A no 11.2: former Q&A no 11.1 - Q&A no 13: addition of the last paragraph - Q&A no 15: addition of the text “After that date … body.” in the last paragraph - Q&A no 17: correction of the reference (Article 120(3a) MDR) in the question’s heading 1 Regulation (EU) 2023/607 of the European Parliament and of the Council of 15 March 2023 amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices (OJ L 80, 20.3.2023, p. 24). Regulation (EU) 2023/607 has entered into force on 20 March 2023. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2023.080.01.0024.01.ENG https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2023.080.01.0024.01.ENG - 3 - TABLE OF CONTENTS Introduction – Objectives of the MDR/IVDR amendment .............................................................................................................................4 PART A – SCOPE OF THE EXTENSION OF THE MDR TRANSITIONAL PERIOD ...................................................................................4 1. Which devices can benefit from the extended transitional period? ....................................................................................................4 2. Can devices that have already been certified in accordance with the MDR benefit from extended transitional period? .....................4 3. What about ‘legacy devices’ for which the manufacturer does not wish to apply for certification under the MDR? ............................5 4. Which classification rules apply to determine whether the extended transitional period ends on 31 December 2027 or on 31 December 2028? ..............................................................................................................................................................................5 5. Does the extended transitional period also apply to custom-made devices? .....................................................................................5 6. If a certificate has expired before 20 March 2023 and a competent authority has granted a derogation in accordance with Article 59 MDR or has applied Article 97 MDR, how long is the transitional period? .........................................................................................5 6.1. Does a national derogation granted in accordance with Article 59 MDR, or the application of Article 97 MDR, after 20 March 2023 trigger the extension of the transitional period?.................................................................................................................................6 6.2. Can a device for which a derogation was granted in accordance with Article 59 MDR benefit from the transitional period even though it was required to not bear a CE marking? ............................................................................................................................6 PART B – EVIDENCE OF EXTENDED TRANSITIONAL PERIOD .............................................................................................................6 7. How can the manufacturer demonstrate that its legacy device benefits from the extension of the transitional period? ......................6 PART C - CONDITIONS TO BE FULFILLED TO BENEFIT FROM THE EXTENDED MDR TRANSITION PERIOD ..................................7 8. What are the necessary elements of a formal application lodged by the manufacturer? ...................................................................7 9. What are the necessary elements of a written agreement between the manufacturer and the notified body? ...................................8 9.1. What happens if the application is withdrawn or the written agreement terminated? .........................................................................8 9.2. What is the impact of changes related to the manufacturer during the transitional period? ...............................................................8 10. What is the meaning of “device intended to substitute that device”? .................................................................................................9 11. Which evidence does the manufacturer have to provide for having put in place a QMS in accordance with the MDR? .....................9 11.1. Do all QMS aspects listed in Article 10(9) MDR have to be addressed? ...........................................................................................9 11.2. Do legacy devices have to comply with UDI requirements during the extended transitional period? .................................................9 12. Do manufacturers, which have lodged an application for conformity assessment and have concluded a written agreement with a notified body before 20 March 2023, have to lodge a new application and/or conclude a new written agreement? ...........................9 PART D – APPROPRIATE SURVEILLANCE TO BE PERFORMED BY NOTIFIED BODIES .................................................................. 10 13. What are the necessary elements of the arrangement for the transfer of the surveillance from the notified body that issued the MDD/AIMDD certificate to the MDR notified body? ......................................................................................................................... 10 14. What does the limitation ‘where practicable’ imply? ........................................................................................................................ 10 15. Which notified body is responsible for carrying out the appropriate surveillance when a written agreement in accordance with Article 120(3c), point e, MDR is signed between the manufacturer and a notified body designated under the MDR? ...................... 11 16. In case there is an arrangement for the transfer of the surveillance to a different notified body designated under MDR, what are the implication on the labelling concerning the notified body’s identification number? ........................................................................... 11 17. Is the notified body which issued the certificate in accordance with Article 120(3a) of Regulation (EU) 2017/745 legally obliged to continue to carry out the surveillance of the products concerned until the end of the new transitional period or until the manufacturer has transferred this surveillance obligation to a notified body whose designation has been made in accordance with Article 42? May this notified body deny the manufacturer the use of its NB number?...................................................................... 11 PART E – DELETION OF THE ‘SELL-OFF’ DATE .................................................................................................................................. 11 18. Which devices will benefit from the removal of the ‘sell-off’ date? ................................................................................................... 11 - 4 - Introduction – Objectives of the MDR/IVDR amendment The amendment of the MDR and of the IVDR through Regulation (EU) 2023/607 aims to ensure a high level of public health protection, including patient safety and an avoidance of shortages of medical devices needed for the smooth functioning of healthcare services, without lowering current quality or safety requirements. For that purpose, manufacturers and notified bodies are given sufficiently more time to carry out, in accordance with the MDR, the conformity assessment of devices covered by a certificate or a declaration of conformity issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC. Moreover, the deletion of the ‘sell off’ date in the MDR and the IVDR aims to prevent unnecessary disposal of safe devices. The answers to the questions set out below have been developed taking into account the objectives pursued by the amendment with a view to making best use of the additional time provided by the extension of the MDR transitional period. PART A – SCOPE OF THE EXTENSION OF THE MDR TRANSITIONAL PERIOD 1. Which devices can benefit from the extended transitional period? Only ‘legacy devices’ can benefit from the extended transitional period. In line with MDCG 2021-252 ‘legacy devices’ should be understood as devices, which, in accordance with the MDR’s transitional provisions, are placed on the market after the MDR’s date of application (i.e. 26 May 2021) if certain conditions are fulfilled. Those devices can be: • devices which are class I devices under Directive 93/42/EEC (MDD), for which an EC declaration of conformity was drawn up prior to 26 May 2021 and for which the conformity assessment procedure under the MDR requires the involvement of a notified body; • devices covered by a valid EC certificate issued in accordance with Directive 90/385/EEC (AIMDD) or the MDD prior to 26 May 2021. The extension of the transitional period beyond 26 May 2024 only applies if the conditions laid down in Article 120(3c) MDR are fulfilled. In case of devices for which the relevant certificate has expired before 20 March 2023, also the conditions laid in the second subparagraph of Article 120(2), points (a) or (b), MDR need to be fulfilled (see below part C). The Commission will make available flowcharts to assist manufacturers and other relevant actors in deciding whether or not a device is covered by the extended transitional period provided for in Article 120 MDR. 2. Can devices that have already been certified in accordance with the MDR benefit from extended transitional period? Yes. As regards legacy devices covered by MDD/AIMDD certificates, the device only benefits from the transitional period as long as the MDD/AIMDD certificates have not been withdrawn by the notified body3. A notified body may withdraw a certificate if the relevant legal requirements are no longer met by the manufacturer or where a certificate should not have been issued, taking account of the principle of proportionality. The MDR certification of the device as such is not a reason for the notified body to withdraw a MDD/AIMDD certificate. Also legacy devices that require certification for the first time under the MDR can benefit from the extended transitional period after issuance of the MDR certificate, provided that they continue meeting the conditions set out in Article 120(3c) MDR. That means that a ‘legacy device’ and the corresponding MDR compliant device can be placed on the market in parallel until the end of the relevant transitional period. 2 MDCG 2021-25 - Regulation (EU) 2017/745 - application of MDR requirements to ‘legacy devices’ and to devices placed on the market prior to 26 May 2021 in accordance with Directives 90/385/EEC or 93/42/EEC (October 2021). It is planned to revise MDCG 2021-25 to adapt it to Regulation (EU) 2023/607. 3 A notified body letter informing about the expiry of the certificate, or a controlled phase-out of production agreed between notified body and manufacturer due to the expiry of a certificate prior to 20 March 2023, is not considered to be a withdrawal of a certificate. https://health.ec.europa.eu/system/files/2021-10/md_mdcg_2021_25_en_0.pdf - 5 - 3. What about ‘legacy devices’ for which the manufacturer does not wish to apply for certification under the MDR? Manufacturers are not obliged to apply for certification of their ‘legacy devices’ under the MDR. Nonetheless, if their device is covered by a certificate that expires after 20 March 2023 and before 26 May 2024, they benefit from the extension of the transitional period until 26 May 2024, provided the conditions set out in Article 120(3c), points (a) to (c), are fulfilled. If the manufacturer does not lodge an application for conformity assessment by 26 May 2024, the transition period will end on 26 May 2024. 4. Which classification rules apply to determine whether the extended transitional period ends on 31 December 2027 or on 31 December 2028? For the purpose of Article 120(3a) MDR, which provides for the new transitional periods depending on the device’s risk class, the classification rules laid down in Annex VIII to the MDR apply. In certain cases, where the classification rules of the MDR result in a different risk class, the device’s risk class indicated on the certificate may differ from the risk class that determines the end date of the transitional period. However, where during the transitional period the risk class of a device is needed to determine applicable MDR requirements (e.g. in relation to PSUR), the class of the device is the one established in accordance with the MDD classification rules (see MDCG 2021-25). 5. Does the extended transitional period also apply to custom-made devices? The new Article 120(3f) MDR has introduced a specific transitional period for class III custom-made implantable devices. While all other custom-made devices can be placed on the market after their manufacturer has drawn up a statement in accordance with Annex XIII to the MDR, the conformity assessment of class III custom-made implantable devices requires the involvement of a notified body. Pursuant to the new transitional provision, class III custom-made implantable devices can be placed on the market without the relevant certificate until 26 May 2026, provided the manufacturer has lodged an application with a notified body for conformity assessment no later than 26 May 2024 and signed a written agreement with that notified body no later than 26 September 2024. 6. If a certificate has expired before 20 March 2023 and a competent authority has granted a derogation in accordance with Article 59 MDR or has applied Article 97 MDR, how long is the transitional period? Certificates that have expired before the entry into force of the amending Regulation 2023/607 (i.e. 20 March 2023) shall only be considered valid if • either before the date of expiry of the certificate, the manufacturer and a notified body have signed a written agreement for the conformity assessment in respect of the device covered by the expired certificate or in respect of a device intended to substitute that device, • or a national competent authority has granted a derogation in accordance with Article 59(1) MDR or has required the manufacturer, in accordance with Article 97(1) MDR, to carry out the applicable conformity assessment procedure within a specified period of time (see the second subparagraph of Article 120(2) MDR). Even if the national derogation is limited in time or the manufacturer has been required to carry out the conformity assessment procedure within a given period of time4, the device benefits from the full transitional period until 31 December 2027 or 31 December 2028, as applicable, provided the conditions set out in Article 120(3c) MDR are fulfilled. The certificate is deemed to be valid until the end of the applicable transitional period, unless it is withdrawn. 4 Depending on national law, decisions of national authorities may need to be adapted. - 6 - 6.1. Does a national derogation granted in accordance with Article 59 MDR, or the application of Article 97 MDR, after 20 March 2023 trigger the extension of the transitional period? No. Where, after 20 March 2023, a competent authority has granted a derogation in accordance with Article 59 MDR, or has required a manufacturer, in accordance with Article 97 MDR, to carry out the applicable conformity assessment procedure, the condition set out in Article 120(2), second subparagraph, point (b), of the MDR is not met. Therefore, an expired certificate will not be considered valid and the extended transitional period set out in Article 120(3a) MDR does not apply.5 6.2. Can a device for which a derogation was granted in accordance with Article 59 MDR benefit from the transitional period even though it was required to not bear a CE marking? Yes. As long as the removal of the CE marking was a condition for or a consequence of the derogation granted by the national competent authority in accordance with Article 59 MDR, the device can be placed on the market with a CE marking, provided that all other conditions are met. PART B – EVIDENCE OF EXTENDED TRANSITIONAL PERIOD 7. How can the manufacturer demonstrate that its legacy device benefits from the extension of the transitional period? The extension of the transitional period and the concomitant extension of the certificate’s validity is done automatically by law, provided the conditions laid down in Article 120(3c) MDR are fulfilled. In case of devices for which the relevant certificate has expired before 20 March 2023, also the conditions laid down in the second subparagraph of Article 120(2), points (a) or (b), MDR need to be fulfilled (see below part C). In line with MDCG guidance 2020-36, during the transitional period, notified bodies cannot issue new MDD/AIMDD certificates. However, they can provide written confirmation correcting or complementing information on an existing certificate. It is acknowledged that the manufacturer may need to demonstrate validity of the certificate to third parties, for example to access the market in third countries or to submit tenders in procurement procedures. For that purpose, manufacturers should have access to different means of demonstrating that their device is covered by the extended transitional period and a valid certificate. The manufacturer should be able to provide a self-declaration confirming that the conditions for the extension are fulfilled, stating the end date of the transition period. Such self-declaration could be based on a harmonised template7. Such self-declaration should clearly identify the devices covered by the extension and certificates concerned. Additional optional evidence could be provided by a ‘confirmation letter’ issued by the notified body stating the receipt of the manufacturer’s application for conformity assessment and the conclusion of a written agreement. Such confirmation should clearly identify the devices covered by the extension and certificates concerned. Such confirmation letter could be based on a harmonised template8 and be issued, in principle, without extra costs. The manufacturer could demonstrate that he has lodged an application for conformity assessment and/or concluded a written agreement with a notified body also by other means, such as a copy of the relevant documents. Competent authorities should be able to issue certificates of free sale for the duration of the extended certificate validity. 5 MDCG 2022-18 - ADD 1 - MDCG Position Paper on the application of Article 97 MDR to legacy devices for which the MDD or AIMDD certificate expires before the issuance of a MDR certificate - Addendum 1 (June 2023). 6 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). A revision of MDCG 2020-3 is planned to be endorsed and published soon. 7 A template for a manufacturer's declaration was jointly developed by, and is available on the websites of, the EU level industry associations AESGP, COCIR, EuromContact, EUROM VI and MedTech Europe. The industry associations and the European Commission do not take any responsibility for the use of the template by the manufacturer nor for the content or the terms of the declaration issued by the manufacturer. 8 See template for notified body confirmation letter endorsed by NBCG-Med, which is the coordination group of notified bodies in the field of medical devices established in accordance with Article 49 of the MDR and Article 45 of the IVDR. https://health.ec.europa.eu/system/files/2023-06/mdcg_2022-18_add-1_en.pdf https://health.ec.europa.eu/system/files/2020-09/md_mdcg_guidance_significant_changes_annexes_en_0.pdf https://aesgp.eu/articles/medical-devices-industry-publishes-manufacturers-declaration-in-relation-to-regulation-eu-2023-607 https://www.cocir.org/media-centre/latest-news/article/manufacturers-declaration-in-relation-to-regulation-eu-2023-607.html https://euromcontact.org/2023/06/23/manufacturer_declaration/ https://view.officeapps.live.com/op/view.aspx?src=http%3A%2F%2Feurom.org%2Fwp-content%2Fuploads%2F2023%2F06%2F230609-final_mdr_manufacturer-declaration.docx&wdOrigin=BROWSELINK https://www.medtecheurope.org/resource-library/manufacturers-declaration-in-relation-to-regulation-eu-2023-607/ https://health.ec.europa.eu/medical-devices-dialogue-between-interested-parties/overview_en - 7 - The European Commission will update its factsheets for competent authorities in non-EU/EEA countries9, for healthcare professionals and healthcare institutions and for the procurement ecosystem, explaining the functioning of the extended transition period. PART C - CONDITIONS TO BE FULFILLED TO BENEFIT FROM THE EXTENDED MDR TRANSITION PERIOD 8. What are the necessary elements of a formal application lodged by the manufacturer? Pursuant to Article 120(3c), point (e), MDR the manufacturer or the authorised representative must lodge a formal application for conformity assessment in accordance with Section 4.3, first subparagraph, of Annex VII MDR no later than 26 May 2024. Manufacturer and notified body must sign a written agreement in accordance with Section 4.3, second subparagraph, of Annex VII MDR no later than 26 September 2024 to benefit from the extended transitional period. Article 120(3c), point (e), MDR does not refer to a review of applications in accordance with Section 4.3, third subparagraph, of Annex VII MDR. That means that a full review of the application by the notified body is not required before the signature of the written agreement. The application should, in principle, include the elements listed in the relevant conformity assessment as referred to in Annexes IX to XI to the MDR. However, it needs to be taken into account that a full review of the application prior to the conclusion of the written agreement is not required and that there may be a certain time span between the deadline for the application (May 2024) and the actual conformity assessment activities to be performed by manufacturers and notified bodies. Therefore, the documentation that the notified body does not need for the conclusion of the written agreement with the manufacturer and that is likely to be updated by the manufacturer before the actual conformity assessment does not need to be submitted with the application. That means that the application does not need to include, for example, the technical documentation for each device covered by the application and which is subject to technical documentation review. However, the application must clearly identify the manufacturer and the devices covered by the application for example by including the list of devices intended to be transferred to the MDR10 and, where applicable, the device(s) intended to substitute a ‘legacy device’. The information submitted11 with the application needs to allow the notified body to verify the qualification of the products as devices, their respective classification and the chosen conformity assessment procedure. When lodging the application, the manufacturer should provide a timeline for possible submission of the individual technical documentation and any other relevant information. Notified body and manufacturer should agree on a plan for submission of the relevant technical documentation or other information needed for the conformity assessment activities in due time. The timing of the submission should provide sufficient time for completing the conformity assessment procedure by notified body and manufacturer before the end of the transitional period, taking into consideration the time needed by the manufacturer to finalise the technical documentation, the notified body's available capacity for the assessment of the relevant product and its indicative timelines for completion of conformity assessment activities. Agreed timelines should be respected by both parties; delays and 'waiting until the last minute' should be avoided to prevent further bottlenecks in the certification process towards the end of the respective transitional period. As the manufacturer needs to comply with the quality management system (QMS) requirements of the MDR by 26 May 2024 at the latest, the application for conformity assessment of the QMS should include the documentation on the manufacturer’s QMS. 9 See updated factsheet for competent authorities in non-EU/EEA countries. 10 E.g. using as basis the list of CE marked devices drawn up by the notified body that issued the certificate(s), see point 5 of the General comment in NBOG BPG 2010-3 – Certificates issued by Notified Bodies with reference to Council Directives 93/42/EEC, 98/79/EC, and 90/385/EEC. 11 Having regard to the obligations of notified bodies (e.g. Article 36(2) MDR), submission of information requires the possibility for the notified body to add the relevant (digital) document(s) to its files. A 'read-only' access to the manufacturer's electronic data platform is not sufficient. https://health.ec.europa.eu/system/files/2023-07/thirdcountries_factsheet_en.pdf http://www.doks.nbog.eu/Doks/NBOG_BPG_2010_3.pdf http://www.doks.nbog.eu/Doks/NBOG_BPG_2010_3.pdf - 8 - Where the manufacturer lodges an application for conformity assessment of a device that is intended to substitute a legacy device, the manufacturer does not only need to identify the substitute device but also the legacy device that is intended to be substituted. The technical documentation of the substitute device can be submitted at a later stage. 9. What are the necessary elements of a written agreement between the manufacturer and the notified body? Pursuant to Article 120(3c), point (e), MDR, a written agreement in accordance with Section 4.3, second subparagraph, of Annex VII MDR must have been signed between the notified body and the manufacturer no later than 26 September 2024. Requirements laid down in Section 4.3, second subparagraph, of Annex VII MDR have not been amended. The formal application lodged by the manufacturer or the authorised representative (see question no 8 of this document) should be the basis for signing the written agreement. The written agreement should include indication about the possible schedule for submission of relevant documentation, such as full technical documentation for all devices covered by the formal application, not provided at the time the application is lodged. With the purpose of promoting consistency among notified bodies, NBCG-Med, in agreement with the MDCG working group Notified Bodies Oversight (NBO), might provide additional clarification on standard elements to be included in the written agreement signed between the notified body and the manufacturer referred to in point (e) of Article 120(3c) MDR. 9.1. What happens if the application is withdrawn or the written agreement terminated? If, after the relevant deadlines, the manufacturer withdraws its application for conformity assessment, or if the written agreement between notified body and manufacturer is terminated, the conditions set out in Article 120(3c), point (e), MDR are not met any more; the transitional period therefore ceases to apply. However, if the manufacturer or the notified body terminates the written agreement and the manufacturer simultaneously enters into a written agreement with another notified body, to which the application is transferred, the conditions set out in Article 120(3c), point (e), MDR are considered to be still met and the transitional period continues to apply, provided that also the other conditions are met. The arrangements for the change of notified body should be defined in an agreement between the manufacturer, the incoming notified body and the outgoing notified body in analogy with the principles laid down in Article 58 MDR. This kind of change of notified body may occur, for example, when the manufacturer intends to make use of available capacity of another notified body e.g. when the incoming notified body has been newly designated under the MDR or when the outgoing notified body has capacity constraints. The manufacturer should make sure that the documentation demonstrating that its legacy device benefits from the extended transitional period is updated after the change of notified body, such as its self-declaration and the notified body's confirmation letter (see question no 7 of this document). In contrast, the transitional period should not continue to apply where, after the relevant deadlines, the manufacturer changes the notified body as a reaction to the notified body's reasoned decision to refuse the manufacturer's application or to refuse the issuance of a certificate due to non-compliance with relevant MDR requirements. 9.2. What is the impact of changes related to the manufacturer during the transitional period? Administrative changes concerning the manufacturer's organisation (e.g. changes of the manufacturer's name, address or legal form, including a merger or acquisition involving the manufacturer) should generally not be considered as changes in the design or intended purpose12. They are therefore possible without impact on the transitional period. Not covered are situations where the manufacturer indicated on the MDD/AIMDD certificate or MDD declaration of conformity transfers device(s) covered by those MDD/AIMDD certificate(s)/MDD declaration(s) of conformity to another manufacturer who intends to place those device(s) on the market under the MDR, unless the 12 MDCG 2020-3 Rev.1 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 (May 2023), section 4.2. and footnote 17. https://health.ec.europa.eu/system/files/2023-05/mdcg_2020-3_en.pdf - 9 - manufacturer indicated on the MDD/AIMDD certificate and the manufacturer seeking MDR certification are part of the same larger organisation. 10. What is the meaning of “device intended to substitute that device”? The term “device intended to substitute that device” is used in the second subparagraph of Article 120(2), point (a), in Article 120(3c), point (e), and in the second subparagraph of Article 120(3e) MDR. A device intended to substitute the legacy device will usually (but not necessarily) differ from the legacy device because the manufacturer has made (significant) changes with regard to its design or intended purpose with a view to replacing the legacy device. It is the responsibility of the manufacturer to determine the device that is intended to substitute a legacy device and to explain the link to the substituted legacy device. It should be noted that the substitute device will need to undergo the full MDR conformity assessment before it can be placed on the market. The transitional period provided for in Article 120(3a) and (3b) MDR only applies to the ‘legacy device’ that is being replaced by the substitute device. Similar to what is stated in question no. 2, after MDR certification of the substitute device, the ‘legacy device’ and the substitute device can be placed on the market in parallel until the end of the relevant transitional period. 11. Which evidence does the manufacturer have to provide for having put in place a QMS in accordance with the MDR? Pursuant to Article 120(3c), point (d), MDR the manufacturer must put in place a QMS in accordance with Article 10(9) MDR no later than 26 May 2024. Manufacturers must draw up the documentation on its QMS, which needs to be part of the application for conformity assessment. Compliance with QMS-related requirements concerning post- market surveillance, market surveillance, vigilance and registration are part of the appropriate surveillance pursuant to Article 120(3e) MDR, while the assessment of the compliance with the MDR of the entire QMS will be done by the notified body as part of its conformity assessment activities. 11.1. Do all QMS aspects listed in Article 10(9) MDR have to be addressed? In principle, yes. However, for some specific QMS aspects listed in Article 10(9) MDR, e.g. points (b), (e) and (f), it needs to be taken into consideration that the QMS covers ‘legacy devices’, i.e. devices that are not yet (fully) MDR compliant. That means that for those devices it is not required that manufacturers have identified all relevant general safety and performance requirements and options to address those requirements, or have put in place a risk management as set out in Section 3 of Annex I MDR, nor conducted a clinical evaluation in line with Article 61 and Annex XIV MDR. However, from 26 May 2024, the manufacturer’s QMS should address how compliance with those requirements will be achieved. 11.2. Do legacy devices have to comply with UDI requirements during the extended transitional period? No. Pursuant to MDCG 2019-513, ‘legacy devices’ are not subject to the MDR UDI requirements. This approach is not changed through the condition that, from 26 May 2024, the manufacturer of the legacy device must put in place a MDR compliant QMS. Article 10(9), point (h), MDR, which states that verification of UDI assignments to all relevant devices is part of the QMS, only applies where UDI assignment is actually required for the relevant devices. 12. Do manufacturers, which have lodged an application for conformity assessment and have concluded a written agreement with a notified body before 20 March 2023, have to lodge a new application and/or conclude a new written agreement? No. Provided the application has not been rejected, applications lodged prior to the entry into force of the amending Regulation 2023/607 (i.e. 20 March 2023) remain valid and are sufficient for fulfilling the condition set out in Article 120(3c), point (e) MDR. No new written agreement needs to be signed either. 13 MDCG 2019-5 Registration of legacy devices in EUDAMED (April 2019). https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_5_legacy_devices_registration_eudamed_en_0.pdf - 10 - PART D – APPROPRIATE SURVEILLANCE TO BE PERFORMED BY NOTIFIED BODIES 13. What are the necessary elements of the arrangement for the transfer of the surveillance from the notified body that issued the MDD/AIMDD certificate to the MDR notified body? According to the third subparagraph of Article 120(3e) MDR, an agreement between the manufacturer and the MDR notified body, to which a formal application has been lodged, and, where practicable, the notified body that issued the MDD/AIMDD certificates, must set arrangements for the transfer of the appropriate surveillance in respect to devices covered by the written agreement referred to in Article 120(3c), point (e) MDR. The written agreement referred to in Article 120(3c), point (e), MDR and the agreement for the transfer of the surveillance address different subjects. However, they can be combined in one document depending on what is more convenient for the interested parties, e.g. when the notified body that issued the MDD/AIMDD certificate is not involved. The arrangement for the transfer of the surveillance should follow the same principles outlined in Article 58(1) MDR and should include the transfer of relevant documentation from the outgoing notified body to the incoming notified body. The agreement between the manufacturer, the outgoing notified body and the incoming notified body (‘tripartite agreement’) should also address the possibility of the MDR notified body to suspend or withdraw a certificate issued by the MDD/ AIMDD notified body, where duly justified. Transfer of surveillance activities takes place also in case the MDR notified body was not previously designated under the MDD/AIMDD. As established by the third subparagraph of Article 120(3e) MDR, the incoming notified body does not take responsibility for conformity assessment activities performed by the notified body that issued the certificate. Involvement of the MDR notified body in respect to devices that were certified under the Directives and for which it has signed a written agreement with the manufacturer for MDR certification is limited to carry out the appropriate surveillance referred to in Article 120(3e) MDR and further clarified in MDCG 2022-414. With the purpose of promoting consistency among notified bodies, NBCG-Med, in agreement with NBO, might provide additional clarification on a standard template for the tripartite agreement between the manufacturer, the MDR notified body and the notified body that issued the Directive certificates. Reminder: Appropriate surveillance in accordance with Article 120(3e) MDR only applies to legacy devices that are covered by a certificate issued by a notified body in accordance with the MDD/AIMDD. This also applies to devices covered by an MDD/AIMDD certificate that had expired and that is considered valid because the conditions set out in the second subparagraph of Article 120(2) MDR are met; in those cases, the appropriate surveillance has to be resumed. Legacy devices for which the conformity assessment procedure pursuant to the MDD did not require the involvement of a notified body ('self-declared' devices under the MDD), but that require the involvement of a notified body under the MDR, are not subject to surveillance by a notified body pursuant to Article 120(3e) MDR. 14. What does the limitation ‘where practicable’ imply? In the third subparagraph of Article 120(3e) MDR, the limitation that requires the notified body that issued the relevant certificate under the MDD/AIMDD to sign the arrangement for the transfer of the appropriate surveillance where practicable takes into account that there might be cases when this notified body could be unable to sign the contract, e.g. termination of business. In any case, it is required to have in place a written agreement between the manufacturer and the MDR notified body to specify the arrangements concerning the appropriate surveillance to be performed by the latter even if the notified body that issued the MDD/AIMDD certificates cannot be involved. 14 MDCG 2022-4 Guidance on appropriate surveillance regarding the transitional provisions under Article 120 of the MDR with regard to devices covered by certificates according to the MDD or the AIMDD. It is planned to revise MDCG 2022-4 to adapt it to Regulation (EU) 2023/607. https://health.ec.europa.eu/system/files/2022-12/mdcg_2022-4_en.pdf - 11 - 15. Which notified body is responsible for carrying out the appropriate surveillance when a written agreement in accordance with Article 120(3c), point e, MDR is signed between the manufacturer and a notified body designated under the MDR? Pursuant to Article 120(3e) MDR, the notified body that issued the relevant certificate under the MDD/AIMDD continues to be responsible for the appropriate surveillance in respect to the applicable requirements relating to devices it has certified. Alternatively, before 26 September 2024, the manufacturer can agree with a notified body designated under the MDR that the latter becomes responsible for the surveillance. At the latest by 26 September 2024, i.e. deadline by when the written agreement referred to in Article 120(3c), point (e), MDR needs to be signed, the notified body that signed that agreement will become responsible for the appropriate surveillance. After that date, the notified body that issued the certificate under the MDD/AIMDD can no longer perform appropriate surveillance. However, either in line with the tripartite agreement (see question no. 13) or in the absence of such agreement, it should cooperate with the MDR notified body to enable a smooth transfer of the surveillance activities, including the transfer of relevant documentation to the incoming notified body. 16. In case there is an arrangement for the transfer of the surveillance to a different notified body designated under MDR, what are the implication on the labelling concerning the notified body’s identification number? Even when the appropriate surveillance is transferred to a different notified body designated under the MDR, legacy devices can continue to be placed on the market and made available without changes to the labelling, including CE marking, and thus indicate the number of the notified body that issued the certificate under the Directive and that is kept valid. However, if practically feasible and depending on details included in the tripartite agreement (see question no 13 of this document) the manufacturer may decide to modify the labelling of legacy devices indicating the number of the notified body to which a formal application under the MDR has been lodged. 17. Is the notified body which issued the certificate in accordance with Article 120(3a) of Regulation (EU) 2017/745 legally obliged to continue to carry out the surveillance of the products concerned until the end of the new transitional period or until the manufacturer has transferred this surveillance obligation to a notified body whose designation has been made in accordance with Article 42? May this notified body deny the manufacturer the use of its NB number? Article 120(3e) MDR provides for the continuation of the surveillance (obligation) by the previous notified body until 26 September 2024 at the latest. Unless otherwise specified in the tripartite agreement (see question no. 16), the use of the number of the notified body that issued the certificate must not be denied until the end of the transition period. To enable the notified body to carry out the surveillance and make the necessary arrangements with the manufacturer, the latter one needs to inform the notified body about the device(s) subject to appropriate surveillance, in particular where surveillance activities have not been continued, e.g. due to the expiry of the certificate before 20 March 2023. PART E – DELETION OF THE ‘SELL-OFF’ DATE 18. Which devices will benefit from the removal of the ‘sell-off’ date? In Article 120(4) MDR and in Article 110(4) IVDR, the deadline for the further making available on the market of devices placed on the market in accordance with the previously applicable Directives has been deleted. That means that medical devices that have been placed on the market prior to 26 May 2021 in accordance with the MDD/AIMDD or after 26 May 2021 during the transitional period provided for in Article 120 MDR (i.e. until 31 December 2027 or 31 December 2028, as applicable) may continue to be made available on the market or put into service without any limitation in time without prejudice to the device’s possible shelf-life or expiry date. The same applies to in vitro diagnostic medical devices that have been placed on the market prior to 26 May 2022 in - 12 - accordance with the IVDD or after 26 May 2022 during the transitional period provided for in Article 110 IVDR (i.e. until 26 May 2025, 26 May 2026 or 26 May 2027, as applicable). Those IVD may continue to be made available on the market or put into service without any limitation in time without prejudice to the device’s possible shelf-life or expiry date.

EN EN EUROPEAN COMMISSION Brussels, 6.1.2023 COM(2023) 10 final 2023/0005 (COD) Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices (Text with EEA relevance) EN 1 EN EXPLANATORY MEMORANDUM 1. CONTEXT OF THE PROPOSAL • Reasons for and objectives of the proposal Regulation (EU) 2017/745 (MDR)1 and Regulation (EU) 2017/746 (IVDR)2 of the European Parliament and of the Council establish a reinforced regulatory framework for medical devices and in vitro diagnostic medical devices. Their objectives are a high level of protection of health for patients and users and the smooth functioning of the internal market for these products. To achieve these objectives and, in light of issues identified with the previous regulatory framework, the Regulations set out a more robust system of conformity assessment to ensure the quality, safety, and performance of devices placed on the EU market. The MDR has been applicable since 26 May 20213. The transition period provided for in Article 120(3) will end on 26 May 2024. The IVDR has been applicable since 26 May 2022. In January 2022, the European Parliament and the Council adopted a staggered extension of its transition period, ranging from 26 May 2025 for high risk in vitro diagnostics to 26 May 2027 for lower risk in vitro diagnostics, and to 26 May 2028 for certain provisions concerning devices manufactured and used in health institutions4. Despite considerable progress over the past years, the overall capacity of conformity assessment (‘notified’) bodies remains insufficient to carry out the tasks required of them. In addition, many manufacturers are not sufficiently prepared to meet the strengthened requirements of the MDR by the end of the transition period. This is threatening the availability of medical devices on the EU market. At present, 36 notified bodies are designated under Regulation (EU) 2017/745. Further 26 applications for designation as notified body are currently being processed; three of them are at an advanced stage5. In October 2022, notified bodies reported they had received altogether 8,120 applications from manufacturers for certification under the MDR and had issued 1,990 certificates in accordance with the MDR. According to an estimation presented 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 (OJ L 117, 5.5.2017, p. 1). 2 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 (OJ L 117, 5.5.2017, p. 176). 3 Regulation (EU) 2020/561 of the European Parliament and of the Council of 23 April 2020 amending Regulation (EU) 2017/745 on medical devices, as regards the dates of application of certain of its provisions (OJ L 130, 24.4.2020, p. 18) had postponed the date of application of Regulation (EU) 2017/745 from 26 May 2020 to 26 May 2021 due to the COVID-19 outbreak and the associated public health crisis. 4 Regulation (EU) 2022/112 of the European Parliament and of the Council of 25 January 2022 amending Regulation (EU) 2017/746 as regards transitional provisions for certain in vitro diagnostic medical devices and the deferred application of conditions for in-house devices (OJ L 9, 28.1.2022, p. 3). 5 In those three cases, the joint assessment team has already reviewed the applicants’ corrective and preventive action plan. The length of the overall designation process varies considerably from case to case. Based on data from December 2021, the average length of the overall process was 842 days for a designation in accordance with the MDR. https://eur-lex.europa.eu/legal-content/EN/AUTO/?uri=OJ:L:2017:117:TOC EN 2 EN by notified bodies to the Medical Device Coordination Group (MDCG)6 on 17 November 2022, the number of certificates issued by May 2024 may reach around 7,000 if the current rate of certificate issuance remains the same with no changes to current conditions. Notified bodies estimate that the transition of all Directives’ certificates to MDR certificates could possibly be completed by December 20277. Source: European Commission, based on data provided by 30 notified bodies in October 2022. This is in stark contrast to 21,376 valid certificates issued under Council Directive 90/385/EEC on active implantable medical devices (AIMDD)8 and Council Directive 93/42/EEC on medical devices (MDD)9 that will expire between January 2023 and 26 May 2024. Of those 21,376 certificates, 4,311 certificates will expire in 2023 and 17,095 certificates will expire in the first five months of 2024. Of note, 3,509 certificates issued under the AIMDD or MDD have already expired between May 2021 and December 2022. Year of expiry Number of expired/expiring certificates issued under Council Directives 90/385/EEC and 93/42/EEC 6 The MDCG has been established by Article 103 of Regulation (EU) 2017/745. It is composed of representatives appointed by Member States and chaired by a representative of the Commission. The MDCG is listed in the Commission’s register of expert groups with the code X03565. 7 Based on the results of a survey among notified bodies conducted end of November/beginning of December 2022; the respondents represent notified bodies that have issued around 80% of all certificates issued under Council Directives 90/385/EEC and 93/42/EEC that were valid in October 2022. This estimation does not take into account the number of first MDR certification of devices for which no certificates have been issued under Council Directives 90/385/EEC and 93/42/EEC and which require notified body involvement under the MDR. 8 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). 9 Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ L 169, 12.7.1993, p. 1). https://ec.europa.eu/transparency/expert-groups-register/screen/expert-groups/consult?lang=en&groupID=3565 EN 3 EN 2021 (from 26 May) 1,139 2022 2,370 2023 4,311 2024 (until 26 May 2024) 17,095 Source: European Commission, based on data provided by notified bodies in 2021 and 2022. After the expiry of the certificates issued under the Directives and without a valid MDR certificate, manufacturers are no longer allowed to place these medical devices on the EU market. This may cause shortages of medical devices, putting patient safety at risk. It is also likely to have a significant negative impact on innovation and business activity in the medical technology sector within the EU. The situation is exacerbated by the impact of the COVID-19 pandemic on clinical investigations, on- site audits and global supply chains, on which Russia’s war of aggression against Ukraine is having a further negative impact. The overall goal of the proposed amendments is to maintain patients’ access to a wide range of medical devices while ensuring the transition to the new framework. The extension will be staggered depending on the risk class of the device, i.e. until December 2027 for devices with a higher risk and until December 2028 for medium and lower risk devices. This proposal thus aims to extend the current transition period laid down in Article 120 of the MDR, based on certain conditions, so that only devices that are safe and for which manufacturers have already taken steps to transition to the MDR will benefit from the additional time. This would give manufacturers and notified bodies more time to conduct the conformity assessment procedures in accordance with the MDR, if those conditions are fulfilled. It also proposes to delete the ‘sell-off’ deadline in the relevant MDR and IVDR provisions, i.e. the end date for the further making available of devices which are placed on the market before or during the transition period and which are still in the supply chain when the extended transition period is over. This would prevent unnecessary disposal of safe medical devices that are already on the market but not yet with the final user. The extension of the transition period is complemented by an extension of the validity of certificates issued under the previous Council Directives 90/385/EEC and 93/42/EEC for the devices benefiting from the extended transition period. Also the validity of certificates that have already expired since 26 May 2021 would be extended, subject to certain conditions. • Consistency with existing policy provisions in the policy area The proposal is coherent with existing policy provisions as well as on-going non- legislative actions, which will complement the proposed amendment. On 25 August 2022, the MDCG endorsed its position paper MDCG 2022-1410. The paper lays out 19 non-legislative actions with a view to enhancing notified body capacity, access to notified bodies and manufacturers’ preparedness and thereby support a successful transition to the MDR and IVDR. Several of the actions listed in MDCG 2022-14 10 MDCG 2022-14 MDCG position paper Transition to the MDR and IVDR - Notified body capacity and availability of medical devices and IVDs (August 2022). https://health.ec.europa.eu/latest-updates/mdcg-2022-14-transition-mdr-and-ivdr-notified-body-capacity-and-availability-medical-devices-and-2022-08-26_en https://health.ec.europa.eu/latest-updates/mdcg-2022-14-transition-mdr-and-ivdr-notified-body-capacity-and-availability-medical-devices-and-2022-08-26_en https://health.ec.europa.eu/system/files/2022-08/mdcg_2022-14_en.pdf EN 4 EN have already been implemented, such as a MDCG position paper on hybrid audits11, new MDCG guidance on appropriate surveillance12, and a revision of MDCG 2019- 6, removing obstacles to the employment of qualified personnel by notified bodies13. On 1 December 2022, the Commission adopted two delegated acts deferring the timing of the first complete re-assessment of notified bodies14. This is expected to free capacities both for designating authorities and notified bodies. Work is ongoing to implement the remaining actions listed in MDCG 2022-14, as they remain important also if the transition period is extended. Further actions to support implementation of the two Regulations are also (co- )funded under the 2022 and 2023 work programmes of the EU4Health Programme15. On 9 December 2022, the MDCG issued its position paper MDCG 2022-1816 which sets out a uniform approach of competent authorities to applying market surveillance measures to bridge the gap between the expiry of MDD or AIMDD certificates and the issuance of MDR certificates. That approach is meant to be a temporary measure until the legislative changes in this proposal take effect. It contributes to avoiding disruption of supply of medical devices on the EU market. However, having regard to the number of certificates expiring in 2023 and 2024, it is not considered a sustainable solution for addressing the expected bottleneck of expiring certificates by 26 May 2024. 2. LEGAL BASIS, SUBSIDIARITY AND PROPORTIONALITY • Legal basis The proposal is based on Articles 114 and 168(4), point (c), of the Treaty on the Functioning of the European Union (TFEU). 11 MDCG 2022-17 MDCG position paper on ‘hybrid audits’ (December 2022). 12 MDCG 2022-15 Guidance on appropriate surveillance regarding the transitional provisions under Article 110 of the IVDR with regard to devices covered by certificates according to the IVDD (September 2022); MDCG 2022-4 rev. 1 Guidance on appropriate surveillance regarding the transitional provisions under Article 120 of the MDR with regard to devices covered by certificates according to the MDD or the AIMDD (December 2022). 13 MDCG 2019-6 Rev.4 Questions and answers: Requirements relating to notified bodies (October 2022). 14 Commission Delegated Regulation (EU) …/... of 1.12.2022 amending Regulation (EU) 2017/745 of the European Parliament and of the Council as regards the frequency of complete re-assessments of notified bodies, C(2022) 8640, and Commission Delegated Regulation (EU) …/... of 1.12.2022 amending Regulation (EU) 2017/746 of the European Parliament and of the Council as regards the frequency of complete re-assessments of notified bodies, C(2022) 8649. The delegated acts are available in the interinstitutional register of delegated acts and are subject to a three months scrutiny procedure by the European Parliament and the Council. 15 E.g. under the 2022 EU4Health Work Programme: a call for proposals aimed to foster capacity-building of existing and new notified bodies, to facilitate access of small and medium-sized enterprises (SMEs) and first-time applicants to notified bodies and to increase preparedness of manufacturers (see HS-g-22- 19.03), various actions supporting the implementation of Regulations on medical devices and in vitro diagnostic medical devices (see HS-p-22-19.04, 06, 07, 08, 09, 10 and 11) and direct grants to Member States’ authorities: reinforced market surveillance of medical devices and in vitro diagnostic medical devices (HS-g-22-19.01). Under the 2023 EU4Health Programme: support to the technical secretariat for Notified Bodies Coordination Group (see HS-p-23-63) and call for proposals for a program on orphan medical devices, in particular targeting paediatric patients (see HS-g-23-65). 16 MDCG 2022-18 MDCG position paper on the application of Article 97 MDR to legacy devices for which the MDD or AIMDD certificate expires before the issuance of a MDR certificate. https://health.ec.europa.eu/system/files/2022-12/mdcg_2022-17_en_0.pdf https://health.ec.europa.eu/system/files/2022-09/mdcg_2022-15_en.pdf https://health.ec.europa.eu/system/files/2022-12/mdcg_2022-4_en.pdf https://health.ec.europa.eu/system/files/2022-10/md_mdcg_qa_requirements_notified_bodies_en.pdf https://webgate.ec.europa.eu/regdel/#/delegatedActs?lang=en https://health.ec.europa.eu/publications/2022-eu4health-work-programme_en#files https://health.ec.europa.eu/publications/2023-eu4health-work-programme_en https://health.ec.europa.eu/system/files/2022-12/mdcg_2022-18_en.pdf EN 5 EN • Subsidiarity According to the principle of subsidiarity, EU action may only be taken if the aims of the envisaged measure cannot be achieved by Member States alone. The legislation being amended was adopted at EU level in line with the subsidiarity principle and any amendment must be made through an act adopted by the EU legislators. In the case of the current proposal for an amendment, EU action is required to avoid disruption in the supply of devices across the EU, to ensure the smooth functioning of the internal market, and to ensure a high level of health protection for patients and users. • Proportionality The proposed EU action is necessary to avert the risk of shortages of medical devices across the EU. The proposed amendments aim to ensure that the intended purpose of the MDR and IVDR can be attained. That purpose is to establish a robust, transparent, predictable and sustainable regulatory framework for medical devices, which guarantees a high level of protection of public health and patient safety and the smooth functioning of the internal market for these products. The proposal maintains the objective of both Regulations to ensure a high level of safety and performance of devices by enhancing their oversight by notified bodies. It only provides for the necessary additional time to achieve this objective. The proposal is proportionate in that it aims to address the identified issue, i.e. that due to shortage of notified body capacity and insufficient preparedness among manufacturers a large number of existing devices may disappear from the market. Therefore, the proposed amendments to the MDR are limited to allowing a gradual phase-in of the requirements, limited to ‘legacy’ devices that need notified body involvement in the conformity assessment, without altering the substance of those requirements, and the deletion of the ‘sell-off’ deadline. The amendment of the IVDR is limited to the deletion of the ‘sell-off’ deadline in order to be consistent with the proposed change in the MDR. The Commission proposes to differentiate between higher risk devices (i.e. class III and class IIb implantable) and lower risk devices (i.e. other class IIb, class IIa and class Im, Is, Ir17), with shorter transition periods for higher risk devices and longer periods for lower risk ones. This approach aims to balance the available notified body capacity and the level of manufacturers’ preparedness with high level of public health protection. • Choice of the instrument The proposed act is a Regulation to be adopted by the European Parliament and the Council, given that the acts to be amended are Regulations adopted by the European Parliament and the Council. 3. RESULTS OF EX-POST EVALUATIONS, STAKEHOLDER CONSULTATIONS AND IMPACT ASSESSMENTS Given the urgent nature of this proposal, it is not accompanied by a dedicated impact assessment. An impact assessment was already carried out when preparing the proposals for the MDR and the IVDR and this proposal does not alter the MDR or IVDR in substance and does not impose new obligations on the concerned parties. It 17 Class Im means class I devices with a measuring function; class Is means class I devices that are placed on the market in sterile condition; class Ir means class I devices that are reusable surgical instruments. EN 6 EN primarily aims to amend the transitional provisions, allowing for additional time to transition to the MDR’s requirements to avoid shortages. The need to act quickly to ensure certainty ahead of the Regulation’s current end of transition period did not allow for a broad public consultation. The Commission therefore collected the necessary input from Member States and stakeholders through targeted exchanges. The initiative aims to assure that patients throughout Europe have access to safe medical devices. As more and more certificates will expire before the May 2024 deadline, the Commission has committed to adopt a proposal in January 2023. This is backed up by urgent calls from the European Parliament, Member States and stakeholders, namely healthcare professionals, patients, academia, scientific bodies, industry and notified bodies. Input from Member States and stakeholders has been sought through targeted interaction, mainly in the framework of the Medical Device Coordination Group (MDCG) with meetings on 24-25 August, 24-25 October and 17 November 2022, dedicated to capacity and preparedness issues. Following a debate in the European Parliament on 24 November 2022 (oral question O-43/2022), the European Parliament’s Committee on Environment, Public Health and Food Safety requested an urgent targeted amendment in a letter of 5 December 2022. An exchange of views with Member States took place on 9 December 2022 during the EPSCO Health Council18; almost all Member States took the floor and supported the urgent adoption of a targeted amendment of the MDR and IVDR as suggested by the Commission. The Commission will continue to closely monitor the developments and the impact of the proposed amendments on the market. It will also consult with the MDCG and stakeholders about the need for complementary actions. 4. BUDGETARY IMPLICATIONS The proposed action has no budgetary implications. 5. OTHER ELEMENTS • Detailed explanation of the specific provisions of the proposal Article 1 contains the proposed amendments to Article 120(2), (3) and (4) and to Articles 122 and 123 of the MDR. Article 2 contains the amendments to Article 110(4) and to Article 112 of the IVDR. • Article 1(1), point (a), of the proposal – extension of the validity of certificates This provision amends Article 120(2) MDR. It extends the validity of certificates issued under Council Directives 90/385/EEC or 93/42/EEC that were valid on the day of the MDR’s date of application (26 May 2021) and have not been withdrawn by a notified body. The extension is directly applicable, so that notified bodies are not required to change the date on the individual certificates. The length of the extension of the certificate’s validity corresponds to the length of the extended transition period laid down in the proposed Article 120(3a) to (3c) of the MDR. As regards certificates that have already expired when the proposed amendment comes into force, the extension would be subject to the condition that, at the moment of the expiry, the manufacturer has signed a contract with a notified body for the 18 See Commission information note circulated as Council document 15520/22 of 6.12.2022. https://www.europarl.europa.eu/doceo/document/O-9-2022-000043_EN.html https://data.consilium.europa.eu/doc/document/ST-15520-2022-INIT/en/pdf EN 7 EN conformity assessment of the device in question. Alternatively, if no such contract has been signed at the moment when the certificate expired, a national competent authority may have granted a derogation from the applicable conformity assessment procedure in accordance with Article 59 of the MDR or have required the manufacturer to carry out the conformity assessment procedure within a specific time period in accordance with Article 97 of the MDR. • Article 1(1), point (b), of the proposal – extension of the transition period This provision amends Article 120(3) MDR. Due to the length of the provision, paragraph 3 is replaced by paragraphs 3a to 3g. The transition period is extended from 26 May 2024 until 31 December 2027 for higher risk devices (class III and class IIb implantable devices except certain devices for which the MDR provides exemptions, given that these devices are considered to be based on well established technologies) and until 31 December 2028 for medium and lower risk devices (other class IIb devices and class IIa, class Im, Is and Ir devices). In the same way as the current Article 120(3) MDR, the extended transition period applies only to ‘legacy devices’, i.e. those covered by a certificate or declaration of conformity issued under Council Directives 90/385/EEC or 93/42/EEC before 26 May 2021. Moreover, the application of the extended transition period is subject to several cumulative conditions, which are: ● the devices must continue to comply with Directive 90/385/EEC or Directive 93/42/EEC, as applicable. This condition is already part of the current Article 120(3) MDR; ● the devices do not undergo significant changes in the design and intended purpose. This condition is already part of the current Article 120(3) MDR; ● the devices do 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. The concept of “unacceptable risk to health and safety” is set out in Article 94 and 95 of the MDR. No systematic check of the device’s safety is required, as devices covered by a certificate issued under the Directives will be under ‘appropriate surveillance’ by the body that issued the certificate or a notified body designated under the MDR. Where, as part of their market surveillance activities, a competent authority finds that a 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, the transition period ceases to apply for that device; ● no later than 26 May 2024, the manufacturer has put in place a quality management system (QMS) in accordance with Article 10(9) of the MDR. This condition aims to ensure that manufacturers gradually move towards full compliance with the MDR requirements. No specific attestation, i.e. no self- declaration nor verification of the appropriateness of the QMS by a notified body, is required at this stage. However, by submitting an application for conformity assessment to a notified body (see next condition), the manufacturer implicitly confirms that its QMS is in compliance with the MDR; ● no later than 26 May 2024, the manufacturer, or its authorised representative, has lodged a formal application in accordance with Annex VII, Section 4.3, of the MDR for conformity assessment in respect of a ‘legacy device’ covered by EN 8 EN a Directive’s certificate or declaration of conformity, or in respect of a device intended to substitute that device under the MDR, and no later than 26 September 2024 the notified body and the manufacturer have signed a written agreement in accordance with Annex VII, Section 4.3, of this Regulation. This condition aims to ensure that only devices that the manufacturer intends to transition to the MDR will benefit from the extended transition period. The extension should, however, also apply to ‘legacy devices’ that the manufacturer intends to replace by a ‘new’ device for which it applies for conformity assessment before 26 May 2024. In this way, unnecessary applications for certification of devices that will in any case be phased out and replaced by a new generation of devices will be avoided, whist keeping the existing models available until the end of the transition period. The devices covered by a certificate issued under the AIMDD or MDD remain subject to ‘appropriate surveillance’ by the notified body that issued the certificate. Alternatively, the manufacturer can agree with a notified body designated under the MDR that the latter becomes responsible for the surveillance. At the latest by the date when the written agreement between the manufacturer and the notified body for conformity assessment in accordance with the MDR needs to be signed, that notified body would by default become responsible for the appropriate surveillance. The amendment introduces a transition period until 26 May 2026 also for class III custom-made implantable devices, which are currently not covered by Article 120(3) MDR. While manufacturers of class III implantable custom-made devices are required to comply with all applicable MDR requirements since 26 May 2021, they will now be given more time to obtain certification of their quality management system by a notified body. Also in this case, the transition period only applies if the manufacturer has lodged an application before 26 May 2024 resulting in the signing of a contract with the notified body before 26 September 2024. • Article 1(1), point (c), of the proposal – deletion of the ‘sell-off’ deadline in the MDR This provision deletes the current ‘sell-off’ date (27 May 2025) in Article 120(4) MDR. Consequently, devices placed on the market before the end of the transition period can be made further available on the market without a legal time restriction. • Article 1(2) and (3) of the proposal – adaptation of Articles 122 and 123 MDR This provision adapts Articles 122 and 123 MDR to reflect the extended transition period and the deletion of the ‘sell-off’ deadline. • Article 2(1) of the proposal – deletion of the ‘sell-off’ deadlines in the IVDR This provision deletes the current ‘sell-off’ dates (25 May 2025 to 26 May 2028) in Article 110(4) IVDR. Consequently, devices placed on the market before the end of the transition period laid down in Article 110(3) IVDR can be made further available on the market without a legal time restriction. • Article 2(2) of the proposal – adaptation of Article 112 IVDR This provision adapts Article 112 IVDR to reflect the deletion of the ‘sell-off’ deadlines. EN 9 EN 2023/0005 (COD) Proposal for a REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL amending Regulations (EU) 2017/745 and (EU) 2017/746 as regards the transitional provisions for certain medical devices and in vitro diagnostic medical devices (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), point (c), thereof, Having regard to the proposal from the European Commission, After transmission of the draft legislative act to the national parliaments, After consulting the European Economic and Social Committee, After consulting the Committee of the Regions, Acting in accordance with the ordinary legislative procedure, Whereas: (1) Regulations (EU) 2017/7451 and (EU) 2017/7462 of the European Parliament and of the Council establish a new regulatory framework to ensure the smooth functioning of the internal market as regards medical devices and in vitro diagnostic medical devices, taking as a base a high level of protection of health for patients and users. At the same time, Regulations (EU) 2017/745 and (EU) 2017/746 set high standards of quality and safety for medical devices and in vitro diagnostic medical devices in order to meet common safety concerns as regards such devices. Furthermore, both Regulations significantly reinforce key elements of the previous regulatory framework in Council Directives 90/385/EEC3 and 93/42/EEC4 and Directive 98/79/EC of the European Parliament and of the Council5, such as the supervision of notified bodies, conformity assessment procedures, clinical evidence requirements, vigilance and market surveillance, whilst introducing provisions ensuring transparency and traceability regarding medical devices and in vitro diagnostic medical devices. 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 (OJ L 117, 5.5.2017, p. 1). 2 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 (OJ L 117, 5.5.2017, p. 176). 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 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). EN 10 EN (2) Due to the impact of the COVID-19 pandemic, the date of application of Regulation (EU) 2017/745 has been postponed by one year to 26 May 2021 by Regulation (EU) 2020/561 of the European Parliament and of the Council6, while the date of 26 May 2024 was maintained as end of the transition period by which certain devices that continue to comply with Directive 90/385/EEC or Directive 93/42/EEC may be placed on the market or put into service. (3) Also due to the impact of the COVID-19 pandemic, the transition period provided for in Regulation (EU) 2017/746 has already been extended by Regulation (EU) 2022/112 of the European Parliament and of the Council7. (4) Despite the steady increase in the number of notified bodies designated in accordance with Regulation (EU) 2017/745, the overall capacity of notified bodies is still not sufficient to ensure the conformity assessment of the large number of devices covered by certificates issued under Directive 90/385/EEC or Directive 93/42/EEC before 26 May 2024. It appears that a large number of manufacturers, especially small and medium-sized enterprises, are not sufficiently prepared to demonstrate compliance with the requirements of Regulation (EU) 2017/745, taking into account also the complexity of those new requirements. Therefore, it is very likely that many devices that may be placed on the market in accordance with the transitional provisions provided for in Regulation (EU) 2017/745 are not going to be certified in accordance with that Regulation before the end of the transition period, which leads to the risk of shortages of medical devices in the Union. (5) In light of reports from healthcare professionals about the imminent risk of shortages of devices, it is necessary, as a matter of urgency, to extend the validity of certificates issued under Directives 90/385/EEC and 93/42/EEC and to extend the transition period during which devices that are in conformity with those Directives can be placed on the market. The extension should be sufficiently long to give notified bodies the time needed to carry out the conformity assessments required of them. The extension aims at ensuring a high level of public health protection, including patient safety and an avoidance of shortages of medical devices needed for the smooth functioning of health services, without lowering current quality and safety requirements. (6) The extension should be subject to certain conditions to ensure that only devices that are safe and for which the manufacturers have taken steps to transition towards compliance with Regulation (EU) 2017/745 will benefit from the additional time. (7) To ensure progressive transition to Regulation (EU) 2017/745, the appropriate surveillance regarding devices benefiting from the transition period should eventually pass over from the body that has issued the certificate in accordance with Directive 90/385/EEC or Directive 93/42/EEC to a notified body designated under Regulation (EU) 2017/745. For reasons of legal certainty it should be provided that the notified body should not be responsible for conformity assessment and surveillance activities carried out by the outgoing body. 6 Regulation (EU) 2020/561 of the European Parliament and of the Council of 23 April 2020 amending Regulation (EU) 2017/745 on medical devices, as regards the dates of application of certain of its provisions (OJ L 130, 24.4.2020, p. 18). 7 Regulation (EU) 2022/112 of the European Parliament and of the Council of 25 January 2022 amending Regulation (EU) 2017/746 as regards transitional provisions for certain in vitro diagnostic medical devices and the deferred application of conditions for in-house devices (OJ L 19, 28.1.2022, p. 3). EN 11 EN (8) As regards the period of time needed to allow manufacturers and notified bodies to carry out the conformity assessment in accordance with Regulation (EU) 2017/745 of medical devices that had been CE marked in accordance with Directive 90/385/EEC or Directive 93/42/EEC, a balance should be struck between the limited available capacity of notified bodies and ensuring a high level of patient safety and public health protection. Therefore, the length of the transition period should depend on the risk class of the medical devices concerned, so that the period is shorter for devices belonging to a higher risk class and longer for devices belonging to a lower risk class. (9) Contrary to Directives 90/385/EEC and 93/42/EEC, Regulation (EU) 2017/745 requires the involvement of a notified body in the conformity assessment of class III custom-made implantable devices. Having regard to insufficient notified body capacity and the fact that manufacturers of custom-made devices are often small or medium-sized enterprises that did not have access to a notified body under Directives 90/385/EEC and 93/42/EEC, a transition period should be provided during which class III custom-made implantable devices may be placed on the market or put into service without a certificate issued by a notified body. (10) Article 120(4) of Regulation (EU) 2017/745 and Article 110(4) of Regulation (EU) 2017/746 prohibit the further making available of devices which are placed on the market by the end of the applicable transition period and which are still in the supply chain one year after the end of that transition period. To prevent unnecessary disposal of safe medical devices and in vitro diagnostic medical devices that are still in the supply chain, thus adding to the imminent risk of shortages of devices, such further making available of devices should be unlimited in time. (11) The adoption of this Regulation takes place due to exceptional circumstances arising from an imminent risk of shortages of medical devices and the associated risk of a public health crisis. In order to attain the intended effect of the amendments to Regulations (EU) 2017/745 and (EU) 2017/746 and to ensure availability of devices whose certificates have already expired or are due to expire before 26 May 2024, to provide legal certainty for economic operators and healthcare providers, and for reasons of consistency as regards the amendments to both Regulations, it is necessary for this Regulation to enter into force as soon as possible. For the same reasons it is also considered appropriate to provide for an exception to the eight-week period referred to in Article 4 of Protocol No 1 on the role of national Parliaments in the European Union, annexed to the Treaty on European Union, to the Treaty on the Functioning of the European Union and to the Treaty establishing the European Atomic Energy Community, HAVE ADOPTED THIS REGULATION: Article 1 Regulation (EU) 2017/745 is amended as follows: (1) Article 120 is amended as follows: (a) in paragraph 2, the second subparagraph is replaced by the following: ‘Certificates issued by notified bodies in accordance with Directives 90/385/EEC and 93/42/EEC as from 25 May 2017 that were valid on 26 May 2021 and that have not been withdrawn afterwards shall remain valid after the end of the period indicated on the certificate until the dates set out in paragraph 3b for the relevant risk class of the devices. Certificates referred to in the first EN 12 EN sentence that have expired before [OP please insert the date – date of entry into force of this Regulation] shall be considered to be valid until the dates set out in paragraph 3b only if one of the following conditions is fulfilled: (a) before the date of expiry of the certificate, the manufacturer and a notified body have signed a written agreement in accordance with Section 4.3, second subparagraph, of Annex VII for the conformity assessment in respect of the device covered by the expired certificate or in respect of a device intended to substitute that device; (b) a competent authority of a Member State has granted a derogation from the applicable conformity assessment procedure in accordance with Article 59(1) or has required the manufacturer, in accordance with Article 97(1), to carry out the applicable conformity assessment procedure’; (b) paragraph 3 is replaced by the following: ‘3a. By way of derogation from Article 5 and provided the conditions set out in paragraph 3d of this Article are met, devices referred to in paragraphs 3b and 3c of this Article may be placed on the market or put into service until the dates set out in those paragraphs. 3b. Devices which have 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 be placed on the market or put into service until the following dates: (a) 31 December 2027, for class III devices and for class IIb implantable devices, except sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips and connectors; (b) 31 December 2028, for class IIb devices other than those covered by point (a), for class IIa devices, and for class I devices placed on the market in sterile condition or having a measuring function. 3c. Devices for which the conformity assessment procedure pursuant to Directive 93/42/EEC did not require the involvement of a notified body, for which the declaration of conformity was drawn up prior to 26 May 2021 and for which the conformity assessment procedure pursuant to this Regulation requires the involvement of a notified body, may be placed on the market or put into service until 31 December 2028. 3d. Devices may be placed on the market or put into service until the dates referred to in paragraphs 3b and 3c of this Article only if the following conditions are met: (a) those devices continue to comply with Directive 90/385/EEC or Directive 93/42/EEC, as applicable; (b) there are no significant changes in the design and intended purpose; (c) the devices do 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; (d) no later than 26 May 2024, the manufacturer has put in place a quality management system in accordance with Article 10(9); EN 13 EN (e) no later than 26 May 2024, the manufacturer, or an authorised representative, has lodged a formal application in accordance with Section 4.3, first subparagraph, of Annex VII for conformity assessment in respect of a device referred to in paragraphs 3b and 3c of this Article or in respect of a device intended to substitute that device, and no later than 26 September 2024 the notified body and the manufacturer have signed a written agreement in accordance with Section 4.3, second subparagraph, of Annex VII. 3e. By way of derogation from paragraph 3a, the requirements of this Regulation relating to post-market surveillance, market surveillance, vigilance, registration of economic operators and of devices shall apply to devices referred to in paragraphs 3b and 3c of this Article in place of the corresponding requirements in Directives 90/385/EEC and 93/42/EEC. 3f. Without prejudice to Chapter IV and paragraph 1 of this Article, the notified body that issued the certificate referred to in paragraph 3b of this Article shall continue to be responsible for the appropriate surveillance in respect of the applicable requirements relating to the devices it has certified, unless the manufacturer has agreed with a notified body designated in accordance with Article 42 that the latter shall carry out that surveillance. No later than 26 September 2024, the notified body that has signed the written agreement referred to in paragraph 3d, point (e), shall be responsible for the surveillance in respect of the devices covered by the written agreement. Where the written agreement covers a device intended to substitute a device which has a certificate that was issued in accordance with Directive 90/385/EEC or Directive 93/42/EEC, the surveillance shall be conducted in respect of the device that is being substituted. The arrangements for the transfer of the surveillance from the notified body that issued the certificate to the notified body designated in accordance with Article 42 shall be defined in an agreement between the manufacturer, the notified body designated in accordance with Article 42 and, where practicable, the notified body that issued the certificate. The notified body designated in accordance with Article 42 shall not be responsible for conformity assessment activities carried out by the notified body that issued the certificate. 3g. By way of derogation from Article 5, class III custom-made implantable devices may be placed on the market or put into service until 26 May 2026 without a certificate issued by a notified body in accordance with the conformity assessment procedure referred to in Article 52(8), second subparagraph, provided that no later than 26 May 2024, the manufacturer, or the authorised representative of the manufacturer, has lodged a formal application in accordance with Section 4.3, first subparagraph, of Annex VII for the applicable conformity assessment, and no later than 26 September 2024 the notified body and the manufacturer have signed a written agreement in accordance with Section 4.3, second subparagraph, of Annex VII.’; (c) paragraph 4 is replaced by the following: ‘4. Devices lawfully placed on the market pursuant to Directives 90/385/EEC and 93/42/EEC prior to 26 May 2021, and devices placed on the market from EN 14 EN 26 May 2021 pursuant to paragraphs 3a, 3b, 3c and 3g of this Article, may continue to be made available on the market or put into service.’ (2) Article 122 is amended as follows: (1) in the first paragraph, the introductory wording is replaced by the following: ‘Without prejudice to Article 120(3a) to (3f) 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 2021, with the exception of:’; (2) the second paragraph is replaced by the following: ‘As regards the devices referred to in Article 120(3a) to (3f) and (4) of this Regulation, the Directives referred to in the first paragraph shall continue to apply to the extent necessary for the application of those paragraphs.’; (3) In Article 123(3), point (d), the twenty-fourth indent is replaced by the following: ‘- Article 120(3e).’. Article 2 Regulation (EU) 2017/746 is amended as follows: (1) in Article 110, paragraph 4 is replaced by the following: ‘4. Devices lawfully placed on the market pursuant to Directive 98/79/EC prior to 26 May 2022, and devices lawfully placed on the market from 26 May 2022 pursuant to paragraph 3 of this Article may continue to be made available on the market or put into service.’; (2) in Article 112, the second paragraph is replaced by the following: ‘As regards the devices referred to in Article 110(3) and (4) of this Regulation, Directive 98/79/EC shall continue to apply to the extent necessary for the application of those paragraphs.’. Article 3 This Regulation shall enter into force on the day of its publication in the Official Journal of the European Union. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Brussels, For the European Parliament For the Council The President The President 1. CONTEXT OF THE PROPOSAL • Reasons for and objectives of the proposal • Consistency with existing policy provisions in the policy area 2. LEGAL BASIS, SUBSIDIARITY AND PROPORTIONALITY • Legal basis • Subsidiarity • Proportionality • Choice of the instrument 3. RESULTS OF EX-POST EVALUATIONS, STAKEHOLDER CONSULTATIONS AND IMPACT ASSESSMENTS 4. BUDGETARY IMPLICATIONS 5. OTHER ELEMENTS • Detailed explanation of the specific provisions of the proposal • Article 1(1), point (a), of the proposal – extension of the validity of certificates • Article 1(1), point (b), of the proposal – extension of the transition period • Article 1(1), point (c), of the proposal – deletion of the ‘sell-off’ deadline in the MDR • Article 1(2) and (3) of the proposal – adaptation of Articles 122 and 123 MDR • Article 2(1) of the proposal – deletion of the ‘sell-off’ deadlines in the IVDR • Article 2(2) of the proposal – adaptation of Article 112 IVDR

1 EUROPEAN COMMISSION DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY Medical Products and Innovation Medical Devices MDR - language requirements for manufacturers Rev. 1 (March 2024) Regulation (EU) 2017/745 on medical devices (MDR) contains different legal provisions that allow Member States to determine language requirements for manufacturers at national level for information accompanying the device. The following table gives an overview of the national provisions, in the case that Member States have made use of the possibility to determine language requirements for manufacturers. Member States are not obliged to determine a specific language. Having regard to the costs related to providing information in various languages, Member States are encouraged to consider whether information to be provided by the manufacturer could be accepted in another language than their national language (e.g. in English) if the safe use of the device is not compromised, especially regarding devices for professional use. The below information is provided based on the information available to the Commission services following a consultation of the Medical Device Coordination Group (MDCG) in October 2023. It is updated when Member State authorities inform about changes. The Commission services do not take responsibility for the correctness of the information in the table. In any case, the provisions of the MDR and the provisions of the Member States implementing the MDR in respect of language requirements take precedence over the information in this table. Revision history Date Action January 2024 Initial issue March 2024 1st update (Rev. 1) - France - documents for conformity assessment: addition of English (for certain parts) Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Austria* Bundesgesetz betreffend Medizinprodukte 30 June 2021 German (§7 para 1)* German or English (§7 para 1)* German (§7 para 4)* German (§7 para 2)* German (§7 para 6)* German or English (§7 para 7 No. 1)* 2 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Medizinproduktegesetz- 2021 Belgium Wet betreffende medische hulpmiddelen 18 January 2021 2020_12_22_Law_on_Me dical_Devices.pdf (vbb.com) French, Dutch and German (Art. 9 para 1) French, Dutch, German or English (Art. 9 para 1) French, Dutch, German or English (choice of the patient) (Art. 13 para 3) French, Dutch, German or English (Art. 14) French, Dutch and German; in case user is a healthcare professional English is allowed (Art. 65) French, Dutch, German or English (Art. 24) Considere d as the Label/IFU informatio n: French, Dutch and German (Art. 9 para 1) Considere d as the Label/IFU informatio n: French, Dutch and German or English (Art. 9 para 1) Bulgaria* LAW ON MEDICAL DEVICES (bda.bg) 12 June 2007 Medical devices - Bulgarian Drug Agency (bda.bg) Bulgarian (Art. 28 para 2 No. 4)* Bulgarian (Art. 28 para 2 No. 4)* Croatia Act implementing Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in vitro diagnostic medical devices 22 November 2018 Zakon.hr Croatian (Art. 30) Croatian and/or English (declaration/agr eement of professional user needed) (Art. 30). “or” is to be read as without prejudice to Art. 10(p.11) MDR – information supplied should be clearly Croatian (Art. 30) as the card is intended for patients Croatian and/or English (Art. 30) Croatian and/or English (Art. 30) Croatian and/or English (Art. 30) Any GUI elements linked to performan ce or safety should follow the same rules as label/IFU. Any GUI elements linked to performan ce or safety should follow the same rules as label/IFU. https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=20011580 https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=20011580 https://www.vbb.com/media/Insights_Articles/2020_12_22_Law_on_Medical_Devices.pdf https://www.vbb.com/media/Insights_Articles/2020_12_22_Law_on_Medical_Devices.pdf https://www.vbb.com/media/Insights_Articles/2020_12_22_Law_on_Medical_Devices.pdf https://www.bda.bg/images/stories/documents/regulations/zakoni/zakon_md.pdf https://www.bda.bg/images/stories/documents/regulations/zakoni/zakon_md.pdf https://www.bda.bg/en/information-for-companies/114-medical-devices-category https://www.bda.bg/en/information-for-companies/114-medical-devices-category https://www.bda.bg/en/information-for-companies/114-medical-devices-category https://zakon.hr/z/1253/Zakon-o-provedbi-Uredbe-%28EU%29-2017-745-o-medicinskim-proizvodima-i-Uredbe-%28EU%29-2017-746-o-in-vitro-dijagnosti%C4%8Dkim-medicinskim-proizvodima 3 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user comprehensible to the intended user Cyprus Cyprus Medical Devices Authority Regulatory Information Ιατρικές Υπηρεσίες (moh.gov.cy) Law 30 (I)/2002 relating to the Basic Requirements of Certain Categories of Products Basic Requirements (Medical Devices) Regulations 598/2003. Greek Greek or English Greek or English Greek or English Greek or English Greek or English Greek Greek or English Czech Republic https://www.zakonyprolidi. cz/cs/2021-89/zneni- 20210526 1 March 2021 375/2022 Sb. Zákon o zdravotnických prostředcích a diagnostických zdravotnických prostředcích in vitro (zakonyprolidi.cz) 7 December 2022 https://www.niszp.cz/sites /default/files/dokumenty/Z oZPaIVD_AJ%20verze.p df Czech (§8 para 2) Czech (§8 para 2) Czech (§8 para 2) Czech, Slovak or English (§8 para 1) Czech (§ 8 para 2) Czech, Slovak or English (§ 8 para 1) Czech Czech or English https://www.moh.gov.cy/moh/mphs/mphs.nsf/All/A82FE3D75F4BF2CAC225850A0036075A?OpenDocument https://www.moh.gov.cy/moh/mphs/mphs.nsf/All/A82FE3D75F4BF2CAC225850A0036075A?OpenDocument https://www.zakonyprolidi.cz/cs/2021-89/zneni-20210526 https://www.zakonyprolidi.cz/cs/2021-89/zneni-20210526 https://www.zakonyprolidi.cz/cs/2021-89/zneni-20210526 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.zakonyprolidi.cz/cs/2022-375/zneni-20221222 https://www.niszp.cz/sites/default/files/dokumenty/ZoZPaIVD_AJ%20verze.pdf https://www.niszp.cz/sites/default/files/dokumenty/ZoZPaIVD_AJ%20verze.pdf https://www.niszp.cz/sites/default/files/dokumenty/ZoZPaIVD_AJ%20verze.pdf https://www.niszp.cz/sites/default/files/dokumenty/ZoZPaIVD_AJ%20verze.pdf 4 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Denmark Executive Order no. 837 of 20 June 2023 on Medical Devices etc. Bekendtgørelse om medicinsk udstyr m.v. (retsinformation.dk) Language requirement for information about medical devices (laegemiddelstyrelsen.dk) Danish (Chapter II § 3) Danish; English possible upon request (Chapter II § 3 para 2) Danish, exception English (Chapter II § 4 para 2 ) English, Danish in specific cases (Chapter II § 6) https://ww w.retsinfo rmation.d k/eli/retsin fo/2021/9 840 Danish Guidance, section 2 Language requireme nt for informatio n about medical devices(la egemidde lstyrelsen. dk) https://ww w.retsinfor mation.dk/ eli/retsinfo /2021/984 0 Danish Guidance, section 2 Language requireme nt for informatio n about medical devices(la egemiddel styrelsen. dk) Estonia Medical Devices Act–Riigi Teataja 1 January 2023 Estonian Medical Devices Act available In English: https://www.riigiteataja.ee /en/eli/ee/515032023005/ consolide/current Labelling and language requirements for medical devices | Government installation profile (terviseamet.ee) Estonian (§16 para 3 No.1 and No.3 for custom- made medical devices) Estonian or English (§16 para 3 No.2) NB! Language Act § 17 gives the professional user the right to demand information in Estonian. Estonian or translated into Estonian (§ 324 No. 1) Estonian or English (§16 para 5) Estonian, initial FSN for urgent cases can be submitted in English (§ 27 (2)) Not stated in the national law, but in practice we accept Estonian or English Interpretat ion of the requireme nts in § 16 para 3: no certain requireme nt to translate GUI, but the manufact urer has to assess and Interpretat ion of the requireme nts in § 16 para 3: no certain requireme nt to translate GUI, but the manufact urer has to assess and https://www.retsinformation.dk/eli/lta/2023/837 https://www.retsinformation.dk/eli/lta/2023/837 https://www.retsinformation.dk/eli/lta/2023/837 https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://www.retsinformation.dk/eli/retsinfo/2021/9840 https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://laegemiddelstyrelsen.dk/en/devices/registration-and-marketing/language-requirement/ https://www.riigiteataja.ee/en/eli/ee/Riigikogu/act/524012023001/consolide https://www.riigiteataja.ee/en/eli/ee/Riigikogu/act/524012023001/consolide https://www.riigiteataja.ee/en/eli/ee/515032023005/consolide/current https://www.riigiteataja.ee/en/eli/ee/515032023005/consolide/current https://www.riigiteataja.ee/en/eli/ee/515032023005/consolide/current https://www.terviseamet.ee/en/labelling-and-language-requirements-medicaldevices https://www.terviseamet.ee/en/labelling-and-language-requirements-medicaldevices https://www.terviseamet.ee/en/labelling-and-language-requirements-medicaldevices https://www.terviseamet.ee/en/labelling-and-language-requirements-medicaldevices https://www.terviseamet.ee/en/labelling-and-language-requirements-medicaldevices 5 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user establish a suitable way to inform the potential/i ntended user(s). establish a suitable way to inform the potential/i ntended user(s). Finland Laki lääkinnällisistä laitteista 719/2021 (`Medical Devices Act´) 15 July 2021 In English: https://www.finlex.fi/en/lak i/kaannokset/2021/en202 10719.pdf Finnish and Swedish (§5) For Custom made MD: Finnish or Swedish, or both, depending on patient/customer need. Finnish, Swedish or English. However, information necessary for ‘safe use’* must be in Finnish and Swedish. (§5). *The manufacturer must determine, based on a risk assessment, which information is necessary for safe use. Finnish, Swedish and English (§5) Finnish, Swedish or English (§5) To be created in languages which are necessary for safety (§5) Finnish, Swedish or English (§5) Not specified, but GUI is in general treated similarly to IFU Not specified, but GUI is in general treated similarly to IFU France Ordinance n° 2022-582 20 April 2022 Ordonnance n° 2022-582 du 20 avril 2022 portant adaptation du droit français au règlement French (Art. R5211-20) French (Art. R5211-20) French (draft decree in progress) French (draft decree in progress) French (draft decree in progress) French or English (for certain parts) (draft decree in progress) French based on the general safety and performan ce French or English based on general requireme nt 5 (no art. in the https://www.finlex.fi/fi/laki/alkup/2021/20210719 https://www.finlex.fi/fi/laki/alkup/2021/20210719 https://www.finlex.fi/en/laki/kaannokset/2021/en20210719.pdf https://www.finlex.fi/en/laki/kaannokset/2021/en20210719.pdf https://www.finlex.fi/en/laki/kaannokset/2021/en20210719.pdf https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ 6 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user (UE) 2017/745 du Parlement européen et du Conseil du 5 avril 2017 relatif aux dispositifs médicaux - Légifrance (legifrance.gouv.fr) (draft decree in progress) The Use of the French Language | economie.gouv.fr Loi n° 94-665 du 4 août 1994 relative à l'emploi de la langue française - Légifrance (legifrance.gouv.fr) requireme nts 5 and 22 (no art. in the national law) national law) taking into account the skills and the means available to the users and the influence resulting from variation that can be reasonabl y anticiped in the user’s technique and environm ent Germany Gesetz zur Durchführung unionsrechtlicher Vorschriften betreffend Medizinprodukte 28 April 2020 MPDG.pdf (gesetze-im- internet.de) German (§ 8 para 2) German or English or users language (in justified cases) (§ 8 para 2) German (§ 8 para 3) German or English (§ 8 para 1) German (§73 para 1) German or English (§ 17) N/A N/A https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.legifrance.gouv.fr/loda/id/LEGIARTI000045615353/2022-04-22/ https://www.economie.gouv.fr/dgccrf/Publications/Vie-pratique/Fiches-pratiques/emploi-langue-francaise https://www.economie.gouv.fr/dgccrf/Publications/Vie-pratique/Fiches-pratiques/emploi-langue-francaise https://www.economie.gouv.fr/dgccrf/Publications/Vie-pratique/Fiches-pratiques/emploi-langue-francaise https://www.legifrance.gouv.fr/loda/id/JORFTEXT000000349929/2023-10-20/ https://www.legifrance.gouv.fr/loda/id/JORFTEXT000000349929/2023-10-20/ https://www.legifrance.gouv.fr/loda/id/JORFTEXT000000349929/2023-10-20/ https://www.legifrance.gouv.fr/loda/id/JORFTEXT000000349929/2023-10-20/ https://www.legifrance.gouv.fr/loda/id/JORFTEXT000000349929/2023-10-20/ https://www.gesetze-im-internet.de/mpdg/MPDG.pdf https://www.gesetze-im-internet.de/mpdg/MPDG.pdf 7 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Greece Directives 90/385/EEC (AIMDD) & 93/42/EEC (MDD) national legislation decrees ΔΥ8δ/Γ.Π.οικ. 130644 (ΦΕΚ Β’ 2197/2009) & ΔΥ8δ/Γ.Π.οικ.130648/ (ΦΕΚ Β’ 2198/2009) Greek (Art. 4 para 4) Greek (MDD/AIMDD Art. 4 para 4) For MDD, exceptionally in English (after CA approval) Greek and/or another EU language accepted from the NB (MDD Art. 11 para 12 & AIMDD Art.9 para 4) Hungary* https://www.ogyei.gov.hu/ medical_devices Hungarian* Hungarian* Hungarian* Hungarian* Hungarian* Ireland Statutory Instrument No. 547/2017 – EU (Medical Devices and In Vitro Diagnostic Medical Devices) Regulations 2017 8 December 2017 S.I. No. 547 of 2017. English language or English language and Irish language (No 5 (a)) English language or English language and Irish language (No 5 (a)) English language or English language and Irish language (No 5 (a)) English language or English language and Irish language (No 5 (a)) English language or English language and Irish language (No 5 (a)) English language or English language and Irish language (No 5 (a)) Italy* DECRETO LEGISLATIVO 5 agosto 2022, n. 137 5 August 2022 Italian (Art. 6)* Italian (Art. 6)* Italian and English (Art. 8)* Italian (Art. 10)* Italian or another EU language accepted by the NB (Art. 11)* https://www.ogyei.gov.hu/medical_devices https://www.ogyei.gov.hu/medical_devices https://www.irishstatutebook.ie/eli/2017/si/547/made/en/print https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2022-09-13&atto.codiceRedazionale=22G00145&elenco30giorni=true https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2022-09-13&atto.codiceRedazionale=22G00145&elenco30giorni=true https://www.gazzettaufficiale.it/atto/serie_generale/caricaDettaglioAtto/originario?atto.dataPubblicazioneGazzetta=2022-09-13&atto.codiceRedazionale=22G00145&elenco30giorni=true 8 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Latvia Regulation No. 461 of the Cabinet of Ministers of the Republic of Latvia "Medical Devices Regulations" adopted on 15 August 2023 Official Language Law 28 November 2017 Latvian Latvian or English if a medical device is intended to be used only in a health care facility and a consent of the health care facility is provided regarding use the foreign language Latvian Latvian Latvian Latvian Latvian or English if an explanatio n of functions is available in the IFU Latvian or English if a device is intended to be used only in a health care facility and a consent of the health care facility is provided Lithuania* XIII-2754 Lietuvos Respublikos sveikatos sistemos įstatymo Nr. I- 552 2, 3, 16, 59-1, 59-2, 59-3, 59-4, 59-5... (e- tar.lt) 1 March 2020 Medical devices (under EU directives) | State Accreditation Service for Health Care Activities under the Ministry of Health (lrv.lt) Lithuanian* Lithuanian* Lithuanian* Luxembourg Grand-Ducal Regulation of 11 August 1996 on medical devices French, German or Luxembourgish (for MD) French, German or Luxembourgish or English (for MD) French or German for AIMD (Art. 4 para 4 of the 1993 regulation) French or German and/or a language accepted by the notified body French or German for AIMD French or German and/or a language accepted by the notified body French or German for AIMD (Art. 4 para 4 of French, German or Luxembo urgish or https://likumi.lv/ta/en/en/id/14740-official-language-law https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://www.e-tar.lt/portal/en/legalAct/3a9a99402df111eabe008ea93139d588 https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas https://vaspvt.lrv.lt/lt/medicinos-priemones-pagal-es-direktyvas 9 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user https://legilux.public.lu/eli/ etat/leg/rgd/1996/08/11/n 12/jo Grand-Ducal Regulation of 5 February 1993 on active Implantable medical devices https://legilux.public.lu/eli/ etat/leg/rgd/1993/02/05/n 1/jo medical-devices-EN.pdf (public.lu)The Luxembourgish legislator expects that the patient or user receive information in a language they understand (Art. 4 para 4 of the 1996 regulation) French or German (for AIMD) (Art. 4 para 4 of the 1993 regulation) (Art. 4 para 4 of the 1996 regulation) French or German (for AIMD) (Art. 4 para 4 of the 1993 regulation) French, German or Luxembourgish for MD (Art. 4 para 4 of the 1996 regulation) Art. 9 para 4 of the 1993 regulation) Art. 9 para 11 of the 1996 regulation) (Art. 4 para 4 of the 1993 regulation) French, German or Luxembourgish for MD (Art. 4 para 4 of the 1996 regulation) Art. 9 para 4 of the 1993 regulation) Art. 9 para 11 of the 1996 regulation) the 1993 regulation ) French, German or Luxembo urgish for MD (Art. 4 para 4 of the 1996 regulation ) English (for MD) (Art. 4 para 4 of the 1996 regulation ) French or German (for AIMD) (Art. 4 para 4 of the 1993 regulation ) Malta SUBSIDIARY LEGISLATION 458.59 MEDICAL DEVICES AND IN-VITRO DIAGNOSTIC MEDICAL DEVICES PROVISION ON THE MALTESE MARKET REGULATIONS 4 August 2020 Medicines Authority (gov.mt) Maltese and/or English Maltese and/or English Maltese and/or English Maltese and/or English Maltese and/or English Maltese and/or English Maltese and/or English Maltese and/or English https://legilux.public.lu/eli/etat/leg/rgd/1993/02/05/n1/jo https://legilux.public.lu/eli/etat/leg/rgd/1993/02/05/n1/jo https://legilux.public.lu/eli/etat/leg/rgd/1993/02/05/n1/jo https://sante.public.lu/dam-assets/fr/politique-sante/ministere-sante/direction-sante/div-pharmacie-medicaments/medical-devices-EN.pdf https://sante.public.lu/dam-assets/fr/politique-sante/ministere-sante/direction-sante/div-pharmacie-medicaments/medical-devices-EN.pdf https://medicinesauthority.gov.mt/mdlegislation https://medicinesauthority.gov.mt/mdlegislation 10 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user The Netherlands Regeling medische hulpmiddelen 26 May 2022 BWBR0043450 (overheid.nl) Dutch (Art. 1 para 1) Dutch or English (Art. 1 para 2) Dutch (Art. 1 para 1) Dutch or English (Art. 1 para 3) Dutch or English (Art. 1 para 3) Dutch or English (Art. 1 para 3) Poland USTAWA z dnia 7 kwietnia 2022 r. o wyrobach medycznych 7 April 2022 https://isap.sejm.gov.pl/is ap.nsf/DocDetails.xsp?id= WDU20220000974 Polish (Art. 12 para 1) Polish or English (Art. 12) Polish (art. 12 para 4)+ art. 12 para 3 ustawa o prawach pacjenta z 6 listopada 2008 r.– https://isap.sejm.g ov.pl/isap.nsf/Doc Details.xsp?id=wd u20090520417 Polish – lay user (Art. 12 para 1) English – professional user (Art. 12 para 2) Polish (art. 49 para 3) Polish or English (Art. 28 para 9) Polish or English but IFU in Polish (art. 12 par. 1, 2) With the exception of devices intended for use in life and health emergenc ies English (art. 12 para 5) Portugal https://diariodarepublica.p t/dr/detalhe/decreto- lei/145-2009-494558 17 June 2009 The national legal framework for the MDR is still under legislative circuit – this will include language requirements Portuguese (Art. 5 para 6) Portuguese (Art. 5 para 6) Portuguese* *The publication of the national legal framework for the MDR is still pending. Portuguese (although English is accepted - current procedure)* *The publication of the national legal framework for the MDR is still pending. Portuguese Portuguese (although English is accepted - current procedure) *The publication of the national legal framework for the MDR is still pending. https://wetten.overheid.nl/BWBR0043450/2022-05-26 https://wetten.overheid.nl/BWBR0043450/2022-05-26 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=WDU20220000974 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=WDU20220000974 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=WDU20220000974 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=wdu20090520417 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=wdu20090520417 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=wdu20090520417 https://isap.sejm.gov.pl/isap.nsf/DocDetails.xsp?id=wdu20090520417 https://diariodarepublica.pt/dr/detalhe/decreto-lei/145-2009-494558 https://diariodarepublica.pt/dr/detalhe/decreto-lei/145-2009-494558 https://diariodarepublica.pt/dr/detalhe/decreto-lei/145-2009-494558 11 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user Romania* http://legislatie.just.ro/Pub lic/DetaliiDocument/2431 91 11 June 2021 Romanian (Art. 3 para 1)* Romanian or English (written consent of healthcare professional needed) (Art. 3 para 2)* Romanian or English (Art. 3 para 7)* Romanian or English (with approval of the CA)* Slovakia Act Nr.362/2011 Coll. on Drugs and Medical Devices Act Nr. 270/1995 Coll. on Offical Language of the Slovak Republic Slovak (Art. 110 b para 1) Label in ENG if intended for a professional use Slovak (Art. 110 b para 1) Slovak (Art. 110 b para 1) Slovak or English English language accepted by the NB (mostly SVK or ENG) Slovak English has to be explained in the Slovak IFU Slovenia Since the national legislation concerning the Regulations is not prepared yet, the Medical Devices act is still in use, from article 33 of Slovenian Medical Devices Act (Official Gazette RS, nr. 98/2009, Zakon o medicinskih pripomočkih (ZMedPri) (pisrs.si) ; available only in slovene language ): (5) The instructions for use must be written in the Slovene language, legible and understandable for the user, and must contain the date of issue or the date of last revision Slovene; Slovene; For professional use: the instructions for use can be written in the language understandable for the user. (Normally English is acceptable Slovene Slovene Slovene Slovene Slovene; For profession al use: the instruction s for use can be written in the language understan dable for the user. (Normally English is acceptabl e http://legislatie.just.ro/Public/DetaliiDocument/243191 http://legislatie.just.ro/Public/DetaliiDocument/243191 http://legislatie.just.ro/Public/DetaliiDocument/243191 https://www.zakonypreludi.sk/zz/2011-362 https://www.zakonypreludi.sk/zz/2011-362 https://www.zakonypreludi.sk/zz/2011-362 http://pisrs.si/Pis.web/pregledPredpisa?id=ZAKO5503 http://pisrs.si/Pis.web/pregledPredpisa?id=ZAKO5503 http://pisrs.si/Pis.web/pregledPredpisa?id=ZAKO5503 12 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user or amendment. If they have been translated into the Slovene language, the content of the translation must be the same as that of the original package leaflet. If a medical device is intended solely to be used for performing a registered activity (e.g. Professional use), the instructions for use can be written in the language understandable for the user. The same applies for labelling and packaging. Spain Real Decreto 192/2023, de 21 de marzo, por el que se regulan los productos sanitarios 22 March 2023 BOE-A-2023-7416 Spanish (art. 5.2) Spanish (art. 5.2) Spanish (art 36.6) Spanish (art 35.6) Sweden Förordning (2021:631) med kompletterande bestämmelser till EU:s förordningar om medicintekniska Swedish (3 chapter 1 §) Swedish (3 chapter 1 §) Swedish or English (3 chapter 1 §, second paragraph) Swedish or English (3 chapter 2 §) Swedish (3 chapter 1 §) Swedish or a language accepted by the notified body See website Language requireme nts | Swedish Medical See website Language requireme nts | Swedish Medical https://www.boe.es/eli/es/rd/2023/03/21/192 https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 13 Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user produkter | Sveriges riksdag (riksdagen.se) Language requirements | Swedish Medical Products Agency (lakemedelsverket.se) (3 chapter 2 §, second paragraph Products Agency (lakemed elsverket. se) Products Agency (lakemed elsverket. se) Iceland Act on Medical Devices No. 132/2020 8 December 2020 X2020132.dvi (government.is) Regulation on IFU with Medical Devices 630/2022 https://island.is/reglugerdi r/nr/0630-2022 Icelandic, allowed to be in English or Nordic language except Finnish for class I and IIa (Art. 12) Icelandic or English (Art. 12) Icelandic (Art. 19) Icelandic or English Icelandic or English English Icelandic, allowed to be in English or Nordic language except Finnish for class I and IIa Icelandic or English Liechtenstein Verordnung über den Verkehr mit Medizinprodukten im Europäischen Wirtschaftsraum 27 April 2021 EWR-MepV | Lilex - Gesetzesdatenbank des Fürstentum Liechtenstein German (Art. 10 para 1) German or English, if certain requirements are met (Art. 10 para 2) German (Art. 11 para 1) German or English (Art. 10 para 4) German (Art. 10 para 3) Norway Medical Device Regulations - Chapter III. Supplementary national Norwegian (Chapter III Sec. 6) Norwegian (Chapter III Sec. 6) Norwegian (Chapter III Sec. 13) English or Norwegian (Chapter III Sec. 8) Norwegian (Chapter III Sec. 12) English (Chapter III Sec. 7) Norwegia n (Chapter Norwegia n (Chapter https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.riksdagen.se/sv/dokument-och-lagar/dokument/svensk-forfattningssamling/forordning-2021631-med-kompletterande_sfs-2021-631/ https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.lakemedelsverket.se/en/medical-devices/regelverk/language-requirements#hmainbody1 https://www.government.is/library/04-Legislation/Act_on_Medical_Devices%20No132_2020.pdf https://www.government.is/library/04-Legislation/Act_on_Medical_Devices%20No132_2020.pdf https://island.is/reglugerdir/nr/0630-2022 https://island.is/reglugerdir/nr/0630-2022 https://www.gesetze.li/konso/2021161000?search_text=ewr-mepv&search_loc=text&lrnr=&lgblid_von=&observe_date=10.06.2021 https://www.gesetze.li/konso/2021161000?search_text=ewr-mepv&search_loc=text&lrnr=&lgblid_von=&observe_date=10.06.2021 https://www.gesetze.li/konso/2021161000?search_text=ewr-mepv&search_loc=text&lrnr=&lgblid_von=&observe_date=10.06.2021 https://lovdata.no/dokument/SF/forskrift/2021-05-09-1476/KAPITTEL_3#KAPITTEL_3 https://lovdata.no/dokument/SF/forskrift/2021-05-09-1476/KAPITTEL_3#KAPITTEL_3 https://lovdata.no/dokument/SF/forskrift/2021-05-09-1476/KAPITTEL_3#KAPITTEL_3 14 Other language requirements: For the Summary of Safety and Clinical Performance of a device (SSCP), Art. 32 MDR, please see the MDCG-2019-9 Rev.1 Guidance Document, that recommends the SSCP to “be written in a way that is clear to the intended user and, if relevant, to the patient (see MDR, Annex II (2), Article 10 (11)), the SSCP should be translated into the languages accepted in the Member States where the device is envisaged to be sold”(p. 6). *Recent information is not available for the country Country Relevant legal provision (reference and hyperlink to official publication) Label/IFU (Art. 10 (11), Annex I, section 23, MDR) Implant card (Art. 18 (I) MDR) Declaration of conformity (Art 19 (I) MDR) Field safety notice (Art. 89 (8) MDR) Documents for conformity assessment (Art. 52 (12) (Graphic) user interface (e.g. Apps) Patient/lay user Professional user Patient /lay user Professio nal user language provisions - Lovdata III Sec. 6) Except: Symbols such as "On", "Off", "Load", "Enter", "Page up". III Sec. 6) Except: Symbols such as "On", "Off", "Load", "Enter", "Page up". Turkey Law No. 7223 on Product Safety and Technical Regulations Dated 02.06.2021 and numbered 31499 Medical Device Regulation (TR-MDR) Circular No. 2022/1 on medical devices Turkish (TR-MDR Art 10 para 11) and Law No. 7223 Art 7 (1)(ğ) ) Turkish ( TR- MDR Art 10 para 11 and Law No. 7223 Art para 7 (1)(ğ) ) Exception: Label may be in English (with approval of the CA) in accordance with Section E, point 2 of Circular No. 2022/1 Turkish and, if necessary, English ( TR-MDR Art 18 para 2) Turkish ( TR-MDR Art 19 para 1) Turkish (TR-MDR Art 87 para 8(a) ) Turkish (TR-MDR Art 52 para 11 ) Turkish Turkish or English provided that IFU are presented in Turkish https://lovdata.no/dokument/SF/forskrift/2021-05-09-1476/KAPITTEL_3#KAPITTEL_3 https://lovdata.no/dokument/SF/forskrift/2021-05-09-1476/KAPITTEL_3#KAPITTEL_3 https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=7223&MevzuatTur=1&MevzuatTertip=5 https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=7223&MevzuatTur=1&MevzuatTertip=5 https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=7223&MevzuatTur=1&MevzuatTertip=5 https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=38657&MevzuatTur=7&MevzuatTertip=5 https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=38657&MevzuatTur=7&MevzuatTertip=5 https://titck.gov.tr/storage/Archive/2022/contentFile/2022-1%20say%C4%B1l%C4%B1%20T%C4%B1bbi%20Cihazlara%20ili%C5%9Fkin%20Genelge_813fcea2-19da-4af6-a8a5-67b11c88fec6.pdf https://titck.gov.tr/storage/Archive/2022/contentFile/2022-1%20say%C4%B1l%C4%B1%20T%C4%B1bbi%20Cihazlara%20ili%C5%9Fkin%20Genelge_813fcea2-19da-4af6-a8a5-67b11c88fec6.pdf

Work Programme of MDCG Borderline and Classification subgroup 2023 Last update: 21 November 2023 This document sets out the work program of the MDCG B&C Working Group for 2023. There are a number of work items which have been given a priority and a timeline, as well as permanent work items and possible future work items. This document was developed with the competent authorities members of the MDCG B&C Working Group and relevant stakeholders were consulted. It was endorsed by MDCG B&C Working Group on 9 December 2022 and by MDCG on 6 February 2023. The present status update has been prepared by the Chairs in view of the MDCG B&C meeting of 28 November 2023 to take stock of 2023. The topics are as follows: · Topic 1: Classification of medical devices · Topic 2: Qualification · Topic 3: Guidance for competent authorities · Topic 4: Helsinki procedure (permanent) · Topic 5: Work items for consultation coming from other MDCG WGs · Topic 6: Possible future work items Explanation of battery pictograms: · Number of bars: approximate indication of how close the work is to completion · Colour of the battery (green, amber or red): approximate indication of how difficult is the discussion Topic 1: Classification of medical devices No. Work item Description Timeline Lead BCWG CA members BCWG stake-holders Links to other WGs Priority Status 1/1 Classification of medical devices 1/1/1 Minor revision of classification guidance MDCG 2021-24 Revision of specific elements Q4 2023 SANTE All consulted All consulted - High Ongoing 1/1/2 Support for development of guidance for classification of Annex XVI products Standalone document also covering qualification Q4 2023 Annex XVI WG TBD All consulted Annex XVI High Ongoing Topic 2: Qualification No. Work item Description Timeline Lead BCWG CA members BCWG stake-holders Links to other WGs Priority Status 2/1 Qualification of IVDs 2/1/1 Guidance on IVD borderline issues Transposition of MEDDEV 2.14/1 for use under IVDR Q1 2024 SANTE, FR All consulted All consulted IVD WG Medium Ongoing Topic 3: Guidance for competent authorities No. Work item Description Timeline Lead BCWG CA members BCWG stake-holders Links to other WGs Priority Status 2/1 Classification disputes 2/1/1 Procedures for notification of decision on dispute Notification of COM and MDCG by CA about its classification decision following a dispute (Art. 51(2) MDR; Art. 47(2) IVDR) Q4 2023 SANTE TBD N/A IVD WG Medium Ongoing Topic 4: Helsinki procedure (permanent) No. Work item Description Timeline Lead BCWG CA members BWG stakeholders Links to other WG Priority Status 3/1 Helsinki procedure 3/1/1 Helsinki procedure Participate in the Helsinki procedure and publish the B&C Manual Permanent Initiating CAs, COM for publication and contact lists All All consulted IVD, NT Medium Ongoing Topic 5: Work items for consultation coming from other MDCG WGs No. Work item Description Timeline Lead BCWG CA members BCWG stakeholders Links to other WG Priority Status 4/1 Software 4/1/1 Software intended to treat or alleviate a disease, injury or disability Targeted revision of MDCG 2019-11 TBD NT WG All consulted N/A IVD Medium 4/1/2 Guidance on medical device software-hardware combination systems Standalone guidance TBD NT WG All consulted N/A IVD Medium 4/2 IVDs 4/2/1 Minor revision of MDCG 2020-16 on classification of IVDs Consideration of clarifications and additional examples (rev.3) End 2023 IVD WG All consulted N/A IVD Medium Topic 6: Possible future work items No. Work item Description Timeline Lead BCWG CA members BCWG stakeholders Links to other WG Priority Status 4/1 Tissues and cells 4/1/1 MDCG guidance on borderline with tissues and cells TBD TBD TBD All consulted IVD Low Not yet started 4/2 Biocides 4/2/2 MDCG guidance on borderline with biocides TBD TBD TBD All consulted IVD Low Not yet started Note: other borderline areas that could be tackled in the future: foodstuffs, cosmetics, software, personal protection equipment Page 2 of 3

1 Ongoing guidance development and deliverables of MDCG Subgroups – March 2023* *This is not an exhaustive list of ongoing work performed by MDCG Subgroups Scope Group Deliverables Consult prior to MDCG** Planned MDCG Endorsement Additional Comments ** Stakeholders are observers in 13 MDCG subgroups and are consulted on a regular basis; further to that other MDCG subgroups are consulted as indicated 1. Notified Bodies Oversight (NBO)1 MDR + IVDR Q&A on requirements notified bodies – update of MDCG 2019-6 Notified bodies N/A Permanent NBO Work Item MDR+IVDR Updates of guidance documents and templates on the designation and re-assessment process Notified bodies 2023 This includes update of MDCG 2022- 13 MDR + IVDR Updates of guidance documents and templates on qualification and authorisation of personnel Notified bodies 2024 Work started in 2022 MDR Notified Body Technical Documentation Assessment Report Notified bodies and relevant MDCG Subgroups 2023 Work started in 2022 MDR Revision of 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 MDCG Stakeholders and relevant MDCG subgroups 2023 MDR + IVDR Revision of MDCG 2019-13 Guidance on sampling of devices for the assessment of the technical documentation MDCG Stakeholders and relevant 2023 1 Stakeholders are not part of this group as it covers requirements set out by designating authorities specifically for notified bodies; stakeholders are consulted on mature and final drafts. 2 MDCG subgroups 2. Standards MDR + IVDR Updates of guidance document MDCG 2021-5 on standardisation for medical devices NBO, IVD Q2 2023 3. Clinical Investigations and Evaluation (CIE) MDR Clinical Investigation Report Summary Template Q1 2023 4. Post-Market Surveillance and Vigilance (PMSV) MDR + IVDR Extension of guidance on Periodic Safety Update Report to IVDR requirements IVD, MS, NBO Q3 2023 MDR + IVDR Extension of Q&A documents on Vigilance terms and concepts to IVDR requirements IVD, NBO Q3 2023 MDR + IVDR Guidance on Post-Market Surveillance requirements MS / IVD Q2 2023 MDR + IVDR Extension of Q&A document on Vigilance terms and concepts to IVDR requirements MDR Vigilance guidance on Articles 87 to 90 MS / IVD MS /IVD Q3 2023 Q4 2023 Q&A document on Art 87 to 90 has been replaced by MDR Vigilance guidance MDR + IVDR MDR + IVDR Development of harmonised reporting forms for incidents Revision of Trend report and associated files MS / IVD MS / IVD Q2 2023 Q2 2023 3 5. Market Surveillance (MS)2 MDR + IVDR Update MDCG 2021-27 Q&A on Importers & Distributors IVD Q.2 2023 MDR + IVDR Update MDCG 2021-26 Q&A on repackaging & relabelling activities under Article 16 IVD Q.2 2023 MDR + IVDR Update MDCG 2019-7 of PRRC Guidance IVD Q.2 2023 6. Borderline & Classification (B&C) N/A 7. New Technologies MDR + IVDR Legal status of app providers To be updated AFTER Q2 MDR + IVDR Guidance on MDSW - Hardware combination systems B&C To be updated AFTER Q2 8. Eudamed N/A 9. Unique Device Identification (UDI) MDR Guidance on Master UDI-DI UDI Q3 2023 2 Stakeholders are not part of this group as it covers requirements set out by competent authorities; stakeholders are consulted on mature and final drafts. 4 10. International Matters N/A 11. In Vitro Diagnostic Medical Devices (IVD) IVDR Common specifications for hepatitis E class D devices N/A Q4 2023 In progress IVDR Common specifications for Plasmodium and Toxoplasma class D devices N/A Q4 2023 In progress IVDR Common specifications for arbovirus (Zika, West Nile Virus, Chikungunya, dengue) class D devices N/A 2024 In progress IVDR Questions and Answers document on performance studies CIE Q3 2023 In progress IVDR Template and guidance for safety reporting in performance studies under IVDR CIE Q3 2023 In progress IVDR Minor revision of MDCG 2022-9 – Summary of Safety and Performance Template CIE Q2 2023 Addition of specific points IVDR Minor revision of MDCG 2020-16 – Classification of IVDs B&C Q4 2023 Addition of specific points IVDR Transposition of MEDDEV 2.14/1 – IVD borderline issues for use under IVDR B&C Q2 2023 In progress IVDR Poss. minor revision of MDCG 2022-10 – Interplay between CTR/IVDR Medicinal product authorities / B&C / CIE Q2 2023 In progress IVDR Analysis of IVDR in context of hypothetical scenarios of an urgent response to a health crisis N/A Q2 2023 In progress 5 IVDR Minor revision of MDCG 2021-14 – Explanatory note on IVDR codes NBO 2023 In progress 12. Nomenclature MDR + IVDR Procedures for the annual and ad-hoc updates of the EMDN N/A To be updated AFTER Q2 MDR + IVDR FAQ on EMDN N/A To be updated AFTER Q2 MDR + IVDR Mapping EMDN-GMDN package N/A N/A The outcome of this exercise is highly dependent on level of cooperation ensured by GMDN. 13. Annex XVI MDR Guidance document on the use of equivalence criteria for Annex XVI products CIE, NBO Q2 2023 MDR Guidance document on the classification of Annex XVI products B&C Q2 2023 MDR Q&A document on the transitional provisions established by the Annex XVI common specifications / Q1/2023 Ongoing guidance development and deliverables of MDCG Subgroups – March 2023* *This is not an exhaustive list of ongoing work performed by MDCG Subgroups Planned MDCG Endorsement Consult prior to MDCG** Additional Comments Group Deliverables Scope 1. Notified Bodies Oversight (NBO) 2. Standards 3. Clinical Investigations and Evaluation (CIE) 4. Post-Market Surveillance and Vigilance (PMSV) 5. Market Surveillance (MS) 6. Borderline & Classification (B&C) 7. New Technologies 8. Eudamed 9. Unique Device Identification (UDI) 10. International Matters 11. In Vitro Diagnostic Medical Devices (IVD) 12. Nomenclature 13. Annex XVI

Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 1 of 11 MDCG 2024-12 Corrective and preventive action (CAPA) plan assessment: guidance and templates for conformity assessment bodies, notified bodies, designating authorities and joint assessment teams October 2024 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 Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 2 of 11 Contents 1 Introduction .................................................................................................................. 3 2 Scope ........................................................................................................................... 3 3 Timelines of the process .............................................................................................. 4 4 Considerations for the NB ............................................................................................ 4 4.1 Corrections ...................................................................................................... 4 4.2 Root cause(s) .................................................................................................. 6 4.3 Corrective and preventive actions ...................................................................... 8 4.4 Actions for verification of effectiveness ............................................................... 9 5 Considerations for the DA .......................................................................................... 10 6 Considerations for the JAT ......................................................................................... 11 Annex I: Template CAPA plan and assessment thereon .................................................... 1 Annex II: Template JAT review of the CAPA and the DA’s opinion..................................... 1 Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 3 of 11 1 INTRODUCTION This guidance document is intended for conformity assessment bodies (CABs), notified bodies (NBs), designating authorities (DAs), and Joint Assessment Teams (JATs) involved in Regulation (EU) 2017/745 on medical devices (hereafter MDR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (hereafter IVDR). It should be read in conjunction with the guidance document MDCG 2022-13 “Designation, re-assessment and notification of conformity assessment bodies and notified bodies”1. This document aims to provide guidance for: − NBs2 when establishing the corrective and preventive action (CAPA) plan to address the non-compliances (NCs) resulting from joint assessments according to Article 39(5) of the MDR or Article 35(5) of the IVDR, − authorities responsible for notified bodies (hereafter, the DAs) when conducting reviews of and providing opinions on CAPA plans of notified bodies according to Article 39(7) of the MDR or Article 35(7) of the IVDR and − JATs when considering the CAPA plan and the DA’s opinion thereon according to Article 39(7) of the MDR or Article 35(7) of the IVDR. The use of the templates in Annex I (hereafter CAPA template) and Annex II (hereafter JAT review template) to this guidance is not mandatory. However, using them according to this guidance to structure CAPA plans and conduct their reviews will facilitate an efficient, consistent and timely CAPA review process for NBs, DAs and JATs. The formal list of non-compliances from the on-site assessment provided by the DA serves as the input to the CAPA process. When completing the CAPA template, the wording, legal references, and classification of the NC(s) should be restated without modification. This includes the official DG SANTE translation of the NC, if applicable and provided3. Clear and traceable communication throughout the CAPA process is crucial to ensure an efficient review by the JAT of CAPA plans confirmed by the DA, as well as the DA's opinion regarding those CAPA plans, ultimately facilitating the JAT’s final opinion. 2 SCOPE This document provides guidance for CABs, NBs, DAs and JATs on using the templates in Annex I and Annex II during assessments of NBs and CABs under the MDR and the IVDR. These templates are primarily designed for re-assessments of NBs. However, they can also be applied during assessments of CABs applying for designation as an NB, assessments relating to extensions of an NB’s scope of designation, and assessments relating to challenges to an NB’s competence under Article 47 MDR or Article 43 IVDR. While this 1 https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other- guidance_en#sec14 2 Reference to NBs throughout this document may also be considered relevant to CABs. 3 MDCG 2022-13 describes the official DG SANTE translations of the NCs in the last paragraph of section 2.2.5. https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en#sec14 https://health.ec.europa.eu/medical-devices-sector/new-regulations/guidance-mdcg-endorsed-documents-and-other-guidance_en#sec14 Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 4 of 11 guidance document provides comprehensive information, it's important to note that specific guidance may not be applicable in every context. For example, the requirement for containment actions may not be relevant during designation assessments (see Section 4.1). The CAPA template is not designed to be used by DAs to document the NCs raised during assessments as DAs may have their own template for this purpose. However, if it suits their needs, DAs may use it for this purpose too. 3 TIMELINES OF THE PROCESS The timelines for the process are described in MDCG 2022-13. Stakeholders should familiarise themselves with that guidance and aim to implement the timelines described. 4 CONSIDERATIONS FOR THE NB If the DA has not already done so, the NB should transfer all NCs from the DA’s assessment report/list into the CAPA template. This should be done exactly as stated and including legal references, classification and the official DG SANTE translations of the NCs, if applicable and provided. It is recommended that the NB completes the relevant sections of the CAPA template in as much detail as possible, focusing on providing clear, comprehensive and appropriate information to enable the DA and JAT to effectively review and make an informed assessment of the information provided. The NB may also consider providing supporting evidence (e.g. updated procedures, new templates, …) together with the completed CAPA template, if deemed helpful for the understanding and assessment of the information provided by the NB in the CAPA template. The NB should assign a person responsible for implementing corrections, corrective and preventive actions and actions to verify their effectiveness. This should be documented in the template along with the target date(s) for the implementation. The completed CAPA plan and, where appropriate, supporting evidence should be sent to the DA by the timeframe communicated by the DA4. If the DA has classified a finding as an observation5 and communicated specific expectations, the NB is encouraged to meet these expectations as part of ensuring effective CAPA management. Additionally, the NB may consider taking steps to address any observation which could involve improving the current situation or implementing preventive measures to avoid similar issues in the future. 4.1 Corrections In this section of the CAPA template, the NB should provide a detailed description of all corrections, whether they are containment actions or not. 4 Language considerations for CAPA plans are addressed in sections 2.3.2 and 2.3.3 of MDCG 2022-13. 5 An observation (MDCG 2022-13, section 2.2.4) is a finding requiring attention from the NB but does not breach a legal requirement. MDR/IVDR and MDCG 2022-13 are silent on specific actions for observations. Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 5 of 11 A ‘correction’ is an action to correct or eliminate a detected NC in whole or in part.6 An ‘containment action’ (also called a ‘’immediate correction’) is a correction that the NB should take without any unjustified delay to address an identified risk or safety issue, aiming to control the situation and prevent further (potential) harm7. Examples which may require a containment action include cases when the DA or JAT detected failure of the NB to adequately assess the validation of the sterilisation process, a certificate which the NB issued having overlooked an open major non-conformity impacting the device safety or performance, or a certificate issued out of the scope of designation (and competence). Containment actions may include for example immediate restriction of the scope of a certificate or suspension of a certificate. Upon identification of an NC, the NB’s first step is to consider and, where appropriate, implement one or more containment actions. Additional corrections may be deemed necessary following the full investigation of the NC. The NB should also provide evidence (documents or adequate information) of the implementation of these corrections, where appropriate: particularly for containment actions and corrections deemed necessary by the DA. The NB should consider the potential impact of each correction on its quality management system (QMS) as a whole. This includes: • The impact on other documents, processes or procedures. For example, if the revision of a deficient procedure has an impact on other procedures/processes, all these procedures/processes should be reviewed, assessed and revised as appropriate. • The impact on other conformity assessment projects and existing certificates. For example, if a deficient sterilisation checklist has had a critical impact on how the NB has assessed ‘sterilisation’ in its conformity assessment projects, not only the project in which the finding was raised as an NC, but all those projects affected by the same deficient checklist should be reviewed, assessed and corrected as appropriate. • The identification of similar shortcomings. The NB should identify issues in other parts of the QMS, even before the root cause is determined. For example, if a deficient checklist for assessing the validation of the sterilisation process is identified, the NB should also consider whether checklists used for the assessment of other sterilisation methods have the same or a similar weakness. If so, potentially affected projects using those checklists might also require review and correction. 6 ISO 9000:2015 Clause 3.12.3, modified. 7 While ‘containment action’ and ‘immediate correction’ are common terms in quality engineering, they are not explicitly defined in the MDR, regulatory guidance or relevant ISO standards. For example, the 8D method, a well-known quality problem- solving approach, describes these concepts. Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 6 of 11 4.2 Root cause(s) The core issues that caused the NC should be identified through a comprehensive root cause analysis. The NB should use a set of analysis and problem-solving techniques aimed at investigating in detail the NC, considering both the severity (e.g. major or minor) and the extent of the NC (e.g. single occurrence, reoccurrence, systemic issue). The root cause analysis should identify the actual root causes or the reasons that caused the NC and not just how to eliminate the symptoms of the issue8. It should be noted that there may be more than one (root) cause for an NC. 8 The European standard EN 62740:2015 describes a structured approach for root cause analysis (RCA), selecting appropriate techniques, and understanding their strengths and weaknesses. While not specific to medical devices nor notified bodies, it offers valuable principles for RCA within quality management systems. Some tips for root cause analysis It may be helpful to first identify the direct cause, i.e., the cause that directly resulted in the NC, followed by the underlying and contributing causes, i.e., causes that contributed to the NC but would not have directly caused it on their own. Finally, identify the root cause, i.e. the initiating cause of the causal chain that led to that specific NC and which, once removed, would prevent the recurrence of the NC. The root cause may not only apply to the individual NC but may have implications for a wider range of possible NCs. It is the most fundamental aspect of the cause that can logically be identified and corrected. It may be useful for the NB to consider including at least the following areas for review (not exhaustive): Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 7 of 11 Procedural-related Issues (e.g. defective/inadequate/lack of procedure) Personnel-related Issues (e.g. inattention to detail, violation of requirement or procedure) ➢ Was there an applicable procedure? ➢ Was the correct procedure used? ➢ Was the procedure followed? ➢ Followed in sequence? ➢ Followed "blindly"--without thinking? ➢ Was the procedure: • Legible? • Misleading? • Confusing? • The approved, up-to-date revision? • Adequate for the task? • In compliance with the Regulations and other applicable regulatory requirements (e.g. MDCG documents)? ➢ Did the procedure: • Have sufficient detail? • List steps in the proper sequence? • Cover all systems involved? • Require adequate work review? ➢ An omitted action? ➢ An extraneous action? ➢ An action performed inadequately, e.g. out of sequence? ➢ Which personnel? ➢ What were: • The qualifications of these staff? • The experience levels of these staff? • The work groups of these staff? ➢ Did the personnel involved: • Have adequate instruction? • Have adequate supervision? • Receive adequate training? • Have adequate knowledge? • Communicate effectively? Training-related Issues Management-related Issues ➢ No or not sufficient training provided? ➢ Inadequate content? ➢ Inadequate presentation or materials? ➢ Insufficient practice or experience? ➢ Insufficient refresher training? ➢ Inadequate control? ➢ Poor work organisation/planning? ➢ Inadequate supervision? ➢ Inadequate allocation of resources? ➢ Policy not adequately defined, disseminated, or enforced? The NB should: 1. Identify the problem: For instance, if a staff member follows a flawed procedure and this leads to an NC, the primary issue is the defective procedure itself rather than the staff member’s actions. However, if the staff member had received training for the task and was expected to identify the flaw in the procedure, then there may also be a personnel issue. 2. Identify the causes: Determine the conditions or actions immediately preceding and surrounding the problem (i.e., the reasons why the problem occurred). 3. Identify the root cause(s): Trace back to the fundamental reasons why the causes in the preceding step existed. The root cause is the fundamental reason that, if corrected, will prevent its recurrence and the occurrence of similar non- compliances. This root cause is the stopping point in the assessment of causal factors. It is the place where, with appropriate corrective action, the problem will be eliminated and will not recur. Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 8 of 11 4.3 Corrective and preventive actions This section in the CAPA template focuses on corrective and preventive actions. As defined in Article 2 (67) MDR and Article 2 (70) IVDR, a corrective action is ‘any action taken to eliminate the cause of a potential or actual non-conformity or other undesirable situation’. In case of an actual NC, CAPAs aim to prevent recurrence. The NB should select CAPAs that are appropriate to the classification and severity of the NC. These CAPAs should be comprehensive, outlining the actions identified to address the root causes and should describe any related preventive actions. For major NCs, the NB should also demonstrate evidence of implementation for both corrective and preventive actions. CAPAs consist of improvements to the NB’s processes to eliminate the causes of NCs, to correct and eliminate recurring NCs and to prevent a potential NC from occurring. The corrective actions identified to eliminate the causes of the NC should be clearly linked and consistent with the causes identified in the root cause analysis section. Corrective actions should address systemic issues. For example, simply changing a procedure and providing training to personnel on the revised procedure may not be appropriate or sufficient to address systemic issues that may have contributed to the NC. When identifying root causes and corrective actions, the NB should also consider whether potential NCs have not (yet) been identified and take preventive actions to avoid them. For example, if one of the causes was a lack of in-depth knowledge of a sterilisation method by the author of the sterilisation procedure, the NB should review other sterilisation procedures written by the same author and act (if appropriate), even if no NC was raised regarding these other procedures during the joint assessment. This approach ensures a comprehensive review of potential issues. In general, root cause analysis, corrections, corrective and preventive actions should address the actual NC and associated potential NCs throughout the NB’s QMS (e.g. site- specific procedures; amended SOP in one language which was not translated, leading to discrepancy between the same SOP in different languages). IMPORTANT Focus on Systems, Not Individuals: Identifying a staff member as being at fault is rarely the true root cause of non-compliance. Instead, focus on uncovering systemic issues that contribute to these situations. This approach leads to more effective corrective actions and prevents future occurrences. Beyond Restatement: Simply repeating or rewriting the non-compliance or explaining it is not acceptable as a description of the root causes. Effective root cause analysis delves deeper. Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 9 of 11 Distinguishing between correction, corrective action, and preventive action can be challenging, depending on the root cause. This document serves as a guide, not a rigid set of rules. When unsure about categorising an action when completing the CAPA template, it is suggested to primarily focus on its effectiveness in enhancing the system and include the action only once in the section in the CAPA template where the NB thinks it fits the best. In the above-mentioned example of a deficient checklist for assessing the validation of the sterilisation process: some of the actions can be considered a corrective action and/or a preventive action instead of a correction, depending on the root cause. 4.4 Actions for verification of effectiveness In this section of the CAPA template, the NB should detail the planned actions, including responsibilities and timelines, to verify the effectiveness of the implemented corrective actions and, where appropriate, preventive actions. The NB should define SMART criteria (Specific - targeting the identified root cause(s), Measurable, Achievable, Realistic and Time- bound) to determine if the NC has been effectively addressed. The NB should establish appropriate timeframes for scheduling effectiveness checks, considering the classification of the NC, the complexity of the implemented corrective actions and, where appropriate, the complexity of the implemented preventive actions. The timeframe should allow sufficient time Some tips on corrective actions Firstly, the NB should identify the corrective action(s) for each (root) cause and then ensure that they are feasible. For this reason, it may be useful to consider the following: - Will the corrective action prevent recurrence? - Is the corrective action feasible? - Do the corrective actions address all the causes? - Will training be required as part of the implementation? - In what time frame can the corrective actions be implemented? - What resources are required to successfully develop the corrective actions? - What resources are required for successful implementation and continued effectiveness of the corrective actions? - Is the implementation of the corrective actions measurable? (For example, “Ensure that the sequence of actions, properly detailed in the work instruction, is correctly performed in the future.” is not measurable.) If the corrective action is not feasible, re-evaluate it and identify other or additional actions that may be needed. As a result, document a list of action items in the corrective actions section in the CAPA template. This may include for example: − a detailed description of the implementation of regulatory requirements, − roles and responsibilities for conducting the action items, − identification of the resources required, − verification and/or validation protocols of the action(s) with acceptance criteria, − implementation plan, including deadlines. Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 10 of 11 for the implemented actions to take effect, typically ranging from several months to a year. Progress may be assessed during scheduled internal audits. The NB should verify and demonstrate that: − the cause has not recurred, − the NC has not recurred, − a similar NC has not occurred and − the corrective action remains effective and continues to be implemented. The NB should document the results of its verification of effectiveness in a clear and accessible manner for the DA. While the actions planned and the criteria which will be used for the verification of effectiveness are part of and should be documented in the CAPA plan, the verification of effectiveness itself falls outside the scope of the joint assessment and will be followed-up under the DA’s monitoring activities. 5 CONSIDERATIONS FOR THE DA It is important that the DA completes the relevant assessment section of the CAPA template in sufficient detail to ensure their assessment and opinion on the CAPA plan are clear and can be fully understood by the JAT, minimising the need for further requests for clarification. The process outlined in Section 2.3.2 of MDCG 2022-13 should be followed for the DA’s assessment of the CAPA plan. If a finding was classified by the DA as an observation, the DA should clearly communicate their expectations on how the NB should address the observation. After confirming the corrective and preventive action plan, if necessary following further successive requests for clarification or modifications from the NB, the DA should forward it to the JAT, together with its opinion thereon9. After receiving the JAT's subsequent review, documented in the appropriate template (Annex II), the DA should carefully consider the JAT's input, finalise their overall assessment of the CAPA plan, and provide feedback to the NB on JAT's review and any follow-up steps. If the JAT has requested further modifications, the DA may request a further update of the CAPA plan from the NB, as appropriate, and update its assessment in the CAPA template. An iterative process may result from this. The NB may update the CAPA plan (if applicable) and the DA may revise its assessment of this CAPA plan. This may result in a further request for clarification and/or modifications from the JAT. This process continues until both parties, DA and JAT, reach agreement on the CAPA plan which should ideally be reached early in the process. The assessment of its implementation can subsequently follow, possibly involving further iteration, before reaching agreement on the consideration of the NCs being satisfactorily addressed. 9 MDR Article 39 (7) / IVDR Article 35 (7) Medical Device Coordination Group Document MDCG 2024-12 applicable for  MDR  IVDR Page 11 of 11 For actions in the CAPA plan requiring implementation prior to the DA’s final report, the DA should document the verification (including identification of evidence, review and conclusions) in the CAPA template. This includes identifying the evidence reviewed by the DA and confirming that the actions were successfully implemented by the NB. Based on experience, providing relevant documentation from the NB demonstrating the implemented actions, along with DA’s assessment, to the JAT during the CAPA assessment phase can help avoid a negative JAT final opinion to the MDCG. Alternatively, if providing such documentation is impractical or not considered necessary, a more detailed description of the DA’s assessment of the implementation should be included in the template. This should include an accurate description of the actions, sufficient for the JAT to consider if it concludes with the DA’s assessment, e.g., that all the major NCs are resolved. 6 CONSIDERATIONS FOR THE JAT The JAT completes the JAT review template after receipt of each update of the CAPA plan, so that the JAT’s appraisal of the CAPA plan and of the DA’s opinion thereon is clear and can be fully understood by the DA. This includes any explicit request for further clarifications and modifications of the CAPA plan. For each NC, the JAT should indicate whether it: − accepts the CAPA plan, including the root cause(s), the correction(s) and corrective action(s), in line with the requirements of the Regulation and agrees with the DA's assessment of it, or − requests further clarification on the CAPA plan (e.g. the CAPA plan describes that a specific procedure will be updated, however detailed information on the planned changes in this procedure is missing), and/or − requests for modifications of the CAPA plan when it considers any corrections, root causes, corrective actions or other aspects to be unacceptable, insufficient or inadequate. These requests will be clearly documented and motivated in the JAT review template. The JAT will not review any of the NB's actions related to observations, nor any of the DA's opinions on them, as observations themselves do not breach a legal requirement. Medical Device Coordination Group Document MDCG 2024-XX Annex I applicable for  MDR  IVDR Page 1 of 3 ANNEX I: TEMPLATE CAPA PLAN AND ASSESSMENT THEREON PART I: Basic information BASIC INFORMATION Name of the national authority responsible for notified bodies: designating authority (DA) Name of the applicant conformity assessment body (CAB) or notified body (NB) (with the identification number) Reference number(s) DA DG SANTE F5 Date(s) of the on-site assessment Type of assessment MDR IVDR designation re-assessment extension of the scope of designation challenge to the competence of the notified body10 DA’s lead assessor JAT coordinator 10 Article 47(3) MDR or 43(3) IVDR assessment Medical Device Coordination Group Document MDCG 2024-XX Annex I applicable for  MDR  IVDR Page 2 of 3 PART II: CAPA plan and assessment thereon (to be copied and completed for each NC) CONFORMITY ASSSESSMENT BODY/ NOTIFIED BODY Where documents are provided, ensure they are clearly referenced, the document file names are understandable for the DA and JAT and the content is clear. Any abbreviations and acronyms should be explained upon first use. Non-compliance (NC) NC No: ……. of ……. Classification of the finding: Major NC Minor NC NB’s reference: Observation Insert NC details exactly as worded by the DA, without any modification: wording, legal reference and classification. Include the official DG SANTE translation of the NCs, if applicable and provided. Note that an observation (section 2.2.4 of MDCG 2022-13) is a finding that does not breach any legal requirement. While the NB may address observations, the DA may have specific expectations. The JAT will not review actions related to observations. Legal reference: Correction(s) Indicate the action(s) taken to eliminate the detected NC (also refer to section 4.1 for further guidance) Provide evidence of implementation (documents or adequate information) of the described correction(s) and containment action(s). Implementation target date: . . / . . / . . . . Responsibility: Root cause(s) Describe the outcome of the investigation of the NC, considering both the classification and the extent of the NC (e.g. single occurrence, reoccurrence, systemic issue) and identify the underlying cause(s). Refer to section 4.2 for further guidance. If applicable, also describe any potential causes that could lead to similar or related NCs. Corrective and preventive actions Provide a detailed description of the corrective action(s), i.e. the action(s) taken to eliminate the root cause(s) to prevent recurrence. Corrective action(s) should be appropriate to the classification of the NC. Provide evidence whenever relevant (e.g. in case of CAPAs linked to major NC). If applicable, provide a description of any preventive actions, i.e. any action(s) taken to eliminate the cause of a potential similar or related NC. (Also refer to section 4.3. for further guidance). Implementation target date: . . / . . / . . . . Responsibility: Actions for verification of effectiveness Provide a detailed description of the action(s) planned and the criteria which will be used for the verification of effectiveness of the implemented corrective and preventive actions. (Also refer to section 3.4 for further guidance). Implementation target date: . . / . . / . . . . Responsibility: Medical Device Coordination Group Document MDCG 2024-XX Annex I applicable for  MDR  IVDR Page 3 of 3 DESIGNATING AUTHORITY Assessment, confirmation and opinion Detail the assessment to determine if the NC has been appropriately addressed by the NB in the CAPA plan, based on the provided information and any necessary evidence. Indicate whether the actions described, and information provided, by the NB are deemed satisfactory before confirming the CAPA plan related to this NC. If the CAPA plan related to this NC cannot yet be confirmed and is therefore classified as unsatisfactory, explain the rationale for this classification, specify the elements needing further clarification and/or additional information required from the NB, including applicable deadlines. Request within a specified timeframe the NB for a revised CAPA plan, addressing the above- mentioned issues (see also section 2.3.2 of MDCG 2022-13). (For additional guidance, see section 4) Assessment and confirmation date(s): . . / . . / . . . . Opinion: Satisfactory Unsatisfactory Assessment of the implementation, where appropriate Where appropriate, insert details of assessment of implementation of CAPAs here, or write ‘Not applicable’ if not relevant. Assessment date(s): . . / . . / . . . . Opinion: Satisfactory Unsatisfactory Medical Device Coordination Group Document MDCG 2024-XX Annex II applicable for  MDR  IVDR Page 1 of 1 ANNEX II: TEMPLATE JAT REVIEW OF THE CAPA AND THE DA’S OPINION The JAT will indicate whether it agrees with the DA’s opinion, if clarifications are needed, or if any of the actions are not deemed as acceptable and therefore a modified CAPA plan should be submitted. An explanation should be provided in the latter cases. JAT's review of the CAPA and the DA’s opinion thereon Basic information Name of the national authority responsible for notified bodies: designating authority (DA) Name of the applicant conformity assessment body (CAB) or notified body (NB) (with the identification number) Reference number(s) of the Joint Assessment DA DG SANTE F5 Date(s) of the on-site assessment Type of assessment MDR IVDR designation re-assessment extension challenge to the competence of the notified body11 DA’s lead assessor JAT coordinator Current review Date of JAT's review: . . / . . / . . . . Reference to the latest D.A. response (e.g. Ares number): General comments and/or comments related to all NCs (if applicable) JAT review of the CAPA and the DA’s opinion thereon NC# JAT Comment Acceptance12 Closed Not (yet) closed Closed Not (yet) closed 11 Article 47(3) MDR or 43(3) IVDR assessment 12 See section 6 in the guidance: if ‘Closed’, the JAT accepts the CAPA plan and the DA’s opinion thereon for this NC. In the other case, the JAT motivates a request for further clarification or modification of this CAPA plan.

Medical Devices Medical Device Coordination Group Document MDCG 2024-10 1 MDCG 2024-10 Clinical evaluation of orphan medical devices June 2024 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 2024-10 2 Table of contents 1. Abbreviations and terminology ....................................................................................................... 3 2. Introduction .................................................................................................................................... 4 3. Scope ............................................................................................................................................... 5 4. Orphan device status and orphan indication .................................................................................. 6 PART A – Clinical Evaluation Considerations ......................................................................................... 9 5. The acceptability of limitations in pre-market clinical data ............................................................ 9 6. The role of non-clinical data.......................................................................................................... 10 7. Clinical evaluation overview.......................................................................................................... 11 8. Generating pre-market clinical data for orphan devices ............................................................... 13 9. Post market surveillance and PMCF for orphan devices ............................................................... 14 PART B – Procedural Considerations .................................................................................................... 17 10. Notified body activities and responsibilities ................................................................................. 17 11. Involvement of expert panels: advice on orphan device status and clinical evidence ................. 18 Appendices ........................................................................................................................................... 22 A.1. Clinical Evaluation Report ............................................................................................................. 22 A.2. Considerations for Clinical Investigations of Orphan Devices ....................................................... 24 A.3. Extrapolation of clinical data to orphan indications ..................................................................... 29 Medical Devices Medical Device Coordination Group Document MDCG 2024-10 3 1. Abbreviations and terminology For the purposes of this guidance document, the below terms are defined as follows: - AIMDD Active Implantable Medical Devices Directive, referring to Directive 90/385/EEC - Benefit-risk determination MDR Article 2(24) - CEP Clinical evaluation plan - CER Clinical evaluation report - Clinical benefit MDR Article 2(53) – may be direct or indirect (see MDCG 2020-6) - Clinical data MDR Article 2(48) - Clinical evaluation MDR Article 2(44) - Clinical evidence MDR Article 2(51) - Clinical investigation MDR Article 2(45) - Clinical performance MDR Article 2(52) - Custom made device MDR Article 2(3) - GSPR General Safety and Performance Requirements, per MDR Annex I - In house device A device that is manufactured and used only within a health institution established in the Union and that meets all conditions set in Article 5(5) of the MDR or IVDR (per MDCG 2023-1) - Intended purpose MDR Article 2(12) - IVDR In Vitro Diagnostic Medical Devices Regulation, referring to Regulation (EU) 2017/746 - Legacy device Device previously CE marked under Directives 93/42/EEC (MDD) or 90/385/EEC (AIMDD) and placed on the market or put into service after the MDR’s date of application pursuant to Article 120 MDR (per MDCG 2021-25) - MDCG Medical Device Coordination Group - MDR Medical Devices Regulation, referring to Regulation (EU) 2017/745 - MDD Medical Devices Directive, referring to Directive 93/42/EEC - Non-clinical data Any relevant data that does not meet the MDR definition of clinical data - Non-orphan Refers to a device, indication, or (sub)population which does not meet the definition of “orphan device”, “orphan indication”, or “orphan (sub)population”, respectively - Orphan device (OD) Device as described in section 4.1 of this document - Orphan indication As described in section 4.3 of this document - Orphan population As described in section 4.2.1 of this document - Orphan subpopulation As described in section 4.2.1 of this document - Performance MDR Article 2(22) - PMCF Post market clinical follow-up - MDR Annex XIV, Part B, section 5 - PMS Post market surveillance - MDR Article 2(60) - Risk MDR Article 2(23) - Similar device Devices belonging to the same generic device group (per MDR Article 2(7)). The MDR defines this as a set of devices having the same or similar intended purposes or a commonality of technology Medical Devices Medical Device Coordination Group Document MDCG 2024-10 4 allowing them to be classified in a generic manner not reflecting specific characteristics (per MDCG 2020-6) - Target population Group of individuals for which the medical device is intended 2. Introduction The level of clinical evidence that is required to place medical devices on the market has been increased by the MDR, including an increased need for pre-market clinical investigations for certain higher risk devices to verify their safety and clinical performance. These increased clinical evidence requirements present a challenge for devices specifically intended for use in rare diseases/conditions, or in specific indications for rare cohorts of patients with an otherwise non-rare disease/condition. By their nature, these ‘orphan devices’ are only intended for use in a small number of individuals each year. Many rare diseases have very few diagnostic or therapeutic options and the orphan device can be particularly crucial to fulfil an otherwise unmet medical need. In the absence of specific guidance for these devices, different understandings can emerge among manufacturers, notified bodies, and regulators on the clinical evidence requirements for these devices for the purposes of MDR certification. In many cases, orphan devices are intended for use solely or predominantly in minors and paediatric populations, and/or in emergency situations. Proactively generating clinical data within an appropriate time in small patient populations is particularly challenging, as is the case for vulnerable populations in light of the ethical and regulatory requirements to appropriately protect these populations1, as well as greater practical challenges of performing clinical studies in certain cohorts such as infants and children. The increased, and at times unpredictable, financial costs associated with compliance with MDR requirements, including MDR certification, can make it prohibitive for manufacturers to place orphan devices on the EU market, as the low volumes of sales may not offset the financial costs. Manufacturers also develop devices that have both ‘orphan’ and ‘non-orphan’ indications, used in separate and distinct population cohorts. For these devices, challenges may emerge in demonstrating sufficient pre-market clinical evidence for their orphan indication, similar to those challenges experienced for orphan devices. In such circumstances, where duly justified and without prejudice to the clinical evidence requirements for the device’s non-orphan indications, the principles outlined in this guidance are applicable to these devices for the purposes of supporting their orphan indications only. Given their unique challenges, and in the absence of specific provisions in the MDR, the application of MDR requirements to orphan devices should be balanced and proportionate in light of Article 35 of the Charter of Fundamental Rights (health care)2, so that the pre-market clinical evidence requirements are sufficiently met without unduly hindering or delaying patient access to these 1 In line with MDR Article 65 (clinical investigations on minors) and MDR Article 68 (clinical investigations in emergency situations). 2 Article 35 of the Charter of Fundamental Rights states: “Everyone has the right of access to preventive health care and the right to benefit from medical treatment under the conditions established by national laws and practices. A high level of human health protection shall be ensured in the definition and implementation of all Union policies and activities.” Medical Devices Medical Device Coordination Group Document MDCG 2024-10 5 important devices. As is described in section 5 of this document, there are circumstances where it is acceptable to place an orphan device on the market with limitations in pre-market clinical data. In such circumstances, it is important that there is an appropriate level of transparency for health care professionals, patients, and members of the public, so that they are aware of the orphan status of the device, any relevant limitations in clinical data, and any relevant conditions or provisions of certification that have been applied. In their August 2022 position paper3, the MDCG acknowledged the unique challenges facing orphan devices and the need to develop specific guidance for these devices. To that end, the MDCG convened a dedicated orphan device task force, which led the development of this guidance document in collaboration with stakeholder representatives including notified bodies, industry, academic societies, and healthcare professionals. To frame this guidance and to highlight the devices for which this guidance is intended, criteria have been developed that a device needs to meet to qualify for orphan device status. These criteria reflect the quantitative and qualitative characteristics of an orphan device, referring respectively to the relevant epidemiology, and to the insufficiency of alternatives and expected clinical benefit. This document is divided into two parts, and includes guidance on the following: PART A – Clinical evaluation considerations - The acceptability of limitations in pre-market clinical data for orphan devices, - Key considerations on the clinical evaluation of new and legacy orphan devices, - Generating post-market clinical data for orphan devices, including PMS and PMCF. PART B – Procedural considerations - Guidance for notified bodies on the assessment of orphan devices, - The role of expert panels in the context of orphan devices. There are three appendices to this document, which include guidance on: - OD-specific factors to include in the clinical evaluation report, - Consideration on clinical investigations of orphan devices, - Extrapolation of clinical data to orphan indications. 3. Scope This document provides guidance to manufacturers and notified bodies on the clinical evaluation pursuant to the MDR of medical devices and accessories for medical devices that qualify as ‘orphan devices’ (OD) and medical devices and accessories for medical devices that have an orphan indication, within the meaning of this guidance. This guidance is relevant to devices across all risk classes as per the classification rules defined in the MDR4. This guidance gives particular attention to the clinical evaluation and investigation requirements stated in MDR Chapter VI and Annex XIV for these devices. Where relevant, this guidance should be read in 3 MDCG 2022-14, point 18. 4 MDR Article 2 and Annex VIII; see MDCG 2021-24. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 6 conjunction with other MDCG guidance on the clinical investigation and evaluation of medical devices, including MDCG 2020-5, MDCG 2020-6, and MDCG 2023-7. Custom-made devices, in-house devices, products without an intended medical purpose listed in MDR Annex XVI and in vitro diagnostic medical devices are outside the scope of this guidance. Please note, this document gives guidance on the clinical evaluation of orphan devices which require clinical data to demonstrate conformity with GSPRs. Guidance is not provided in this document for those specific circumstances where MDR Article 61(10) applies to an orphan device. 4. Orphan device status and orphan indication 4.1. Orphan device criteria For the purpose of this guidance, a medical device or an accessory for a medical device should be regarded as ‘orphan device’ (hereafter also referred to as ‘OD’), if it meets the following criteria: • the device is specifically intended to benefit patients in the treatment, diagnosis, or prevention of a disease or condition that presents in not more than 12,000 individuals in the European Union per year5; and at least one of the following criteria are met: o there is insufficiency of available alternative options for the treatment, diagnosis, or prevention of this disease/condition, or o the device will offer an option that will provide an expected clinical benefit compared to available alternatives or state of the art for the treatment, diagnosis, or prevention of this disease/condition, taking into account both device and patient population- specific factors. It is important to note that the status as an orphan device does not confer market exclusivity for that device. For the sustainable development of orphan devices (and retention of legacy orphan devices), the criteria should not be interpreted so as to prevent more than one device in a given therapeutic area being designated as an OD. Similarly, the existence of an OD in a specific therapeutic area is not alone a reason to prevent a manufacturer from justifying OD status for another similar device intended for use in the same disease or condition. 4.2. Justification of orphan device status A manufacturer who claims that his device is an OD should provide information that supports the OD status. This information should be included in any documentation submitted to a notified body or an expert panel for the purpose of determining the OD status and, eventually, in the Clinical Evaluation Report (CER), see also section 11 and Appendix A.1. The information justifying the OD status should be based on scientific rationale addressing at least epidemiological and device-related considerations (see non-exhaustive guiding principles below). It is to be distinguished from the clinical evidence that is required for the purpose of conformity assessment. 5 Extrapolated from the population estimate criteria for Humanitarian Use Device (HUD) designation established by the U.S. Food and Drug Administration (FDA) and calculated on the basis of an EU population of 447 million, see www.fda.gov/regulatory-information/search-fda-guidance-documents/humanitarian- use-device-hud-designations http://www.fda.gov/regulatory-information/search-fda-guidance-documents/humanitarian-use-device-hud-designations http://www.fda.gov/regulatory-information/search-fda-guidance-documents/humanitarian-use-device-hud-designations Medical Devices Medical Device Coordination Group Document MDCG 2024-10 7 Manufacturers and notified bodies may seek advice from the expert panels on the OD status (see section 11). 4.2.1. Epidemiology of the disease or condition The manufacturer should provide a description of the specific disease/condition that presents in not more than 12,000 individuals in the EU per year for which the respective orphan device is intended to be used (hereafter referred to as ‘orphan population’). The manufacturer may also justify that the device is intended to be used to benefit patients in the treatment, diagnosis, or prevention of a disease or condition that presents in a clinically valid patient sub-population (not more than 12,000 individuals in the EU per year) within a disease or condition with an annual incidence of more than 12,000 in the EU (hereafter referred to as an ‘orphan subpopulation’). The manufacturer should provide documentation to support that it meets the epidemiological based criterion by way of population incidence estimates. It is acknowledged that documentation to support the incidence criteria will be limited in some cases. Authoritative references (e.g., from peer-reviewed medical literature and/or public health statistics) relevant to the EU population should be provided where available. The manufacturer may consider including additional supporting data for incidence estimates, for example from national level data, health service level data or from independent clinical experts or medical society consensus statements. Where data available to the manufacturer are limited, for example to national or regional level only, the OD status may be justified by providing an EU population incidence based on extrapolation and considering relevant factors including heterogeneity of the incidence across the EU. In cases where the device is intended to treat, diagnose, or prevent a rare disease as defined in the EU and affecting no more than 5 in 10,000 persons in the EU6, and where the device is expected to be used in not more than 12,000 such individuals per year, this can be accepted as sufficient justification of the epidemiological part of the criteria. For orphan subpopulations, the manufacturer should provide information to justify the existence of a valid orphan subpopulation for the purpose of justifying OD status for a device used in a disease/condition that presents in more than 12,000 individuals per year. This can include providing a scientific rationale for why the device is only intended for use within that subpopulation and the intended use would not be appropriate for the wider population with a non-rare disease/condition. Arbitrary limitations of use to only a subpopulation of patients to meet the incidence criteria will not be considered sufficient as it could be clinically appropriate to use the same device and therefore generate more clinical data in the remaining larger population with the non-rare disease or condition. Factors to consider when determining if a valid and medically plausible orphan subpopulation exists include device-specific factors such as mechanism of action, and patient-specific factors that make it medically plausible that the device is for use only for that specific subpopulation of patients. For 6 Pursuant to the Council Recommendation of 8 June 2009 on an action in the field of rare diseases (OJ C 151, 3.7.2009, p. 7), for the purpose of Union-level policy work a common definition of ‘rare disease’ as a disease affecting no more than 5 per 10,000 persons should be used. https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2009:151:0007:0010:EN:PDF Medical Devices Medical Device Coordination Group Document MDCG 2024-10 8 example, an OD may be intended for use in a paediatric subpopulation or in a subpopulation within a disease/condition based on device and patient factors that make it appropriate for use only in that valid subpopulation, for example based on diversity of anatomy7. Other patient factors may demonstrate a valid orphan subpopulation, for example, the benefit/risk of using the device may only be positive in a subpopulation of patients who are refractory to, or not medically suitable for, alternative treatments. Literature references and clinical expert statements should be provided where available to substantiate the justification. 4.2.2. Device description, insufficiency of alternatives, expected clinical benefit The manufacturer should provide a description of the device, its intended purpose, and a scientific rationale for why the proposed intended use is considered necessary or important in the context of the management of the orphan population (or orphan subpopulation) in question, with reference to device-specific factors. If relevant, the manufacturer may choose to describe a specific indication for use in addition to, or in place of, an intended use, to assist in providing this justification. The device description should include a description of the current state of the art and alternative therapies (if any, including the relative availability of alternatives) to justify the relevance of the intended use or indication. An explanation should be provided as to why the device would provide an expected clinical benefit compared to available alternatives or state of the art for the treatment, diagnosis or prevention of the disease/condition. Information from medical literature (for example clinical treatment guidelines) or consensus statements from clinical experts or medical societies, which may include patient representative groups, may be used to support the justification of the expected clinical benefit, for example where they detail relevant gaps in clinical management of the disease in the existing state of the art and why the therapeutic option to be provided by the proposed OD is needed. Relevant non- clinical and preliminary clinical data on the device, and/or data on similar devices, may be used in support of a statement that the OD will provide an expected clinical benefit. 4.3. Orphan indication In addition to devices considered to have OD status based on the criteria described in section 4.1, it is recognised that a device may have a specific intended purpose/indication for an orphan population, or orphan subpopulation, where the device also has another intended purpose/indication in larger patient populations. In such cases, where duly justified, the principles outlined in this guidance for demonstrating sufficient clinical evidence may be applicable to these devices for the purposes of supporting their orphan indication only and without prejudice to the clinical evaluation requirements for other intended purpose/indications in view of their certification in accordance with the MDR. In such cases the manufacturer should justify that the intended purpose in the orphan population, or orphan subpopulation, is sufficiently different to the other intended purpose/indications, such that the clinical evidence for the non-orphan intended purpose/indication(s) is not applicable and there is an authentic challenge to generating clinical data for the orphan indication. 7 For example, a cardiac valve implant may be intended to treat a rare subpopulation of patients with valvular disease which have specific anatomical characteristics, such as extreme ventricular outflow tract dilation. Other examples may include devices intended to treat a rare subpopulation of an otherwise non-rare condition, which requires definitive intervention in the neonatal population (e.g., a rare subpopulation of haemodynamically significant patent ductus arteriosus that requires acute surgical closure). Medical Devices Medical Device Coordination Group Document MDCG 2024-10 9 In the case of orphan indications, the extrapolation of (clinical) data available about the device intended for use in the non-orphan (e.g., adult) population may be of particular relevance. The appropriateness of extrapolation largely depends on - similarity between the existing non-orphan and orphan (sub-)population characteristics; - the quality of the available data in terms of study design, data collection, and measurement; - and whether the extrapolated evidence constitutes valid scientific evidence. Further considerations for extrapolation of data are provided in Appendix A.3. PART A – Clinical Evaluation Considerations 5. The acceptability of limitations in pre-market clinical data Having regard to the challenges to generate clinical data in the premarket phase, orphan devices may be granted market access with acceptable limitations in the amount and quality of pre-market clinical data, provided that appropriate measures are implemented, as described in this document. There must be sufficient clinical evidence to demonstrate an expected clinical benefit and that the device performs as intended with an acceptable level of safety. To address and resolve any limitations in pre- market clinical evidence as soon as possible, an adequate PMCF plan must be developed to ensure appropriate collection and generation of post-market clinical data. As with all devices, orphan devices must meet the GSPRs that apply to it8. For relevant GSPRs9, there must be sufficient clinical evidence to demonstrate conformity. The manufacturer must specify and justify the level of clinical evidence necessary for demonstrating conformity with those relevant GSPRs, taking into consideration the characteristics of the device and its intended purpose10. When specifying the level of clinical evidence necessary for an orphan device, important characteristics to consider include the clinical disease/condition being treated, the anticipated risks, the insufficiency of alternatives and unmet medical need, and the expected clinical benefit that the device offers, balanced against the anticipated risks. An overall evaluation should be completed, to determine and justify whether the current level of clinical evidence is sufficient for the purpose of placing the orphan device on the market. In general, a limited level of pre-market clinical data is acceptable for the purpose of conformity assessments pursuant to MDR Article 52 of an orphan device if the following can be justified for the orphan device in question: - all available non-clinical and clinical data relevant to the orphan device have been evaluated11, and any limitations in clinical data have been identified; - the existing non-clinical and limited clinical data is sufficient to demonstrate that the relevant GSPRs in Annex I MDR are met, that the benefit-risk ratio is acceptable, and that it is expected that the device will provide a clinical benefit taking into account the clinical condition, the state of the art, and the safety of patients; - it is not feasible or proportionate to generate further clinical data within an acceptable time frame in the pre-market setting; 8 Per MDR Article 5(2). 9 I.e. for those GSPRs where clinical data are needed to demonstrate conformity. 10 Per MDR Article 61(1). 11 Per MDR Annex XIV. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 10 - the manufacturer has an adequate PMCF plan that, once executed, will generate clinical data in an appropriate time frame that will fully address the remaining limitations in clinical data. - users of the device will be adequately informed (e.g. by provision of information in the IFU, SSCP (for implantable and class III devices), and/or other accompanying documentation) of the orphan status of the device, the limitations in pre-market clinical data, and instructions to users on how to report incidents, complaints, and other clinical experience to the manufacturer. For example, an orphan device might have known limitations with respect to clinical data confirming the long-term safety or performance of the device, but there may be sufficient clinical evidence for the purposes of market access, provided that the above listed points have been adequately justified, including the development of a PMCF plan that will collect long-term data in an appropriate way. While the general principles and methodology of the clinical evaluation process also apply for OD, the following sections will give granular detail on specific considerations for the clinical evaluation of orphan devices and its assessment by notified bodies. 6. The role of non-clinical data ‘Non-clinical data’ is understood as any relevant data that does not meet the MDR definition of clinical data12. This includes pre-clinical data as described in the MDR13. Non-clinical data can have a supportive role in establishing what the acceptable safety, performance and benefit-risk profile of the device will be. In addition to their role in pre-clinical evaluation, some non-clinical data may have a greater role in clinical evaluation of certain devices. The previously discussed limitations in the ability to generate pre-market clinical data increase the importance and relevance of robust, high-quality non-clinical data. All potential sources of non-clinical data should be considered for orphan devices. If the non-clinical data provide substantial high-quality evidence to support the safety and performance of the orphan device and its expected clinical benefit, this can reduce the burden of required pre-market clinical data and can help to justify CE marking with limitations in clinical data that can be met through PMCF activities. Useful sources of non-clinical data can include: - Results of laboratory and animal tests; - Data from computer modelling and simulated use testing, including software-based models, 3D printed models, and other physical models; - Data from ex vivo studies and cadaveric studies; - Data from similar devices (per MDCG 2020-5, section 5), for which equivalence is not demonstrated (not qualifying as clinical data per MDR); - Information with regard to the state of the art of the technology; - Datasets with previously collected information on patients’ health. These can be used to test the device without exposing patients, most commonly to validate software. - Any other relevant data involving humans, which does not qualify as MDR clinical data. 12 Per MDR Article 2(48). 13 MDR Annex II, section 6.1; MDR Annex XV, Ch II, section 2.3. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 11 The use of these data should be duly justified by providing clear explanation on their relevance with regard to the orphan device. 7. Clinical evaluation overview The requirements for the clinical evaluation of medical devices laid down in Article 61 and Annex XIV of the MDR also apply to orphan devices. These include the following steps: - establish and update a clinical evaluation plan; - identify relevant clinical data and any limitations in clinical data; - appraise all relevant clinical data; - analyse all relevant clinical data; - generate new or additional clinical data needed to address outstanding issues; - document this evaluation in a clinical evaluation report; and - update the clinical evaluation through PMCF activities. 7.1. Clinical evaluation plan The aspects listed below should be addressed when developing the clinical evaluation plan for orphan devices, as they are important factors that need consideration when determining the acceptability of limitations in pre-market clinical data. Disease-specific factors - Information on the relevant disease(s)/condition(s) o Epidemiology, including incidence supporting the OD status; o Patient population affected by the disease or condition where the OD is intended to be used, including vulnerable populations such as minors; o Severity of the disease/condition, including details on its morbidity and mortality; o Factors of the disease or condition that contribute to the challenges and difficulties to generate pre-market clinical data in this population, including (if applicable) legal or ethical challenges to conducting clinical investigations in relevant vulnerable populations. - Current state of the art in management of the disease/condition in question o Identify and describe all relevant alternative diagnostic and/or therapeutic options (if any) o Explain the relevant limitations (if any) in clinical management of the disease in the existing state of the art. Device-specific factors - Summary of supporting information to justify that the device meets the criteria for orphan device status, as described in section 4; - Summary of pre-clinical evaluation, including relevant non-clinical data; - Justification for acceptability of limitations in pre-market clinical data, as described in 5. 7.2. Identifying, appraising, and analysing clinical data As with all medical devices, the clinical evaluation of orphan devices requires appropriate identification of relevant clinical data, appraisal of the quality and scientific validity of each data source, and analysis of the results and conclusions of these data sources. These steps should be followed when evaluating Medical Devices Medical Device Coordination Group Document MDCG 2024-10 12 clinical data for the device, e.g. from previous clinical investigations and studies, previous use under derogations/compassionate use, use in the post-market setting (e.g. data from use in the EU for legacy devices, data from devices already in use outside of the EU). Once all existing non-clinical and clinical data have been evaluated, the manufacturer should be able to determine the following, regarding their device: - which GSPRs and clinical evidence requirements have been met, in total or in part, through existing non-clinical and clinical data, - which requirements (if any) require additional clinical evidence, either pre-market or post- market, to fully meet these requirements. - what are the current limitations in clinical data. By knowing the current limitations in clinical data, the manufacturer can generate additional clinical data in a focussed manner to address those specific limitations, with objectives and endpoints that specifically aim to address those limitations. It may be acceptable for some limitations in clinical data to be addressed through specific PMCF activities. 7.3. Clinical evaluation of orphan devices which are legacy devices A substantial group of orphan devices also qualify as legacy devices, here referred to as ‘legacy orphan devices’. Thus, in addition to the guidance in this document, the detailed guidance on clinical evidence requirements for legacy devices, including those outlined in MDCG 2020-6 and MDCG 2023-7, are directly relevant to this group of orphan devices. The following observations should be noted regarding orphan devices which are legacy devices: 7.3.1. Sufficient clinical evidence For orphan devices which are legacy devices, it may be justifiable to generate some or all new clinical data in the post-market phase following CE-marking under the MDR, provided that the guidance and provisions outlined in this document are appropriately followed. 7.3.2. Data from clinical investigations and legacy orphan devices As outlined in MDCG 2023-7, the requirement for a pre-market clinical investigation specified in MDR Article 61(4) does not apply to legacy devices, provided they can otherwise demonstrate sufficient clinical data (per MDR Article 61(6)a). This clinical data can include data from prior use under the AIMDD or MDD, such as PMCF data, PMS safety data, retrospective studies of registry data, data from previous independent research, etc. Further guidance is outlined in MDCG 2020-6. 7.3.3. Clinical data from equivalent devices Orphan devices, like all devices, may avail of the MDR provisions for equivalence, in line with the requirements laid out in MDR Article 61 and Annex XIV. In some circumstances, a manufacturer of an orphan device which is a legacy device may intend to demonstrate equivalence with a device or devices that are no longer on the EU market. Manufacturers should refer to MDCG 2020-5 and MDCG 2023-7 if considering the use of equivalence as a source of clinical data for a legacy orphan device. 7.3.4. Clinical data from off-label use For certain legacy devices, there may be circumstances where the device has been systematically used off-label for an orphan indication by the clinical community across the EU/world for many years, to the Medical Devices Medical Device Coordination Group Document MDCG 2024-10 13 extent that it is now considered by clinical experts as part of best clinical practice for the management of that disease or condition. As such, there may be an existing substantial body of clinical data, e.g. real-world data, supporting this indication as part of the clinical evaluation. In some circumstances, it may not be feasible or appropriate to conduct a clinical investigation prior to extending the intended purpose for these devices, for example, where there is a lack of equipoise in the clinical community and the clinical evidence demonstrates that the off-label use is standard clinical practice and offers clinical benefit above any available alternative therapeutic options. In such circumstances, with respect to the MDR clinical evidence requirements, it might be acceptable to consider clinical data from off-label use when considering revision or expansion of a device’s intended purpose to include this use/indication, provided that (in addition to the guidance stated in this document): - the decision to not perform a clinical investigation is justified and compliant with relevant MDR requirements14; - the off-label clinical data is of sufficient amount and quality to allow clinical evaluation and notified body assessment; and - the PMCF plan sufficiently justifies how the limitations in clinical data will be addressed through PMCF activities. Please note, this scenario is only foreseen for exceptional cases of legacy orphan devices or orphan indications with respect to legacy devices and is not expected to apply to new orphan devices. 8. Generating pre-market clinical data for orphan devices For ODs which are implantable devices and/or class III devices, MDR Article 61(4) requires the performance of clinical investigations, unless one of the exemptions laid down in MDR Article 61(4), (5) or (6) applies15. Clinical investigations of orphan device can be challenging to perform due to the limited numbers of affected subjects and the scarcity of the available data. When designing a clinical investigation for orphan devices, involvement of appropriate clinical experts should be sought to ensure the study is appropriately designed to reflect the clinical needs of the target population. In addition, engagement with patients, patient associations, parents and/or caregivers of the target population may also be helpful in confirming whether the study includes patient-relevant clinical outcomes. When designing a clinical investigation for orphan devices, potential recruitment challenges and sample size implications should be taken into account. Strategies should be considered on how best to recruit and retain patients, considering the geographical distribution and potential logistical challenges. Efforts should be made to collaborate with multiple centres where appropriate and proportionate to ensure sufficient participation and to enhance the potential for generalisability of results. Appendix A.2 provides further considerations that should be made when designing a clinical investigation for orphan devices, with particular attention to: 14 Including MDR Article 61(4)-(6), see MDCG 2023-7. 15 See MDCG 2023-7. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 14 - Defining the study population - Selecting appropriate objectives and endpoints - Choice of study design - Choice of comparator - Study monitoring For the clinical evaluation of orphan indications, it may be appropriate to avail of clinical data extrapolated from the use of the device in other, non-orphan populations. Considerations on the appropriate extrapolation of these data are outlined in Appendix A.3. 9. Post market surveillance and PMCF for orphan devices The specific characteristics of orphan devices and the limitations in pre-market clinical data make the post-market surveillance and clinical follow-up processes more important for the life-cycle evaluation of orphan devices. If pre-market limitations in clinical data have been identified and deemed acceptable (as described previously), it is important that these limitations will be filled through well-defined and structured PMCF activities. Therefore, for orphan devices, the manufacturer must have an appropriately structured and detailed PMCF plan which is subject to notified body review in line with the conformity assessment pursuant to MDR Article 52. It should be ensured and verified that the PMCF plan is implemented and followed to completion, otherwise increased reliance on post-market clinical data collection could undermine patient safety if necessary and timely data collection does not take place. The PMCF plan should include information about: - All limitations in clinical data identified pre-market, that need to be addressed, - Justification as to how the PMCF activities will address these specific limitations, - The type of data to be generated in the post-market phase to further evaluate the clinical performance and safety of the device, - How these data will be generated in an appropriate time frame, including projections on the numbers of patients that will be managed with the device per year, and pre-defined milestones on the periodic analysis of these data, where appropriate. This may include data collected from PMCF investigation(s), registries or other clinical data and clinically relevant information in the post-market setting, including real-world data, as described below. It should be noted that PMCF investigations and registries are not necessarily both required. Depending on the limitations in pre-market clinical data and the reliance on PMCF to address these limitations, it may be appropriate for specific conditions or provisions to be defined by the notified body for the certification of these devices16. For example, it may be appropriate for specific PMCF activities and milestones to be required by the notified body as specific provisions of certification of the device. When developing a PMCF plan, due consideration needs to be given with respect to the potential challenges that may be faced during execution of the PMCF plan, which may require adjustment of the 16 See MDR Article 56(3) and Annex VII, section 4.8. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 15 expected time frame and milestones for the collection of post-market clinical data. To this end, continued structured dialogue between the manufacturer and the notified body may be appropriate to discuss any challenges faced with respect to delivery of the PMCF plan. 9.1. PMCF and benefit-risk determination The data generated from PMCF is important to enable the continued assessment of the benefit-risk profile of orphan devices with a higher degree of certainty. Thus, it will be important to develop a detailed risk management plan adapted to the unique characteristics of the orphan device, its intended use, and the limitations in pre-market clinical evidence. This plan should outline how risks will be monitored, assessed, and mitigated throughout the PMCF, and outline how the manufacturer will take appropriate action where this data raises new concerns regarding the safety or performance of these devices. 9.2. PMCF investigations The considerations outlined in Appendix A.2 on clinical investigations with orphan devices also apply for PMCF investigations and should be taken into account. Furthermore, in addition to the general requirements and expectations for PMCF investigations, particular attention should be made for PMCF investigations with orphan devices in the following areas: - Consider any possible condition(s)/specific provision(s) provided by the notified body in the certification and their impact on the PMCF investigation. - Consider how the proposed study will address any limitations in clinical evidence identified in the pre-market phase. - Orphan devices may require long-term follow-up studies to assess the durability of the device's benefits and to identify any potential long-term safety concerns. While pre-market studies may include limited follow-up periods, PMCF investigations should allow for continuous monitoring and evaluation of orphan devices over extended periods of time. Long-term follow- up is especially important in diseases or conditions with slow progression or where the benefits of the device may manifest over an extended period. - Where possible, for the duration of recruitment into a PMCF investigation, the manufacturer should plan to enrol a representative majority (e.g. greater than 90% where feasible17) of patients exposed to the device in each investigational site. This is particularly important for devices that carry significant risks (i.e. high residual risks or risks of causing serious adverse events). - In addition to collecting objective clinical data reflecting safety and performance, PMCF studies may also capture, as secondary endpoints, real-world usability data from the user/healthcare professional perspective and/or considering need for additional usability studies in case pre- market data are incomplete due to not being able to replicate the real-life conditions of use (see also section 9.4). 9.3. Registries In relation to orphan devices, registries are considered as a valuable tool in building a broad and comprehensive knowledge base for these often-heterogeneous diseases. As such, it is recommended that orphan devices are enrolled in registries as part of PMCF plan where appropriate and feasible. 17 See IMDRF Principles of International System of Registries Linked to Other Data Sources and Tools (2016). Medical Devices Medical Device Coordination Group Document MDCG 2024-10 16 As part of PMCF, the manufacturer should identify and/or support the development of suitable registries for collecting sufficiently representative (e.g., greater 90% where feasible) data on patients with the disease/condition as well on those receiving the specific orphan device, with the aim of comparing outcomes in patients treated and not treated with the OD across Europe. Where available and suitable, manufacturers are strongly encouraged to use registries established and governed by national bodies or speciality medical associations. The manufacturer should substantiate and justify why chosen registries are suitable for providing this data and how they will address the identified limitations in pre-market clinical data. The manufacturer should use available guidance and suitable methodologies to demonstrate sufficient access to, and quality of, the data within the registries, for the purposes of confirming the safety and performance of the device throughout the device’s life cycle. 9.4. Other post-market clinical data and post-market surveillance In the post-market setting, clinical data can be collected from sources other than through PMCF clinical investigations. These sources are often referred to as ‘real world data’ and can be used to generate ‘real world evidence’. This clinical data is collected in the post-market setting (e.g., during PMS or certain PMCF activities like registries), during the routine use of the device in clinical practice. As with all devices, manufacturers of orphan devices must have an appropriate PMS system in place18. In addition to the PMCF activities discussed above, the clinical data collected from PMS should be evaluated as appropriate, as part of the life-cycle evaluation of these devices. The target population of an orphan device can be geographically, ethnically, and physiologically diverse. The evaluation of real-world data can help to detect rare complications and understand factors such as ethnicity, which may affect the clinical performance of the device. This data is of particular relevance to legacy orphan devices and should be considered where available, provided that the clinical data is of sufficient quality for the purpose of clinical evaluation and assessment. 18 Per MDR Article 83. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 17 PART B – Procedural Considerations 10. Notified body activities and responsibilities 10.1. Notified body activities prior to the certification The OD status of the device should be checked by the notified body as early as possible, for example as part of structured dialogue19 before or during initial conformity assessment activities. This should be based on the justification and information provided by the manufacturer (see section 4.2) and, if applicable, advice provided by an expert panel to the notified body or the manufacturer (see section 11). When the orphan device status is established, the technical documentation should be assessed following the same principles as for non-orphan medical devices. However, when assessing the manufacturer’s clinical evaluation plan and clinical evaluation report (CER), the product reviewers/clinical experts should consider the aspects addressed in this guidance, including the acceptability of limited pre-market clinical data and appropriate PMCF activities to generate additional clinical data. The notified body’s assessment of the CER should address the information supporting the orphan device status and, where applicable, the rationale for accepting limitations in the pre-market clinical data and the activities proposed by the manufacturer in its PMS plan and PMCF plan to obtain the necessary additional clinical data. 10.2. Specific conditions/provisions for certification The MDCG acknowledged in its position paper MDCG 2022-14, point 17 that the use of certificates with conditions will contribute to increasing the necessary flexibility to apply the reinforced clinical evidence requirements to devices that have a demonstrable track record of safety. Orphan devices for which the pre-market clinical evidence is deemed sufficient but needs to be completed or confirmed through PMCF, are a good example where notified bodies can make use of the possibility to issue certificates with specific conditions or provisions. Specific conditions or provisions20 may consist, for example, in requiring the manufacturer: - to conduct defined PMS or PMCF activities21 within a specified period of time to generate additional clinical data (see section 9), - to adequately inform users of the device of the orphan status of the device, the limitations in pre-market clinical data, and instructions to users on how to report incidents, complaints, and other clinical experience to the manufacturer, e.g. by provision of information in the IFU, SSCP (for implantable and class III devices) and/or other accompanying documentation (see section 5). 19 As described in MDCG 2022-14, point 15. 20 Per MDR Annex VII section 4.8, the notified body shall have procedures in place to allow them to decide on specific milestones for further review by the notified body of the up-to-date clinical evaluation (3rd indent) and to decide whether specific conditions or provisions need to be defined for the certification (4th indent). 21 In accordance with MDR Article 56(3), notified bodies may require manufacturers to undertake specific PMCF studies pursuant to MDR Annex XIV, part B. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 18 10.3. Surveillance by the notified body The notified body should consider PMS data, in particular the main findings from PMCF as part of the agreed surveillance activities and PSUR evaluation pursuant to MDR Article 86, and verify whether the device’s benefit-risk profile continues to support the placing of the device on the market. As part of their surveillance activities and post-certification monitoring, notified bodies need to monitor compliance with any conditions/provisions that are binding for the manufacturer and associated with the certification decision, such as updates to clinical data at defined intervals22. Where applicable, especially if listed as part of the conditions for certification, the notified body also needs to review the clinical evaluation that the manufacturer has updated based on its PMS, PMCF23. When the conditions/provisions on the certificates are not fulfilled/met by the manufacturer, the notified body should consider the impact thereof on the certificate’s validity, as specified in their procedures. Not fulfilling the conditions/provisions could ultimately lead to suspension or withdrawal of the certificate. 11. Involvement of expert panels: advice on orphan device status and clinical evidence While it rests with the manufacturer to demonstrate that its device meets the criteria for orphan device status, the expert panels established in accordance with MDR Article 10624 may be requested to provide advice on the orphan device status and the clinical data needed for the clinical evaluation. 11.1. Consultation of expert panel The consultation of an expert panel in relation to an orphan device described in this section is optional/voluntary and independent of the clinical evaluation consultation procedure (CECP) provided for in MDR Article 54(1). The following paragraphs address different scenarios for the consultation of an expert panel depending on the state of advancement of the device development or the conformity assessment. To improve predictability with respect to clinical evidence requirements, a manufacturer or notified body may seek independent advice from an expert panel as to whether its device meets the criteria of an orphan device as early as possible. 11.1.1. Early scientific advice pursuant to MDR Article 61(2) Article 61(2) MDR provides the possibility for a manufacturer, prior to its clinical evaluation and/or investigation, to consult an expert panel with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation. The scope of MDR Article 61(2) is limited to class III devices and class IIb active devices intended to administer and/or remove a medicinal product. The orphan device status will influence the expected level of pre-market clinical evidence, notably the justification for limitations in the pre-market clinical evidence and an acceptable level of pre-market 22 See MDR Section 4.10 of Annex VII (1st subparagraph, 1st indent). 23 See MDR Section 4.10 of Annex VII (4th subparagraph, 1st indent). 24 See more information about expert panels on the Commission’s website and on the website of the European Medicines Agency (EMA), which provides the expert panels’ secretariat. https://health.ec.europa.eu/medical-devices-expert-panels_en https://www.ema.europa.eu/en/human-regulatory-overview/medical-devices#ema-inpage-item-13045 Medical Devices Medical Device Coordination Group Document MDCG 2024-10 19 clinical uncertainty (see sections 3-7 of this guidance). It is therefore recommended that manufacturers of devices that fall within the scope of MDR Article 61(2) and that may qualify as OD consult an expert panel on their intended clinical development strategy in accordance with MDR Article 61(2). This advice procedure may be particularly useful for new orphan devices. Where a request for such an early scientific advice concerns an orphan device, the expert panel will, as a necessary first step, assess the manufacturer’s justification regarding the orphan device status. In a second step, the expert panel will review the manufacturer's intended clinical development strategy and proposals for clinical investigation, which – for orphan devices – may particularly include proposals for PMCF. Pursuant to MDR Article 61(2), the manufacturer shall give due consideration to the expert panel’s views on the orphan device status and on its clinical development strategy and document this consideration in its clinical evaluation report. 11.1.2. Advice in cases where the clinical evaluation is in an advanced stage or completed The early scientific advice pursuant to MDR Article 61(2) would be too late for manufacturers who have already drawn up their clinical evaluation report or are in an advanced stage with their clinical evaluation. Having regard to the deadline for lodging applications for conformity assessment by 26 May 2024 in accordance with MDR Article 120(3c), point €25, this will be the case for many legacy devices, but it is not limited to them. In those cases, an expert panel’s advice regarding the orphan device status and regarding the clinical data required for the clinical evaluation of a device may be requested by a notified body in accordance with MDR Article 106(11) in the framework of an ongoing conformity assessment procedure (see below point (a)). In exceptional cases the manufacturer may request advice from an expert panel on the orphan device status and the clinical data required for its clinical evaluation, even though the clinical evaluation is in an advanced stage or already completed (see below point (b)). The scope of the expert panel advice will depend on the request made by the notified body or the manufacturer: it may concern only the OD status, or it may also concern the clinical data required for the manufacturer’s clinical evaluation, including any justification regarding limited clinical data, the acceptability of clinical uncertainty and proposed post-market clinical follow-up activities. (a) Advice requested by a notified body The notified body involved in the conformity assessment of a device for which the manufacturer claims an orphan device status may seek advice from an expert panel in accordance with MDR Article 106(11). Before submitting such a request, the notified body should consult the manufacturer, for example to inform them of their plan to request advice from the expert panel and where appropriate to give the manufacturer the opportunity to provide input into the request. Having regard to the limited capacity of the expert panels, notified bodies are advised to reach out to the EMA expert panel secretariat as early as possible to include an envisaged request for advice in the expert panels’ planning. 25 The lodging of a formal application for conformity assessment is one of the conditions to benefit from the extended transitional period provided for in MDR Article 120. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 20 The request for advice from the notified body may concern the orphan device status and possibly also the clinical data required for the manufacturer’s clinical evaluation, including any justification provided by the manufacturer regarding limited clinical data, the acceptability of clinical uncertainty and proposed post-market clinical follow-up activities. For that purpose, the notified body should put forward to the expert panel specific questions for which it seeks the panel’s advice. Those questions should be based on a preliminary analysis of the clinical evaluation provided by the manufacturer. To ensure a consistent approach in the conformity assessment of orphan devices, the MDCG encourages notified bodies to make use of this consultation , particularly in those cases where the notified body does not agree with the manufacturer’s claim that the device qualifies as an orphan device, or if it is uncertain in this regard, unless an expert panel has already provided advice on the orphan device status to the manufacturer. In those cases, the notified body should consult the expert panel at an early stage of the conformity assessment procedure, e.g. in the application review phase. Where the requested advice concerns the clinical evaluation, the notified body should determine the timing of the consultation in agreement with the manufacturer depending on how it fits best in the overall conformity assessment procedure. The notified body will need to include the expert panel’s considerations in its clinical evaluation assessment report. If the notified body has a different view than the expert panel, it should give reasons for such divergent views in its clinical evaluation assessment report. (b) Advice requested by the manufacturer As an extraordinary measure during the MDR transitional period, which ends on 31 December 2027 or 31 December 2028 depending on the device’s risk class, a manufacturer who has already completed its clinical evaluation, or is in an advanced stage with it, may request advice from an expert panel on the orphan device status and possibly also on the clinical data required for the clinical evaluation, provided that the request for an expert panel advice does not interfere with the assessment by the notified body. To avoid any overlap with the technical documentation assessment by the notified body, a manufacturer should only request advice from an expert panel if it will be able to update its clinical evaluation report taking into consideration the expert panel’s views, before the notified body assesses the manufacturer’s clinical evaluation26. The manufacturer’s clinical evaluation plan or its draft clinical evaluation report could be suitable documents to be submitted with the request. The manufacturer should inform the notified body about the request and about any advice provided by the expert panel, for example, in its application for conformity assessment. The manufacturer should make the expert panel advice available to the notified body, for example as an annex to the clinical evaluation report. 26 This possibility may be particularly useful for orphan devices for which the manufacturer has not yet submitted its clinical evaluation report to the notified body. As explained in section 8 of the Q&A on practical aspects related to the implementation of Regulation 2023/607, for the purpose of meeting the conditions for the extended MDR transitional period, the manufacturer’s application does not necessarily include the documentation that the notified body does not need for the conclusion of the written agreement and that is likely to be updated by the manufacturer before the actual conformity assessment. https://health.ec.europa.eu/system/files/2023-07/mdr_proposal_extension-q-n-a.pdf Medical Devices Medical Device Coordination Group Document MDCG 2024-10 21 If the manufacturer intends to request advice from an expert panel after it has already lodged an application to a notified body, the manufacturer and notified body should agree that the expert panel consultation does not interfere with the notified body’s assessment. If this cannot be ensured, a consultation of the expert panel should be left to the notified body pursuant to MDR Article 106(11). 11.2. Timelines for expert panel’s advice The MDR does not set a deadline for expert panels to provide their advice. However, Table 2 of the Commission Implementing Decision (EU) 2019/1396 as regards the designation of expert panels in the field of medical devices27 lays down the maximum number of days for which experts may be remunerated for certain tasks, such as scientific advice, distinguishing between simple matters, complex matters, and very complex matters. 11.2.1. Early scientific advice pursuant to MDR Article 61(2) For early scientific advice under MDR Article 61(2), EMA’s expert panels’ secretariat has set up a process consisting of different steps which aims to ensure that the applicant manufacturer submits an appropriately prepared request and that the expert panel provide its advice in a timely manner. 11.2.2. Advice in cases where the clinical evaluation is in an advanced stage or completed Where the expert panel advice is limited to the question whether a device meets the criteria of an orphan device, the expert panel will endeavour to provide its advice within 60 days. Where the expert panel advice concerns both the orphan device status and the clinical data used by the manufacturer for its clinical evaluation, the expert panel will endeavour to provide its advice within 90 days provided it is simple advice. The advice should clearly distinguish between the expert panel’s views on the orphan device status and its views on clinical data related aspects. If considered appropriate by the expert panel, it can provide its advice in two steps: first advice on the orphan device status (to be provided within 60 days) and second advice on the clinical data used by the manufacturer for its clinical evaluation (to be provided within 60 days from the date of the issuance of the advice on the orphan device status, if it is simple advice as mentioned before). 11.3. Relationship with CECP The CECP provided for in MDR Article 54(1) may apply to a device for which the manufacturer or a notified body have requested expert panel advice in accordance with this guidance. In such a case, the expert panel advice and how it has been taken into consideration by the manufacturer or the notified body should be reflected in the notified body’s clinical evaluation assessment report that is submitted for CECP. The notified body should indicate in their CECP submission if the device has been subject to a voluntary advice procedure28. 27 Commission Implementing Decision (EU) 2019/1396 of 10 September 2019 laying down the rules for the application of Regulation (EU) 2017/745 of the European Parliament and of the Council as regards the designation of expert panels in the field of medical devices (OJ L 234, 11.9.2019, p. 23). 28 See also MDCG 2020-13, section K. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 22 Appendices A.1. Clinical Evaluation Report A.1.1. OD-specific information to be included in the CER As part of the general requirements regarding the CER for all devices, the manufacturer should ensure that the CER includes summary descriptions of the orphan device-specific considerations laid out in this guidance, including: - summary of how the device meets the criteria for orphan device status, per section 4; - summary of any identified limitations in clinical data and residual risks, including a description of how these were identified; - acceptability of these limitations in clinical data and residual risks, per section 5, with particular justification that: o all available non-clinical and clinical data relevant to the orphan device have been evaluated29, and any limitations in clinical data have been identified; o the existing non-clinical and limited clinical data is sufficient to demonstrate that the relevant GSPRs in Annex I MDR are met, that the benefit-risk ratio is acceptable, and that it is expected that the device will provide a clinical benefit taking into account the clinical condition, the state of the art, and the safety of patients; o it is not feasible or proportionate to generate further clinical data within an acceptable time frame in the pre-market setting; o the manufacturer has an adequate PMCF plan that, once executed, will generate clinical data in an appropriate timeframe that will fully address the remaining limitations in clinical data. o users of the device will be adequately informed (e.g. by provision of information in the IFU, SSCP (for implantable and class III devices), and/or other accompanying documentation) of the orphan status of the device, the limitations in pre-market clinical data, and instructions to users on how to report incidents, complaints, and other clinical experience to the manufacturer. - summary of the applicable non-clinical data that was evaluated as part of clinical evaluation planning as outlined in section 6; - summary of pre-market clinical data that have been identified and evaluated, including any clinical investigations, with due regard to sections 7 and 8 and Appendix A.2; - a clear, stringent, and detailed PMCF plan30 with due regard to section 9, including: o summary of the risk management plan as described in section 9.1. o description of the type and quality of data that needs to be generated in the post- market phase in order to further evaluate the clinical performance and clinical safety of the device and address identified limitations in clinical data; 29 Per MDR Annex XIV. 30 This may be documented in the CER or as a separate ‘PMCF Plan’ document that is referenced in the CER. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 23 o description on how the manufacturer plans to generate these data in an appropriate, timely manner; o projections on the number of patients that will be managed with the device per year in the EU; o a summary of planned PMCF activities including, as applicable, PMCF investigations and registries in the EU and globally for this device; o for orphan devices that carry significant risks (i.e. significant residual risks and/or high risk of causing serious adverse events), confirmation that the manufacturer will prospectively enrol a representative majority (e.g. greater than 90% if feasible) of patients into PMCF activities including PMCF investigations and/or registries; - summary of any interactions with expert panels as described in section 11; - a plan to update the clinical evaluation report at pre-defined intervals as appropriate, based on the PMCF plan, and whenever new information becomes available that may change the benefit-risk profile of the device. A.1.2. Post-market updates to the CER As part of updates to the CER in the post-market setting, the following OD-specific information should be highlighted and kept up to date as necessary, based on latest available information: - up-to-date information with respect to the orphan device status, per section 4, - total product sales in the EU and worldwide, - summary of state of the art, highlighting any changes to available alternatives (if any), - updates on clinical evidence including any changes to limitations in clinical data, - summary of up-to-date determination of benefit-risk ratio, - summary report of ongoing PMCF activities and their progress towards addressing limitations in pre-market clinical data. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 24 A.2. Considerations for Clinical Investigations of Orphan Devices A.2.1. Introduction The purpose of this section is to provide illustrative examples of different approaches and considerations that device developers could consider when designing a clinical investigation of an orphan device. It is not intended to be an exhaustive or prescriptive list of requirements with respect to study characteristics. As with all clinical investigations, it is expected that clinical investigations of orphan devices will be designed and conducted in compliance with the relevant MDR requirements and in line with relevant good clinical practice principles, including an appropriate level of engagement with stakeholder groups such as clinicians, users, and patient representatives. For more guidance on clinical investigations, please also refer to MDCG 2021-6 rev. 1, MDCG 2024-3, and MDCG 2024-5. A.2.2. Defining the study population Careful definition of the study population is key. For orphan devices the target population is small (i.e. not more than 12,000 individuals per year) and may be vulnerable, for example infants and children. The fact that rare diseases/conditions usually affect patients from birth makes circumstances even more complex. To this point, inclusion and exclusion criteria should be wide enough to enrol the maximum number of target population without being too general in the sense that it may introduce too much variability (i.e., heterogeneity or 'noise') and obscure the clinical investigation results. Many orphan devices are used in vulnerable populations, and thus it is anticipated and expected that clinical investigations may include these vulnerable populations, where appropriate. In these cases, the requirements set out in MDR Articles 64 – 68 relating to inclusion of vulnerable populations must be met. A.2.3. Objectives For many orphan devices, it may be suitable for the primary objectives of their pre-market clinical investigation(s) to focus on assessment of short- to medium-term clinical benefit, patient safety, and benefit-risk ratio. Additional objectives should focus on the short- to medium-term performance and technical success of the procedure and device. For PMCF investigations, the objectives should aim to evaluate the overall safety, performance, and clinical benefit of the device throughout its life cycle, with a suitable focus on long-term endpoints. A.2.4. Selection of endpoints Clinical performance endpoint(s) should be predefined on the basis of relevant indicators to assess the clinical outcome, safety, and clinical benefit. The appropriateness and relevance of the chosen endpoints should be clearly justified in the clinical investigation plan (CIP), to help regulatory authorities, notified bodies, and expert panels (as applicable) understand and accept these endpoints. Continuous monitoring of safety through regular reporting serious adverse events is a key endpoint throughout the evaluation program. Secondary endpoints can also be included to further establish the overall clinical benefit of the device. Although disease-specific clinical endpoints remain the standard, such endpoints may not be sufficiently established, understood, or validated in the clinical setting for certain conditions involving orphan devices. In this regard, appropriately validated surrogate endpoints can be considered, if justified. In these cases, relevant disease-specific clinical endpoints should subsequently be investigated, where possible, in the post-market setting, e.g., in PMCF investigations. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 25 When selecting endpoints to investigate clinical benefit, it is important to identify and consider the priorities and unmet medical needs from the perspective of the patient. To that end, patient-reported outcomes (PROs) and other patient-centric measures can be considered for inclusion as secondary/exploratory outcomes and endpoints. These can help to assess the impact of the device on the quality of life and daily functioning of the patient. However, it is acknowledged that, by their nature, PROs can be vulnerable to bias and confounding factors, and so, they should only be relied upon as primary endpoints for evaluating clinical benefit in exceptional circumstances where it can be justified that other, objective clinical performance outcomes and endpoints cannot be collected in the target population, and where the study also includes adequate, objective safety endpoints. When considering the inclusion of PROs and other clinically relevant endpoints, input from independent patients’ representatives should be sought, if available and appropriate. A.2.5. Study design While randomized controlled trials (RCT) are often considered the preferred study design for clinical investigations of medical devices, this study design may present challenges for orphan devices. These can include ethical challenges – for example, where there are no alternatives or where available alternatives are not considered to offer similar patient benefit (lack of equipoise) – or practical challenges – for example where the device is intended for very small patient populations, randomising some of them to a control arm may severely inhibit the ability to collect sufficiently powered data in a timely manner. In these cases, less commonly used methodological approaches may be acceptable if well justified. Many study designs may be suitable for the clinical investigation of an orphan device. The choice of design should be carefully considered in terms of its strengths and limitations (e.g. vulnerability to bias or confounders) and its ability to address any ethical and practical challenges, and should be justified on a case-by-case basis. Illustrative examples of alternative study designs which may be suitable include cross-over designs, adaptive designs, and sequential designs. A.2.5.1. Cross-over designs Within a cross-over investigation each participant receives two treatments (i.e. intervention and comparator) in a random order and acts as their own control, with a “wash out” period in between. For some devices, a crossover design may be appropriate in some cases, as it will reduce the risk of confounding while also reducing the number of participants needed. A.2.5.2. Adaptive and sequential designs Adaptive and sequential designs are based on interim analyses planned to be carried out in the course of the clinical investigation. Adaptive investigations may allow for potential changes in several parameters (e.g. sample size requirements, randomization ratios, number of analyses) as the study progresses. However, care should be taken to ensure the integrity of the investigation is not compromised as a consequence of excessive or unnecessary adaptations. Where possible, all anticipated or potential adaptations of the investigation should be described in the clinical investigation plan, based on anticipated results of the planned interim analyses. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 26 For certain high-risk devices, a stepwise approach within an adaptive study design, may be appropriate and could help to assess critical but uncertain aspects such as those related to patient recruitment, methods used and variables studied, follow-up visits, and investigator and site qualifications. Sequential designs are mainly based on interim analyses of the study’s primary endpoints, and unlike adaptive clinical investigations, no adaptation of parameters is allowed. Instead, the stepwise methodology allows for continued, periodic analyses after each predefined group/cohort/stratum of patients reach their outcome, thus allowing for interim opportunities to determine whether there is sufficient evidence of clinical benefit or lack thereof. Although adaptive and sequential methodologies can provide more flexibility, it is important to note that this approach can be vulnerable to type I (false positive) error. This potential for error should be considered when evaluating clinical data generated from these study designs. Where appropriate, interim analyses may be enough to support the initial clinical evaluation for conformity assessment. In this event, where possible and where there still is equipoise, the study should continue to completion as planned in the CIP, to ensure continued collection of clinical data and to ensure appropriate long-term follow-up for the study participants. A.2.5.3. Other study designs Other potentially suitable pre-market clinical investigation designs may include: - Prospective observational studies of all patients exposed to the device (e.g. single arm with outcomes reported on all consecutive patients), - Comparative studies with concurrent matched control subjects, - Comparative studies with historical controls (if appropriate and justifiable, for example where the OD is intended for a life-threatening disease and there are no alternatives). Within the PMCF plan, manufacturers should consider the following clinical investigation designs where appropriate: - RCTs comparing the OD with state of the art, with appropriate blinding (e.g., double- or single- blinding, and/or blinded determination of clinical endpoints), - Unblinded, open-label RCTs, - Additional prospective observational cohort studies, with concurrent matched controls, - Registry-based RCTs (a.k.a. nested trials and ‘simple RCTs’) from a suitable registry. The choice of study design needs to be justified and appropriately documented (e.g., in the CEP, CER, and/or PMCF plan), with acknowledgement to the ethical and practical challenges for choice of study design. Consideration needs to be given with respect to minimisation of bias, representativeness of the study, and transparency of the study findings. A.2.6. Statistical considerations and Bayesian approaches For many clinical investigations of orphan devices, frequentist approaches to statistical analysis can be particularly challenging, as patient recruitment from an orphan (sub)population may make inferential statistical analysis unachievable or inappropriate. In such cases, descriptive statistical methods, or in some situations, alternative methods to frequentist approaches such as Bayesian approaches, may be more appropriate. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 27 Bayesian approaches cover a very broad range of possibilities. In Bayesian analyses and hybrid Bayesian analyses, probability statements (e.g., “the probability that the experimental treatment is effective”) are made on the basis of accumulated data combined with prior (existing) data. In this sense, Bayesian approaches can also be considered adaptive. Use of an external control, including historical control data from sources such as prior clinical investigations or ongoing registries, might be a viable approach too if it helps to improve the interpretability of the clinical investigation data. Care should be taken so that only patients with the same condition or disease and comparable clinical and demographic characteristics are used as controls. While the use of prior data is not common to Bayesian applications, the expression of belief about prior data is however different in this framework. Belief about prior data (e.g. from literature, experts, registries) is expressed in the form of a plausible distribution. Observed data from the study are then collected and when combined with the belief about the prior data/evidence, an updated prior, known as the posterior belief (distribution) is determined. In this way, accumulated observed data combined with historical knowledge and expert opinion forms a basis for continued evaluation. A potential advantage of using Bayesian approaches is avoidance of the constraints of the type I error which are associated with larger sample sizes. However, the absence of a type I error, does not mean that Bayesian approaches are free from other decision errors, and these should be considered. The flexibility to form a prior which expresses more or less uncertainty about prior belief can impact the sample size requirements. Alternatively, a ‘hybrid Bayesian’ approach can be considered, which allows expression of uncertainty in the historical data, while allowing use of the frequentist approach. The justification for expression of prior belief around existing data should be rigorously supported with clinical and statistical evidence as this can have a meaningful impact on the conclusions of the study results. Where statements such as “The probability that device A has a higher response rate than device B” are used, it will be important to ensure the differences are clinically meaningful. Other approaches may also exist which are less commonly used, for example, decision theoretic, value of information, and meta-analytic (including Bayesian evidence synthesis) approaches could be used. However, extreme care should be exercised to ensure the methodologies are pre-specified and the clinical interpretation is clear, to avoid data driven approaches which may increase the chance of a false conclusion. A.2.7. Choice of comparator/control In general, a concurrent active comparator is the preferred option but may be difficult to achieve given the large number of rare diseases or conditions for which no alternative option is currently available. In some cases, clinical data from open-label studies without control or with historical controls might be acceptable but must be well justified in terms of choice of study design; these kinds of studies are primarily intended for patients for whom there is no clinical ‘equipoise’. Sham or no comparator can be considered but might be problematic given that those assigned to the control group may have no direct benefit. In such an event, subjects in the control arm must receive the state of the art in management of their condition – i.e., they must receive care at least to the same level as the care they would receive in normal clinical practice. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 28 A.2.8. Monitoring In general, appropriate monitoring by the sponsor should aim to ensure adherence to study protocols and regulatory requirements. In addition, independent monitoring (e.g., by Data Safety Monitoring Boards (DSMBs) and/or Clinical Events Committees (CECs)) should be included as appropriate to confirm that acceptable levels of safety for study participants is maintained throughout the conduct of the study. Some statistical methods31 can assist in the real time monitoring of severe adverse events associated to medical devices. These can be well suited for small-sized investigations and allow to re-estimate the frequency of specific emerging risks in an ongoing process (after each inclusion or group of inclusions) and allow to set stopping rules in clinical investigations by anticipating situations where the risk(s) would exceed an acceptable incidence or frequency threshold. 31 E.g., Stopping boundaries, such as O’Brien-Fleming, Pocock, or Haybittle-Peto boundaries. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 29 A.3. Extrapolation of clinical data to orphan indications A.3.1. Key aspects Devices that are intended by the manufacturer to be used for orphan populations or indications, as well as in non-orphan populations, may have clinical data from use of the device in the ‘other population/indication’. In some circumstances, it may be appropriate to extrapolate these clinical data from other population(s)/indication(s), for the purposes of clinical evaluation of the intended use in the orphan population/indication. The appropriateness of this extrapolation of clinical data should be considered on a case-by-case basis, and will depend on several factors, including the characteristics of the device, the existing knowledge of the device in the non-orphan population/indication, what is known or can be extrapolated about the device to the intended orphan population/indication, and the underlying disease or condition being treated. The extent to which extrapolated clinical data can be relied upon will vary from device to device. In general, it is anticipated that extrapolated clinical data could be combined with other clinical data to provide sufficient clinical evidence for the purpose of approval of the orphan indication (so-called ‘partial extrapolation’). Less commonly, it may be appropriate for the extrapolated clinical data to provide sufficient clinical evidence for the orphan indication without requiring additional clinical data (so-called ‘full extrapolation’). In both cases, the appropriateness of this extrapolation will need to be evaluated and justified by the manufacturer and assessed by the notified body. The notified body may consider the extrapolated data alongside any other existing clinical and non-clinical data and the PMCF plan. The PMCF plan should build on the existing data, to evaluate the safety and performance of the device throughout the device’s lifecycle for its orphan indication/intended purpose. Partial Extrapolation: Extrapolated clinical data are combined via a suitable statistical model or methodology with other sources of clinical and non-clinical data, to provide sufficient clinical evidence to support the orphan indication/intended purpose. The construction of such a statistical model is anticipated to require the availability of measured variables that will help connect the available outcomes to the outcomes of intended orphan (sub)population/indication. If the necessary variables are not available in the data sources, partial extrapolation may not be appropriate. If the model is determined to be appropriate, then the inferences obtained from it may be used to support the orphan device indication. Full extrapolation: Extrapolated clinical data are used as the main or sole source of clinical data (i.e. a complete substitute) to provide sufficient clinical evidence to support the orphan indication/intended purpose. Minimal to no additional clinical data are needed for the purpose of initial certification of an orphan indication/intended purpose. The appropriateness of extrapolation of clinical data from use in other (sub)populations/indications depends on three main factors: - the relevance of the data, including the similarity of characteristics between the proposed orphan subpopulations/indications, and the others from which the data were collected; - the quality of the data in terms of scientific validity32 and suitability; and 32 When appraised as required by MDR Annex XIV section 1(c). Medical Devices Medical Device Coordination Group Document MDCG 2024-10 30 - the extent to which the data can provide sufficient clinical evidence to assess the safety, performance and expected clinical benefit for the orphan indication. A.3.2. Decision process for considering extrapolation To determine the suitability of clinical data for extrapolation, the following steps should be followed and documented in the clinical evaluation report. I. Suitability for extrapolation of clinical data Are the clinical data relevant to the orphan (sub)population(s)/indication? Clinical data can be considered relevant for the purposes of data extrapolation if it is justified that: (a) the indication(s) for the device is the same, but in a different population; (b) the endpoint(s) or outcome(s) that has been measured in the non-orphan population is the same or similar as would be measured as an endpoint when used in the intended orphan (sub-)population; and/or (c) the clinical data from the non-orphan population provide validated surrogate endpoints that are expected to be relevant to the orphan population. o In this case, a reliable and valid model might be used to predict the endpoint for the orphan population using clinical data from the other population, e.g., a validated surrogate endpoint in the available data set(s) that has been shown to predict a different, longer- term endpoint of interest. - If any of I(a)-I(c) is TRUE → potentially suitable for extrapolation; proceed to II. - If NOT → unsuitable; do NOT extrapolate II. Determining the extent of extrapolation Do the characteristics of the device, patients, or diseases/conditions differ between the orphan and other (sub)populations/indications to an extent that the expected safety and/or performance of the device could be impacted in a clinically meaningful way? In particular, are there clinically meaningful differences with respect to: (a) the intended location and/or duration of use? (b) characteristics of the device (e.g. size, morphology, indications)? (c) patient characteristics? o e.g., characteristics that are unique to the orphan (sub)population/indication that may impact the device’s expected safety/performance. Some devices might require special considerations relevant to only a particular subgroup of patients. For example, special considerations may be needed with respect to difference in: • Pharmacokinetics/pharmacodynamics • Risks related to the duration of exposure (e.g., differences in long-term toxicity) • Age, sex, ethnicity, or body size • For paediatric populations, potential impact of the device on physiological changes in a growing child and vice versa (d) disease characteristics between the two populations/indications? (e) any other relevant differences or factors? Other factors that may limit extrapolation include: o insufficient knowledge of the disease or condition in the intended (sub)population, Medical Devices Medical Device Coordination Group Document MDCG 2024-10 31 o no suitable statistical methodology has been identified for the purposes of partial extrapolation and combination with other clinical data, e.g., the expected differences between the two (sub)populations/indications, o the clinical data was obtained from off-label use or misuse within the non-orphan population (i.e., use in the non-orphan population is outside the intended purpose), o the state of the art has changed since the creation of the data to such an extent that historical data would likely be different to new prospectively collected data, o specific applicable regulatory requirements, such as the necessity for mandatory clinical investigations for certain devices (per MDR Article 61(4), see MDCG 2023-7). - If II(a)-II(e) are ALL answered “NO” → potentially suitable for FULL EXTRAPOLATION; appraise and analyse the clinical data33 and proceed to III. - If any of II(a)-II(e) answered “YES” → potentially suitable for PARTIAL EXTRAPOLATION; appraise and analyse the clinical data2 and proceed to IV. III. Suitability for full extrapolation Are the extrapolated clinical data of sufficient amount and quality to provide sufficient clinical evidence for the evaluation of the device’s safety, performance, and clinical benefit for the orphan indication? - If “YES” → likely suitable for FULL EXTRAPOLATION; conduct clinical evaluation accordingly34. - If “NO” → potentially suitable for PARTIAL EXTRAPOLATION; Proceed to IV. IV. Suitability for partial extrapolation Despite any differences or limitations identified, are the extrapolated clinical data suitable2 for use as part of the clinical evidence for the orphan indication? - If “YES” → likely suitable for PARTIAL EXTRAPOLATION; conduct clinical evaluation accordingly3. - If “NO” → do NOT extrapolate 33 In line with MDR Annex XIV section 1(c) and 1(e). 34 Per MDR Annex XIV part A. Medical Devices Medical Device Coordination Group Document MDCG 2024-10 32 Medical Devices Medical Device Coordination Group Document MDCG 2024-10 33 1. Abbreviations and terminology 2. Introduction 3. Scope 4. Orphan device status and orphan indication 4.1. Orphan device criteria 4.2. Justification of orphan device status 4.2.1. Epidemiology of the disease or condition 4.2.2. Device description, insufficiency of alternatives, expected clinical benefit 4.3. Orphan indication PART A – Clinical Evaluation Considerations 5. The acceptability of limitations in pre-market clinical data 6. The role of non-clinical data 7. Clinical evaluation overview 7.1. Clinical evaluation plan 7.2. Identifying, appraising, and analysing clinical data 7.3. Clinical evaluation of orphan devices which are legacy devices 7.3.1. Sufficient clinical evidence 7.3.2. Data from clinical investigations and legacy orphan devices 7.3.3. Clinical data from equivalent devices 7.3.4. Clinical data from off-label use 8. Generating pre-market clinical data for orphan devices 9. Post market surveillance and PMCF for orphan devices 9.1. PMCF and benefit-risk determination 9.2. PMCF investigations 9.3. Registries 9.4. Other post-market clinical data and post-market surveillance PART B – Procedural Considerations 10. Notified body activities and responsibilities 10.1. Notified body activities prior to the certification 10.2. Specific conditions/provisions for certification 10.3. Surveillance by the notified body 11. Involvement of expert panels: advice on orphan device status and clinical evidence 11.1. Consultation of expert panel 11.1.1. Early scientific advice pursuant to MDR Article 61(2) 11.1.2. Advice in cases where the clinical evaluation is in an advanced stage or completed 11.2. Timelines for expert panel’s advice 11.2.1. Early scientific advice pursuant to MDR Article 61(2) 11.2.2. Advice in cases where the clinical evaluation is in an advanced stage or completed 11.3. Relationship with CECP Appendices A.1. Clinical Evaluation Report A.1.1. OD-specific information to be included in the CER A.1.2. Post-market updates to the CER A.2. Considerations for Clinical Investigations of Orphan Devices A.2.1. Introduction A.2.2. Defining the study population A.2.3. Objectives A.2.4. Selection of endpoints A.2.5. Study design A.2.5.1. Cross-over designs A.2.5.2. Adaptive and sequential designs A.2.5.3. Other study designs A.2.6. Statistical considerations and Bayesian approaches A.2.7. Choice of comparator/control A.2.8. Monitoring A.3. Extrapolation of clinical data to orphan indications A.3.1. Key aspects A.3.2. Decision process for considering extrapolation

Medical Device Medical Device Coordination Group Document MDCG 2024-5 MDCG 2024-5 guidance on content of the Investigator’s Brochure for clinical investigations of medical devices April 2024 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 2024-5 2 Medical Device Medical Device Coordination Group Document MDCG 2024-5 3 Table of contents Abbreviations....................................................................................................................................... 5 1. Introduction ................................................................................................................................... 7 2. Content of the Investigator’s Brochure ...................................................................................... 7 Administrative details .......................................................................................................................... 8 2.1. Investigational device information .......................................................................................... 8 2.1.1. Identification of the device ................................................................................................. 8 2.1.2. Intended purpose ............................................................................................................... 8 2.1.3. Intended clinical performance ............................................................................................ 9 2.1.4. Qualification and classification ........................................................................................... 9 2.1.5. Literature and evaluation supporting the rationale for the design and intended use of the investigational device .................................................................................................................... 10 2.1.6. General description of the device: ................................................................................... 10 2.1.6.1. Design ..................................................................................................................... 10 2.1.6.1.1. Description of the key functional elements ..........................................................10 2.1.6.1.2. Overview of materials used .................................................................................10 2.1.6.1.3. Technical specifications ......................................................................................11 2.1.7. Summary of relevant manufacturing processes .............................................................. 11 2.1.8. Reference to previous and similar generations of the device .......................................... 11 2.1.9. Overview of identified equivalent or, if any, similar devices available ............................. 11 2.2. Labels and instructions for use ............................................................................................ 12 2.2.1. Instructions for use .......................................................................................................... 12 2.2.2. Labels .............................................................................................................................. 13 2.2.3. Training ............................................................................................................................ 13 2.2.4. Implant card ..................................................................................................................... 13 2.3. Pre-clinical evaluation .......................................................................................................... 13 2.3.1. General recommendations regarding pre-clinical evaluation .......................................... 13 2.3.2. Specific recommendations regarding pre-clinical evaluation .......................................... 15 2.3.2.1. In design calculations .............................................................................................. 15 2.3.2.2. Bench testing - “horizontal” tests (valid for any device) .......................................... 15 2.3.2.2.1. Performance tests ...............................................................................................15 2.3.2.2.2. Reliability tests.....................................................................................................16 2.3.2.2.3. Interoperability and compatibility tests ................................................................16 Medical Device Medical Device Coordination Group Document MDCG 2024-5 4 2.3.2.2.4. Usability tests ......................................................................................................17 2.3.2.3. Bench testing - “Vertical”tests (depending on the device type) .............................. 18 2.3.2.3.1. Mechanical, electrical safety and electromagnetic compatibility tests ................18 2.3.2.3.2. Biocompatibility and biological safety ..................................................................18 2.3.2.3.3. Software verification and validation .....................................................................19 2.3.2.3.4. Cybersecurity tests ..............................................................................................19 2.3.2.3.5. Validation of cleaning, disinfection and sterilization ............................................19 2.3.2.3.6. Packaging validation ...........................................................................................20 2.3.3. Animal tests ..................................................................................................................... 20 2.4. Existing clinical data ............................................................................................................. 21 2.5. Risk management of the investigational device ................................................................... 21 2.5.1. Anticipated Serious Adverse Events (SAEs) and Serious Adverse Device Effects (SADEs) 23 2.6. 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 ......................................................................................................................................... 24 2.6.1. General requirements ...................................................................................................... 24 2.6.2. Quality aspects ................................................................................................................ 25 2.6.2.1. Information on incorporation of the medicinal substance in the device .................. 26 2.6.2.2. Information on the final investigational device ........................................................ 26 2.6.2.3. Specific requirements for starting materials, intermediates or substances of biological origin 26 2.6.2.4. Specific requirements for adventitious agents ........................................................ 27 2.6.2.5. Additional information required for substances from human plasma ...................... 27 2.6.2.6. Substance of animal origin ...................................................................................... 27 2.7. Fulfilment of General Safety and Performance Requirements ............................................ 27 2.8. Procedures ........................................................................................................................... 28 Appendix A ........................................................................................................................................ 30 Medical Device Medical Device Coordination Group Document MDCG 2024-5 5 Abbreviations AE Adverse Event1 ARRIVE Animal Research: Reporting of In Vivo Experiments ASMF Active Substance Master File CE Marking on a product to signify that it meets the legal requirements to be sold on the extended Single Market in the European Economic Area (EEA). CEP Certificate of suitability to the monographs of the European Pharmacopoeia CS Common Specification DD Device deficiency2 EDQM European Directorate for the Quality of Medicines EMA European Medicines Agency EU European Union EUDAMED European Database on Medical Devices Eudralex The collection of rules and regulations governing medicinal products in the European Union. FMEA Failure mode and effects analysis FTA Fault tree analysis GLP Good Laboratory Practice GMP Good Manufacturing Practice GSPR General Safety and Performance Requirements HAZOP Hazard and Operability IB Investigator’s Brochure IFU Instructions for use IMDRF International Medical Device Regulators Forum IMP Investigational Medicinal Product ISO International Organization for Standardization IVD In vitro diagnostic MDCG Medical Device Coordination Group MDR Medical Device Regulation – Regulation (EU) 2017/745 on medical devices MIR Manufacturer Incident Report 1 Defined in article 2(57) of the MDR. 2 Defined in article 2(59) of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 6 Ph Eur European Pharmacopoeia PMF Plasma Masterfile PMSR Post Market Surveillance Report PSUR Periodic Safety Update Report SADE Serious Adverse Device Effect3 SAE Serious Adverse Event4 TSE Transmissible Spongiform Encephalopathy 3 Any adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event. An adverse device effect is any adverse event related to the use of an investigational device or a comparator, if the comparator is a medical device. 4 Defined in article 2(58) of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 7 1. Introduction When a sponsor of a clinical investigation shall submit an application according to article 70(1) of the MDR, the application shall be accompanied by the documentation referred to in Chapter II of Annex XV of the MDR. The Investigator’s Brochure (IB) is part of the required documentation and is one of the means by which the sponsor is to fulfil the requirement in section 2.7 of Chapter I of Annex XV of the MDR which states that the investigator shall have access to technical and clinical data regarding the device that is being investigated. This includes the intended purpose(s), design, the basic fundamental scientific principles behind the design and the level of objective evidence already in place, to assure its safety and functionality during the investigation. For the purpose of this guidance document, medical devices, accessories for medical devices, and products listed in Annex XVI shall hereinafter be referred to as ‘devices’.5 Section 2 of Chapter II of Annex XV of the MDR describes the required content of the IB. Please note that by submitting complete applications and documents that contain all the required content, this helps competent authorities in assessing the application, which facilitates the review process. Prior to submission of the IB, sponsor is recommended to complete the checklist in Appendix A of this guidance, to ensure the IB meets the minimum requirements for validation of the application per article 70 of the MDR. The checklist, if used, should be included together with the IB in the submission. When preparing the IB, sponsors are encouraged to review the full details of the regulation as well as the normative Annex B of the international standard ISO14155:2020 Clinical investigation of medical devices for human subjects - Good clinical practice. This guidance document is intended to support sponsors in developing their IB by describing in greater detail what type of information is expected in the respective IB sections, in order to pre- empt questions from the competent authorities during the assessment of the clinical investigation application. The guidance is based on the requirements of both the MDR and ISO14155:2020 as well as experience from the competent authorities. Note that 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 manner6. Further, when the IB is updated, the sponsor needs to notify the member states concerned within one week7. Changes made to the IB shall be clearly identifiable. Note that the scope of this guidance is IBs written for clinical investigations as defined by the MDR, and it is not intended to be applied for performance study IBs under the IVDR. 2. Content of the Investigator’s Brochure The 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. The information shall be presented in a concise, simple, objective, balanced, and non-promotional form that enables a potential investigator and the investigation site team, to understand it and make his/her own 5 Article 1.4 of the MDR. 6 Section 2, Chapter II, Annex XV of the MDR. 7 Per article 70.2 of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 8 unbiased benefit-risk analysis of the appropriateness of exposing study participants to the investigational device. Further the IB should contain sufficient information to allow safe and correct use of the device. Note that it is preferred for all necessary information to be included in the IB. However, if it is decided to move part of the information to annexes, then a clear reference should be made in the IB and the annexes enclosed with the application. The reference in the IB should clearly state the title of the referenced document and the section in which the information is given. A summary of the referenced document should still be provided in the IB, as the IB should be possible to read as a stand-alone document. Administrative details The IB shall be clearly identified. The first page(s) should contain a proper identification of the IB with the name of the investigational device, a document reference number, version and date of the IB, if appropriate a confidentiality statement, a summary of the revision history and table of contents. The name and address of the sponsor of the clinical investigation should be given, and of the manufacturer of the investigational device, if different from the sponsor. The page number and total number of pages of the document should be indicated on each page of the IB. 2.1. Investigational device information According to section 2.1, chapter II, Annex XV of the MDR, the IB should include identification and description of the device, including information on the intended purpose, the risk classification and applicable classification rule of the regulation, design and manufacturing of the device and reference to previous and similar generations of the device. This investigational device information should include the following elements, if applicable: 2.1.1. Identification of the device If several names are used for the same device, this should be explained, and care taken to use consistent terminology throughout the study documentation, to avoid confusion. 2.1.2. Intended purpose State the intended purpose8 with a clear specification of the indications, contra-indications, the patient target group or groups, and the intended users, as appropriate9. If there is a known difference between the intended purpose in the clinical investigation (due to development stage, study design or other reasons) and the planned intended purpose when the device will be placed on the market, this difference should be clearly stated. 8 Article 2(12) of the MDR. 9 Aligned with section 23(4)b in Annex I of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 9 If the device has already been CE-marked and placed on the market, it should be explained whether the intended purpose of device in the clinical investigation is different from the intended purpose for which the device has been CE marked, or if it is to be further assessed within the scope of its intended purpose. This should be clearly specified. 2.1.3. Intended clinical performance10 Describe in clinical terms the performance that the device is intended to achieve. I.e. describe how (the mechanisms through which) the device is able 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. The ‘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 health11. Describe the intended clinical benefits to patients with relevant and specified clinical outcome parameters. The clinical benefit could be resulting from any direct or indirect medical effects which stem from the technical or functional characteristics of the device, including diagnostic characteristics. For products without an intended medical purpose that are covered by Annex XVI of the MDR, the requirement to demonstrate a clinical benefit shall be understood as a requirement to demonstrate the performance of the device12. 2.1.4. Qualification and classification Provide a rationale for why the device qualifies i.e. has regulatory status as a medical device, an accessory for a medical device or a product listed in Annex XVI. Compare the intended purpose to the applicable definition in article 2(1), 2(2) or annex XVI of the MDR, and state the applicable risk class according to Annex VIII of the MDR. For borderline products (i.e. where there could be uncertainty whether the product is a device or a medicinal product), it is of particular importance to include the scientific rationale for the qualification as device, and to align with the MDCG 2022-5 guidance13. Further, if the study is a study combining device and medicinal product, clear information on the regulatory status of both device and drug components should be provided. 10 Article 2(52) of the MDR. 11 Article 2(53) of the MDR. 12 Article 61(9) of the MDR. 13 MDCG 2022-5 Guideline on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices. https://health.ec.europa.eu/system/files/2023-06/mdcg_2022-5_en.pdf https://health.ec.europa.eu/system/files/2023-06/mdcg_2022-5_en.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 10 For classification, relevant guidance is available in MDCG 2021-2414, MDCG 2019-1115 and MDCG 2023-516. Classification under previous legislation, i.e. for legacy devices may be mentioned as supplementary information. 2.1.5. Literature and evaluation supporting the rationale for the design and intended use of the investigational device Provide a summary of the literature, previous research and evaluation supporting the rationale for the design and intended use of the investigational device, if available. 2.1.6. General description of the device: 2.1.6.1. Design The IB shall contain a description of the critical and fundamental design (e. g. the technical or scientific principles applied) of the relevant components/parts of the device, so that the device, when used according to the instructions, will be able to achieve the intended purpose. The description should be as clear and fundamental as reasonably possibly, not assuming that all intended readers are already experts in the field. Describe the operation of the device and its mode of action, along with supporting scientific literature if available. 2.1.6.1.1. Description of the key functional elements Include a general description of the key functional elements, e.g. its parts/components (including software if appropriate), its formulation17, its composition, its functionality and, where relevant, its qualitative and quantitative composition. Where appropriate, this should include labelled pictorial representations (e.g. diagrams, photographs, and drawings), clearly indicating key parts/components, including sufficient explanation to understand the drawings and diagrams. Often, animations or recordings are made to clarify the mechanism of action and specific features of a device; if this is the case, a copy or link to these can be provided in or together with the IB as a supporting way to explain the design and working principles of complex devices; nevertheless, these are considered complementary and do not fully replace a written description of the mechanism of action in the IB. 2.1.6.1.2. Overview of materials used A clear overview of materials used in the device should be provided, preferably in a tabular format. In addition, detailed information for all materials coming into contact with the human body (i.e., in contact with tissues or body fluids of a patient, health care professional, or other user, even if 14 MDCG 2021-24 Guidance on classification of medical devices. 15 MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 - MDR and Regulation (EU) 2017/746 - IVDR. 16 MDCG 2023-5 Guidance on qualification and classification of Annex XVI products - A guide for manufacturers and notified bodies. 17 Relevant for substance based devices. https://health.ec.europa.eu/system/files/2021-10/mdcg_2021-24_en_0.pdf https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_11_guidance_qualification_classification_software_en_0.pdf https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_11_guidance_qualification_classification_software_en_0.pdf https://health.ec.europa.eu/document/download/ea4acf26-979a-4dbb-92ff-8d1d804da51a_en?filename=mdcg_2023-5_en.pdf https://health.ec.europa.eu/document/download/ea4acf26-979a-4dbb-92ff-8d1d804da51a_en?filename=mdcg_2023-5_en.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 11 contact is only brief, occasional or indirect) should be provided in a separate section on biocompatibility and biological safety. Refer to section 2.3.2.3.2 below for further guidance. If relevant, details of any medicinal substances, non-viable human or animal tissues or their derivates, or other biologically active substances must also be included. See also section 2.6 below. 2.1.6.1.3. Technical specifications Technical specifications, such as features, dimensions and performance attributes, of the device and any variants/configurations and accessories that would typically appear in the device specification made available to the user, for example in brochures, catalogues and similar publications should be provided. This concerns the variants/configurations and accessories to be used in the clinical investigation. 2.1.7. Summary of relevant manufacturing processes The IB should contain information on how the manufacturing process has been designed to ensure sufficient device quality and robustness, considering e. g. known or foreseeable variability inherent to biological materials and other critical components or raw materials which may cause challenges that might jeopardize device performance unless they are sufficiently controlled. Provide a summary of relevant manufacturing processes and the corresponding quality controls (including verifications and validations as well as final testing) applied to demonstrate that the investigational devices are manufactured and verified under a controlled process according to the applicable regulations. This can be done by means of a manufacturing flowchart. 2.1.8. Reference to previous and similar generations of the device An overview of the previous and similar versions of the device (e.g., in table format) is recommended, if applicable. This overview should specifically focus on the devices used clinically and in confirmatory pre-clinical testing, i.e. the late stages of development. Preferably, this table contains for each iteration the version number, a photograph/drawing and a brief overview and rationale of changes with regards to the previous iteration. 2.1.9. Overview of identified equivalent or, if any, similar devices available As background for the evaluation of clinical data (refer to section 2.4 in chapter II Annex XV of the MDR as well as section 2.4 in this guidance document) and for the assessment of anticipated benefits per article 62(4e) of the MDR, the sponsor should provide an overview of identified equivalent if any, or relevant similar devices available in the Union or international markets. A brief description of similar devices including the key features and their intended purpose(s) focusing on the novelty of the current device when compared to other is sufficient. Medical Device Medical Device Coordination Group Document MDCG 2024-5 12 2.2. Labels and instructions for use According to section 2.2, chapter II, Annex XV of the MDR, the IB should include manufacturer’s instructions for installation, maintenance, maintaining of hygienic standards and use of the investigational device, including any necessary 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. In addition, information relating to any relevant training required is to be included. Sponsor needs to check national legislation, which may require labelling and instructions for use to be in national language. 2.2.1. Instructions for use For devices which do not bear CE marking, “Instructions for Use” (IFU) document(s) should be included in the application dossier, as part of the IB or as a separate document referenced from IB. Instructions for use should contain: • The information to be provided with the device when placed on the market according to the requirements listed in chapter III, Annex I of the MDR,to the extent that such information is available, • Instructions on the use and operation of the device need to be sufficiently detailed to prevent user errors and should allow the reader to understand how the device is to be operated without having an actual device at hand. Graphic illustrations are recommended. • Information on preparation for use and any intended re-use (e.g., cleaning, sterilization), any pre-use safety or performance checks and any precautions to be taken after use (e.g., disposal), if relevant. • Instructions for installation and maintenance of the device, including any precautions to be taken into consideration prior to installation and service, to ensure user and patient safety. • Storage and handling requirements as well as shelf life (when appropriate) of the investigational device should be specified. If the investigational device already bears the CE-marking and is to be used outside the intended purpose of the CE mark during the clinical investigation study specific IFU document(s) should be included in the application dossier, as part of the IB or as a separate document referenced from IB. Moreover: • A description of how the device will be used differently during the clinical investigation must be included in the IB. There may be situations when the difference in use vs the CE mark is minimal and there may be situations where the difference is significant. Only where there are minimal differences of use, it may be sufficient that the clarification of the use difference is provided in the IB itself. Provided that safe and effective use of the device can be ensured without a study specific IFU, the CE marked IFU does not need to be updated. • The manufacturer’s IFU, covered by the CE mark, should be provided, in addition. Medical Device Medical Device Coordination Group Document MDCG 2024-5 13 If the investigational device and/or comparator device already bears the CE-marking, and is to be used within the intended purpose of the CE-mark during the clinical investigation, the manufacturer’s IFU, covered by the CE mark, must be provided. 2.2.2. Labels Labels of the investigational device should contain, to the extent that such information is available, the information to be provided with the device when placed on the market18, according to the requirements listed in chapter III, Annex I of the MDR. Note in particular the specific requirement which is applicable if the investigational device is intended for clinical investigation only; to include the text ‘exclusively for clinical investigation” on the labels. Sponsor needs to check national legislation, which may require labels to include ‘exclusively for clinical investigation” in national language. It is recommended to include the graphic presentation of the device labels, either in the IB or as separate documents which are referenced from the IB. Note that the requirements for labelling apply also to investigational software devices. 2.2.3. Training Training needs and plans for training should be described in the IB. 2.2.4. Implant card In the case of a clinical investigation with an implantable device, it is recommended that a study implant card is provided to the patient for safety reasons. Refer to article 18 of the MDR for detailed requirements on content of the implant card, and to MDCG guidance documents MDCG 2019-819 and MDCG 2021-1120 for additional guidance. 2.3. Pre-clinical evaluation According to section 2.3, chapter II, Annex XV of the MDR, the IB should include a pre-clinical evaluation based on relevant pre-clinical testing and experimental data, in particular 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. 2.3.1. General recommendations regarding pre-clinical evaluation Note that it is a requirement of the MDR that the investigational device(s) conform(s) to the applicable general safety and performance requirements (GSPR) set out in Annex I of the MDR 18 Investigational devices are not required to include UDI labelling. 19 MDCG 2019-8 Guidance document Implant Card relating to the application of Article 18 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices 20 MDCG 2021-11 Guidance on Implant Card – ‘Device types’ https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_8_implant_guidance_card_en_0.pdf https://health.ec.europa.eu/system/files/2020-09/md_mdcg_2019_8_implant_guidance_card_en_0.pdf https://health.ec.europa.eu/system/files/2021-06/md_2021-11_en_0.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 14 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.21 As a general principle, pre-clinical tests have to be completed before a clinical investigation application is made. Testing would at least have to be completed to an extent that supports the planned use of the device in the clinical investigation. As an example, if the exposure to the device in the clinical investigation is shorter than the planned exposure of the final marketed device, it might be sufficient to provide the data that ensures that the characteristics and performance of the device is not adversely affected during the time the device is used in the clinical investigation. The level of objective evidence of compliance available versus planned should be easily accessible through the GSPR information (refer also to section 2.7 below). In situations where some aspects of pre-clinical testing have not been completed, this should be clearly highlighted and justified. If equivalence is claimed as a reason for not performing some of the pre-clinical testing, clarify the technical, biological, and clinical grounds for this22. The IB should include a summary of the pre-clinical testing that has been performed on the investigational device, together with an evaluation of the results of such testing, justifying its use in/on human subjects. Pre-clinical testing should be made according to relevant standards and common specifications, unless a justification based on scientific grounds is provided to not conduct certain tests or not adhering to standards and/or common specifications. Any deviations from acceptance criteria need to be justified. Test summaries could preferably be provided in tabular format and should include: • Reference standard or common specification • Reference to test report for traceability23 • For each test, information on: • Specific reference in the standard applied • GLP status when relevant (if non-GLP, this should be justified) • Acceptance criteria • Test method • Sample (including type and size) and its rationale • Brief summary of results • Conclusion (e.g. pass/not pass) 21 Article 62(4)l of the MDR 22 MDCG 2020-5 (Clinical Evaluation - Equivalence A guide for manufacturers and notified bodies)provides guidance on equivalence. 23 Indicating the identifier of the report, in order to allow tracking and requests for particular reports. https://health.ec.europa.eu/document/download/575a0f79-e3a0-4a96-9ce0-930576c12aa2_en?filename=md_mdcg_2020_5_guidance_clinical_evaluation_equivalence_en.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 15 • The applicant should either confirm that the device used was identical to the investigational device for clinical use (including e.g., sterilization) or detail any differences between the device used tested pre-clinically (e.g., mechanical testing, fatigue testing, reliability testing, animal studies, biocompatibility studies) and used clinically. If the device that will be used in the clinical investigation differs from the device used in pre-clinical studies, a justification of the transposability of the pre- clinical results should be provided. • It should be clearly indicated whether the test has been performed on parts of, or the entire device. Note that during assessment of the clinical investigation application, the full study reports of any pre-clinical study may be requested; to reduce the overall time to clinical investigation approval (take into consideration there is only one possible round of questions following MDR), the applicant may consider submitting the full study reports of certain critical studies (such as animal tests, if applicable) at the time of the initial application along with a justification for doing so. Please note that even if full pre-clinical study-reports are submitted, there is an obligation to include a summary of the pre-clinical studies in the IB. This summary should provide an overview of the scope, results and evaluation of the results, accessible also to non-experts. Note that if references are made to separate reports, the reference should point to the sections of interest in the referenced document. 2.3.2. Specific recommendations regarding pre-clinical evaluation 2.3.2.1. In design calculations In design calculations may support the design and mechanical strength of the device. 2.3.2.2. Bench testing - “horizontal” tests (valid for any device) 2.3.2.2.1. Performance tests The primary objective of performance24 testing is to evaluate whether the device achieves the intended purpose as stated by the manufacturer. The manufacturer should establish (i.e. define, document, and implement) the clinical performance requirements of the device and the corresponding device performance specifications for the intended use and device claims. Provide information on conducted performance tests. If no performance testing has been conducted, this should be explicitly justified (e.g. when there is a previous version of the device with the same intended purpose and function, for which performance has been evaluated, that is already placed on the market, and the current investigational device does not implement any significant change that might impact performance). 24 Article 2(22) of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 16 Discuss whether it is possible and relevant to perform in vitro, ex vivo or animal testing in order to demonstrate performance of the device. 2.3.2.2.2. Reliability tests Reliability could be defined as the probability that a device, system, or service will perform its intended function adequately for a specified period of time, or will operate in a defined environment without failure. Describe how durability of the device has been evaluated, to ensure the occurrence of device deficiencies during the lifetime of the device, or at least during its use in the clinical investigation, will be kept at an acceptable level. Summarize results of stability testing and simulations, accelerated tests (may be necessary for devices that will be used for longer time periods), aging tests to evaluate wear after repeated use and reprocessing etc. There are specific requirements regarding reliability for some device types, e.g.: • For devices with a measuring function25, summarize tests which document that the device has sufficient accuracy, precision and stability for the intended purpose. Indicate the limits of accuracy. • Interoperability and compatibility with other devices26 needs to be addressed in relation to reliability, if applicable. Provide summary of evidence supporting that the device is reliable and safe when operated together with other devices or products. Refer to section 2.3.2.2.3 for further details. • If the device incorporates an electronic programmable system, including software and software that are devices in themselves, the manufacturer shall ensure repeatability, reliability and performance in line with the intended use27. Summarize how repeatability, reliability and performance have been tested to ensure that it is in line with the intended use. The reliability of the energy source for active implantable devices28 has to be ensured. Describe how this has been tested. • Devices for use by lay persons shall, where appropriate, include a procedure by which the lay person is warned if the device has failed to provide a valid result29. 2.3.2.2.3. Interoperability and compatibility tests When a device, including software, is intended to be operated together with other devices or products, from the same manufacturer or from different manufacturers, it shall be designed and manufactured in such a way that the interoperability and compatibility are reliable and safe. The (natural or legal) person who is responsible for the combination of devices, has to verify: • that the combination is done compatibly with the intended purposes of the devices, i.e. within the limits of use specified by their manufacturers (in the instructions for use). 25 Section 15.1 in Annex I of the MDR. 26 Section 14.5 in Annex I of the MDR. 27 Section 17.1 in Annex I of the MDR. 28 Section 19.2 in Annex I of the MDR. 29 Section 22.3 in Annex I of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 17 • the mutual compatibility between the device and other devices or products, i.e. the devices have to perform as intended, have to integrate and operate without any modification or adaptation and have to be used without conflict/interference or adverse reaction. • the interoperability of the devices, i.e. the ability to exchange information and use information that has been exchanged for the correct execution of a specified function without changing the data and/or to communicate with each other and/or work as intended. A summary of the evidence produced to demonstrate the compatibility and interoperability of combined devices should be provided. For a clear understanding of the interoperability and compatibility test results, a detailed description of the types of elements to be combined (e.g. CE marked devices, CE marked IVD devices, other products which are in conformity with legislation that applies to them), the types of connection, the type of established data exchange and any restrictions on use applying to such combination should also be provided. Specific risks related to interoperable devices and cybersecurity should be considered, please refer to section 2.3.2.3.4 on cybersecurity testing. 2.3.2.2.4. Usability tests Usability is defined in the European standard EN 62366-130 as the characteristic of the user interface that establishes effectiveness, efficiency, ease of user learning and user satisfaction in the intended use environment. All aspects of usability, including effectiveness, efficiency, and user satisfaction, can either increase or decrease safety of a medical device. Usability is created by characteristics of the user interface that facilitate use, i.e., to make it easier for the user to perceive information presented by the user interface, to understand and to make decisions based on that information, and to interact with the medical device to achieve specified goals in the intended use environments. Many of these factors can influence safety and performance31 to various extents. Usability test is defined as a method for exploring or evaluating a user interface with intended users within a specified intended use environment32. Usability tests may be preclinical or clinical depending on the test design. In situations where the usability test fulfils the definition of a clinical investigation33, the test is to be reported in the Existing clinical data section of the IB, while the pre-clinical usability tests are to be presented in the Preclinical evaluation section. 30 EN 62366-1 Medical devices - Part 1: Application of usability engineering to medical devices (IEC 62366-1:2015) section 3.16 31 The words ”and performance” have been added vs the text in standard EN 62366-1 32 EN 62366-1 Medical devices - Part 1: Application of usability engineering to medical devices (IEC 62366- 1:2015) section 3.19. 33 Additional guidance available in MDCG 2021-6. https://health.ec.europa.eu/system/files/2023-12/mdcg_2021-6_en.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 18 2.3.2.3. Bench testing - “Vertical”tests (depending on the device type) 2.3.2.3.1. Mechanical, electrical safety and electromagnetic compatibility tests Mechanical and electrical safety tests are important to ensure that the investigational device is safe for users and patients. The extent of testing required varies depending on type of device, and may include tests of both materials, parts, and the final device. There are specific standards for some types of devices, and the manufacturer is expected to adhere to those that are relevant, or describe the measures taken and procedures used to achieve at least the same requirement level as described in the relevant standard. As an example, the IEC 60601 standard series is applicable to electrical devices. 2.3.2.3.2. Biocompatibility and biological safety To address the compatibility between an investigational device and biological tissues, cells and body fluids, a biological risk assessment should be carried out according to ISO 10993 standard series. ISO 10993 part 1 provides the general principles for a risk-based approach to biological safety evaluation and material characterization. The other parts of the ISO 10993 standard series cover tests methods for different aspects of biocompatibility and biological safety. The extent of biocompatibility and biological testing will depend on the intended purpose, available information, and demonstration of equivalence to other devices. Guidance on equivalence is provided in MDCG 2020-5. Results from the evaluation of biocompatibility and biological safety shall be summarized in the IB. The following information will have to be provided, at a minimum, - Overview of the material composition of the device, focussing on body-contacting materials (both direct and indirect). Preferably, the information is provided in a tabular format. Detailed information about materials should be available upon request, such as generic name, brand name and if applicable, the grade, quality, specification or standard adhered to and if anything has been added such as additives or colorants. - The nature, degree, frequency, and duration of the exposure. - Criteria for determining the acceptability of the material for the intended purpose and if applicable demonstration of equivalence to other devices. - Rationale for test strategy (selection and/or waiving of tests) and test samples. Material characterization according to ISO 10993-18 is expected, and when applicable toxicological risk assessment according to ISO 10993-17. Further, there are special requirements in point 12, Annex I of MDR for 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. - Test methods used, acceptance criteria, results, and conclusion. Preferably presented in table format. - Separate and specific discussion of substances which are carcinogenic, mutagenic, toxic to reproduction, or endocrine disrupting, according to point 10.4.1, Annex I of MDR. - Overall biocompatibility and biological safety conclusion in relation to the foreseen exposure to the device due to the clinical investigation. Medical Device Medical Device Coordination Group Document MDCG 2024-5 19 2.3.2.3.3. Software verification and validation For devices that incorporate software or for software that are devices in themselves, describe the software design and development process and evidence of the validation of the software, as used in the finished device. This information should 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 should also address all of the different hardware configurations and, where applicable, operating systems identified in the information supplied by the manufacturer. For software, a number of standards are available. Three standards are elaborated upon underneath, but this list is not exhaustive, and it should be noted that other standards can also be applicable. IEC 62304:2006 Medical device software – Software life cycle processes, covers both software as a component of a medical device and standalone software (a medical device in its own right). IEC 82304-1:2017 Health Software – Part 1: General requirements, provides requirements for the safety and security of health software products. IEC 60601-1:2005 Medical electrical equipment – Part 1: General requirements for basic safety and essential performance, contains a section specifically on programmable electrical medical systems. For the choice of methods and standards used for software verification and validation, the manufacturer should provide a rationale. 2.3.2.3.4. Cybersecurity tests For devices that incorporate software or for software that are devices in themselves, the software should be designed and manufactured in accordance with the state of the art, considering the principles of the development life cycle, risk management, including information security, verification and validation34. A description of how testing for verification and validation of security was performed should be provided. Methods can include security feature testing, fuzz testing, vulnerability scanning and penetration testing. Additional security testing can be done by using tools for secure code analysis and tools that scan for open source code and libraries used in the device, to identify components with known issues. Please refer to MDCG 2019-16 Guidance on Cybersecurity for medical devices for further details. 2.3.2.3.5. Validation of cleaning, disinfection and sterilization The sterilization method, cleaning and disinfection used should be stated and justified in the IB. A broad range of standards are available for disinfection and sterilisation methods, such as radiation, ethylene oxide, dry and moist heat. For sterilization, a validation report should be provided35. Validation reports for cleaning and disinfection are not expected with the submission, but need to be summarised in the IB and referenced in relation to the overview of GSPR (section 34 Section 17.2, Annex I of the MDR. 35 Article 71(3f) of the MDR. Medical Device Medical Device Coordination Group Document MDCG 2024-5 20 2.7). Compatibility of the method used and the device should be discussed, if applicable. Clearly state the validated method for reprocessing reusable devices. Should ethylene oxide be used as sterilizing agent, please specify whether testing for residuals is performed and provide the results and conclusions of these tests36. For invasive devices please specify how endotoxin levels have been tested37 and which acceptance criteria38 have been used. 2.3.2.3.6. Packaging validation Packaging systems need to be validated for both sterile and non-sterile devices. Describe how the ability of the packaging has been validated to ensure the device maintains its integrity and, when applicable, sterility, considering its distribution and storage (as specified by the manufacturer). In cases of sterile packaging, validation of the packaging’s ability to maintain sterility is important. Packaging validation may also be necessary for other packaging situations, e.g. mechanical and thermal stability. 2.3.3. Animal tests If applicable, include a summary of all in vivo animal tests that have been conducted (a reference to external documents is typically not sufficient). Each summary should include information on the laboratory where the test has been performed, as well as study design choices including: • Species used, breed • Number of animals per group • Age of animals • GLP status (if non-GLP, this should be justified) • Version of the device used • Choice or absence of comparator, with justification • Duration of exposure • Standard applied, if any • Results • Evaluation of results An overview of the analyses performed should be provided. Acceptance criteria, results, any deviations and conclusions should be presented. Any notable findings should be mentioned and discussed. In case of non-GLP studies, it is expected that study reports (which may be requested by the competent authority) are compliant with the ARRIVE guidelines39 or equivalent (to the extent that this is possible). In addition to the summaries provided in the IB, sponsors are recommended to submit the referenced full study reports from preclinical animal tests to the competent authority. 36 Refer to standard ISO 10993-7. 37 Such as ISO standard 11737-3 “Sterilization of health care products — Microbiological methods — Part 3: Bacterial endotoxin testing”. 38 Often available in pharmacopoeia. 39 https://arriveguidelines.org/arrive-guidelines . https://www.nc3rs.org.uk/sites/default/files/documents/Guidelines/NC3Rs%20ARRIVE%20Guidelines%202013.pdf https://arriveguidelines.org/arrive-guidelines Medical Device Medical Device Coordination Group Document MDCG 2024-5 21 2.4. Existing clinical data According to section 2.4, chapter II, Annex XV of the MDR, the IB should include 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. If applicable an overview of ongoing and completed clinical investigations with the investigational device should be provided. Tabular presentation of clinical investigation information is recommended, including number of subjects, indication for use, endpoints, etc. In addition, it might be relevant to provide such information on devices that have similar characteristics, as well as information on studies with the investigational device that relate to other indications for use. If equivalence with previous generations of the device or competitor devices based on the same technology is claimed, the demonstration of equivalence should be done in line with the provisions in Section 3 of Annex XIV of the MDR and the MDCG guidance 2020-5 Clinical Evaluation - Equivalence. A guide for manufacturers and notified bodies. The overview must provide sufficient and clear information on the previous clinical investigation(s), including sites/centres, safety and performance results and an analysis of adverse device effects, serious adverse events (SAE) and any history of modification or recall of the investigational device. In case the clinical investigation has a phased approach, and the study is expanded to other sites that were not involved in the initial phase, it is recommended to review and update, if necessary, the IB with a summary or interim analysis of the current status discussing any notable information such as SAEs. Ensure that interim analyses are based on clean data. For CE-marked devices evaluated outside the intended purpose as well as in situations where there are previous marketed generations of the device, please provide a summary of the latest Periodic Safety Update Report (PSUR) for class II-III devices or Post Market Surveillance Report (PMSR) for class I devices. If applicable any compassionate use of the device should be described, with information on the extent of use and any relevant finding if available. 2.5. Risk management of the investigational device According to section 2.5, chapter II, Annex XV of the MDR, the IB should include a summary of the benefit-risk analysis and the risk management, including information regarding known or foreseeable risks, any undesirable side-effects, contraindications, and warnings. Sponsors conducting clinical investigations of CE marked devices which are being investigated outside the intended purpose for which they have been CE-marked, need to make sure that the differences in use (e.g. different duration, location, user or patient population) and any new risks that arise from them have been appropriately addressed in the risk management and that this is described in the IB. The risk management process needs to be described. It should describe risk Medical Device Medical Device Coordination Group Document MDCG 2024-5 22 analysis, risk evaluation and risk control/mitigation (this last part includes benefit-risk analysis). It should also describe the levels used for assigning probabilities and severities of harm and the risk-acceptability criteria that are used (in other words: When do the benefits outweigh the risks?). Refer to ISO 14971:201940 and ISO/TC 24971:202041 for more info on the application of risk management to medical devices and Annex H in ISO 14155:2020 on the application of ISO 14971 to clinical investigations. When needed, the competent authority may request that the full Risk Analysis Table, Risk Management Plan and/or Risk Management Report as well as actual data and evaluations from specific tests are provided. If these documents are referenced in the IB, the references to the sections of interest in the documents should be provided in the IB. Some examples of types of risk analyses: - HAZOP: Hazard and Operability - FMEA: Failure mode and effects analysis - FTA: Fault tree analysis - Procedure analysis The risk management methods and techniques listed above should normally be used in combination so that all reasonably foreseeable risks are identified and managed. Detail what information was used to estimate the risks. For example published standards or articles about similar devices, expert assessments, tests or simulations. It might be useful to describe the estimation scales that are used for probability and severity estimations. For example, is it a risk matrix of 3 x 3, a 4 x 5, a 5 x 5. Note that matrices with more than five levels can require significantly more data to be able to distinguish between the various levels and to avoid overlap of the levels. Rationales for the selection of matrices and their outcome scores should be documented. It is also to be noted that matrices with three levels might not always be sufficiently accurate for adequate decision making. There is no need that these matrices be balanced. For example, a 4 × 5 matrix could be appropriate for a given application. Regarding probabilities levels such as 1:10, 1:100 may be used. The levels of severity should be selected based on what is relevant for the device, its intended use and users. Risk control measures should be taken to reduce any identified risks as far as possible. Risk control measures are generally divided into three broad categories, in order of priority: • Risk elimination/reduction through safe design and manufacture, e.g. identifying risks through pre-clinical testing and pre-clinical evaluation and making changes in design or manufacturing in advance of the clinical investigation; completion of bench testing, pre-clinical evaluation, and verification and validation of design prior to commencement of the clinical investigation application; designing the clinical investigation to be conducted in accordance with relevant international standards, consensus guidance, and good clinical practice; performance of the study at specialised clinical sites only, with investigators meeting specific specialist criteria. • Protective measures, e.g.; physical protective measures of the device; in the context of a clinical investigation, measures such as staged enrolment and interim pre- 40 Medical devices – Application of risk management to medical devices (ISO 14971:2019). 41 ISO/TR 24971:2020 Medical devices — Guidance on the application of ISO 14971. Medical Device Medical Device Coordination Group Document MDCG 2024-5 23 specified subject safety assessment, pre-specified stopping rules, narrow study population with more favourable benefit-risk profile, independent study oversight (such as data monitoring committees, clinical events committees), frequent and accurate reporting and investigation of SAEs and device deficiencies (DDs), accurate recording of AEs/SAEs/DDs, including the timing and clinical context and a description of any medical interventions provided and the associated outcomes. • Communication of safety information and residual risks, e.g., through patient information sheet; training of investigational staff on residual risks; provision of warnings, precautions, and contra-indications on labelling, in the instructions for use, and in the IB; optimizing communication among sites in order to rapidly communicate and informs sites of any emerging risks; communicating safety data and residual risks with ethics committee(s) and competent authority(ies) to determine if any additional subject protection measures are needed. Please provide, in the IB, information on any identified residual risks, including risk-benefit analysis of these residual risks. Please provide a list of warnings, precautions, and contra- indications for the investigational device. 2.5.1. Anticipated Serious Adverse Events (SAEs) and Serious Adverse Device Effects (SADEs) Based on their internal risk management documents sponsors are expected to assess anticipated frequency of occurrence of serious adverse events (SAEs) and serious adverse device effects (SADEs). The outcomes of this assessment could preferably be presented in a tabular format in the IB.The following table is an example of recommended characteristics of the events to include. Such a table will help the sponsor with its duties regarding the risk assessment of the device and the procedures. It could also be used by the competent authorities for the assessment of the risk- benefit of the clinical investigation and safety follow up during the conduct of study. When the same source is used, it can reduce the risk of divergent interpretation between sponsor and competent authorities. In the safety analysis of the SAE reports, the table would help determine whether the benefit/risk ratio of the clinical investigation has changed due to the reported SAE/SADE. When a SAE/SADE is reported it can be compared to the table to determine whether it was listed among the anticipated SAEs/SADEs and the observed/reported frequency of SAEs/SADEs can be compared to the expected/previously reported frequency. Anticipated SAE/SADE Related to device or procedure Probability of occurrence Reference (basis of these numbers) Medical Device Medical Device Coordination Group Document MDCG 2024-5 24 Sponsors are reminded that if new data arises that is likely to substantially impact the safety, health or rights of the subjects or the robustness or reliability of the clinical data generated by the clinical investigation, it shall notify within one week the member states in which the clinical investigation is being conducted42. The new data needs to be reflected in updated documents included with the notification of substantial modification to the competent authorities. When updating the IB during the conduct of the clinical investigation, the sponsor is expected to revise the table with up-to-date information including safety reports arising from the ongoing clinical investigation. Sponsors are further encouraged to link information in the anticipated SAE table to the IMDRF codes43 that will be used in the future European database on medical device (EUDAMED)44, and which are already used in the manufacturers incidents report (MIR)45. This will support the device community (manufacturer, competent authorities, notified body) to get a global view of the safety of a device throughout its lifecycle. 2.6. 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 According to section 2.6, chapter II, Annex XV of the MDR, the IB should include 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. Note that methods specified in Annex I to Directive 2001/83/EC shall be used to verify the quality, safety and usefulness of substances which, if used separately, would be considered to be a medicinal product within the meaning of point (2) of Article 1 of that directive.46 For CE-marked devices which are unaltered but used outside the intended purpose, the quality aspects in section 2.6.2 may be considered as appropriately addressed during the conformity assessment by the Notified Body, and the evidence submitted may be adapted accordingly. 2.6.1. General requirements For medicinal substances the chemical name, chemical and structural formula should be presented. In case a medicinal product is included in the device, it could be relevant to reference that a Marketing Authorization has already been obtained in EU (e.g. the number of the authorization for placing the medicinal product on the market). Also, the general information that can be provided for the medicinal product is the name of the medicinal product. i.e. both the common 42 Article 75 Substantial modifications to clinical investigations. 43 Terminologies for Categorized Adverse Event Reporting (AER): terms, terminology and codes | International Medical Device Regulators Forum (imdrf.org). 44 Medical Devices – EUDAMED (europa.eu). 45 Manufacturer incident report 2020 and Questions and Answers document regarding the Implementation of the new Manufacturer Incident Report (MIR) Form. 46 Section 12.1, Annex I of the MDR. https://www.imdrf.org/documents/terminologies-categorized-adverse-event-reporting-aer-terms-terminology-and-codes https://www.imdrf.org/documents/terminologies-categorized-adverse-event-reporting-aer-terms-terminology-and-codes https://health.ec.europa.eu/medical-devices-eudamed_en https://ec.europa.eu/docsroom/documents/41681 https://ec.europa.eu/docsroom/documents/41322 https://ec.europa.eu/docsroom/documents/41322 Medical Device Medical Device Coordination Group Document MDCG 2024-5 25 name, which is the international non-proprietary name (INN) as well as the trade mark ; qualitative and quantitative composition; pharmaceutical form (e.g. tablet, capsule, cream, ointment, solution for injection etc). Then main physical, chemical, pharmaceutical, toxicological and pharmacokinetic properties of the substance as well as available clinical data should be summarised. It is necessary to elaborate not only on the safety, quality and effectiveness of the active substance itself, but also on possible interactions between the substance and the materials used in devices and/or other substances. Note that where relevant, the pharmacodynamics, pharmacokinetics, toxicity and local tolerance of the substance may need to be specifically addressed during the pre-clinical evaluation and should be covered in the relevant subsection(s) under 2.3 above. Justify the inclusion of the medicinal substance, human blood or plasma derivative, non-viable tissues or cells of human or animal origin (or their derivatives) in relation to the intended clinical use and clinical benefit of the device. If there is already a scientific opinion47 issued on the quality and safety of the substance, tissues or cells of human or animal origin or their derivates, this opinion should be summarized and referenced in the IB, and a copy of the scientific opinion should be provided with the application to the Competent Authority. 2.6.2. Quality aspects Sponsors are encouraged to provide the detailed information on quality aspects required for the competent authority’s assessment in a separate document, e.g. for commercial confidentiality or readability reasons, and to provide a summary in the IB which is relevant to the investigators. Sponsors are further recommended to consult the EMA guidances on Investigational Medicinal Product Dossiers48,49, which provides information on expected content and structure for quality documentation related to the incorporated medicinal substance, human blood or plasma derivatives, non-viable tissues or cells of human or animal origin, or their derivatives. It is expected that relevant aspects of EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines50 are applied. • The manufacturer of the medicinal substance51 should be stated and compliance to EU- GMP or a relevant quality system verified. A GMP certificate, manufacturing authorisation or similar should be referenced in the IB if available and copies included with the application to the Competent Authority. The date of the last inspection should be indicated. • A sufficiently detailed description of the manufacturing process to allow assessment of the specification with regards to e.g. impurities. • A specification for the medicinal substance should be provided together with descriptions of the analytical methods used as well as verification of their suitability (unless references to Ph Eur methods are given). Results from batch analysis should be presented. • The container/closure systems used for storage should be described. • A shelf-life and a storage condition should be proposed and supported by stability data. 47 Refer to sections 5.2, 5.3 and 5.4 in Annex IX of the MDR. 48 Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (europa.eu). 49 Guideline on quality for biological IMPs (europa.eu). 50 EudraLex – Volume 4 (europa.eu). 51 Also relevant for human blood or plasma derivatives, non-viable tissues or cells of human or animal origin, or their derivatives even in situations where they may not be considered medicinal substances. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational_en.pdf https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational_en.pdf https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-quality-documentation-concerning-biological-investigational-medicinal_en-2.pdf https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en Medical Device Medical Device Coordination Group Document MDCG 2024-5 26 For chemical medicinal substances a Certificate of suitability to the monographs of the European Pharmacopoeia issued by the European Directorate for the Quality of Medicines (EDQM) or an Active Substance Master File (ASMF) could be referred to. Note that when reference is made to a EDQM Certificate of suitability to the monographs of the European Pharmacopoeia (CEP), the certificate should be included in the application. If reference is made by the device manufacturer to the substance manufacturer’s documentation, a Letter of Access is required. If no certificate of suitability or ASMF is available, complete documentation of the substance is required. Note that for substances of biological origin, it is not possible to refer to a certificate of suitability or ASMF. 2.6.2.1. Information on incorporation of the medicinal substance in the device The IB needs to contain sufficient information to allow evaluation of the quality of the medicinal substance after it has been incorporated in the device. The incorporation process, including sterilisation may impact the quality of the medicinal substance. If the substance is chemically modified, mixed with excipients and/or solvents during the process, this should be described, even if the excipients or solvents used are not present in the final device. Information on the quality and purpose of excipients should be provided. The complete composition of the final device must be provided. The methods to verify the amount/activity and release of medicinal substance from the final device should be presented and data from these tests should be provided. 2.6.2.2. Information on the final investigational device52 • The manufacturer should be stated and compliance to EU-GMP or a relevant quality system (ISO) verified. The date of the last inspection should be indicated. • A complete composition of the investigational device should be provided. • A detailed description of the manufacturing process including details about the sterilisation process, in-process controls and control of all raw materials and intermediates. • A specification for the investigational device together with descriptions of the analytical methods used (unless references to Ph Eur methods are given). Results from batch analysis should be presented. • The container/closure system used should be stated. A shelf-life and storage condition should be proposed and supported by stability data. 2.6.2.3. Specific requirements for starting materials, intermediates or substances of biological origin • Information on the collection and control of starting material should be provided 52 With incorporated medicinal substance, human blood or plasma derivatives, non-viable tissues or cells of human or animal origin, or their derivative. Medical Device Medical Device Coordination Group Document MDCG 2024-5 27 • Information on the manufacturing process should include details relevant for inactivation of viral and bacterial contamination (reagents used, time, temperatures pH, irradiation dose etc.) should be provided. • The EU Tissue Directive (2004/23/EC) and EU Blood Directive 2002/98/EC should be followed for tissues, cells and blood respectively 2.6.2.4. Specific requirements for adventitious agents • A TSE statement confirming compliance to EN ISO 22442-3:2007 and the TSE guideline EMA/410/0153 should be provided. • A viral risk assessment in accordance with EN ISO 22442-1:2015 and Ph Eur 5.1.7 Viral safety should be provided. The risk assessment should also include information about the capacity of the manufacturing process to remove viral contamination. 2.6.2.5. Additional information required for substances from human plasma • Information in accordance with the EMA guideline EMA/CHMP/BWP/706271/2010 Guideline on plasma-derived medicinal products is to be provided. • Information regarding the contract that has been established between the supplier of the plasma derived product/substance and the manufacturer of the device to ensure that the traceability is maintained from donation to the device for at least 30 years and that the manufacturer of medical device and Competent Authorities would be informed if, in exceptional circumstances, post collection information would lead to measures regarding the product.54 • If a product licensed in an EU country is used for the manufacture of the device, please state which product, the country(ies) where it is authorised and include information on whether the human plasma used for the medicinal product in question is covered by an EMA certified PMF (Plasma Master File). 2.6.2.6. Substance of animal origin The source countries for collection of the substance should be stated together with information about the health status of the animals. 2.7. Fulfilment of General Safety and Performance Requirements According to section 2.7, chapter II, Annex XV of the MDR, the IB should include a list detailing the fulfilment of the relevant GSPR set out in Annex I of the MDR, including the standards and any common specifications applied, in full or in part, as well as a description of the solutions for fulfilling the relevant GSPRs, in so far as those standards and common specifications have not or have only been partly fulfilled or are lacking. The IB should provide an overview of which GSPRs are applicable for the investigational device and a rationale for any GSPRs indicated as not applicable. Further, it should be clearly indicated 53 Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01 rev.3) (europa.eu). 54 EMA/CHMP/BWP/706271/2010 Committee for medicinal products for human use (CHMP) Guideline on plasma-derived medicinal products. https://www.ema.europa.eu/en/documents/scientific-guideline/minimising-risk-transmitting-animal-spongiform-encephalopathy-agents-human-veterinary-medicinal_en.pdf https://www.ema.europa.eu/en/documents/scientific-guideline/minimising-risk-transmitting-animal-spongiform-encephalopathy-agents-human-veterinary-medicinal_en.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 28 which GSPRs that have already been addressed by objective evidence and which GSPRs that will be addressed in the proposed study. Reference can be made to the relevant GSPR documentation. The overview should indicate the means (e.g. standard, CS, internal procedure) to address each applicable GSPR and the corresponding evidence, e. g. by listing the report(s). It is not sufficient to list the standards only and it is not sufficient to list the file in which the report will be placed, e. g. the risk management file. It is also not appropriate to list the title of a report that is not yet available. The GSPR documentation should thus contain both a prospective and retrospective summary of compliance, and clearly show the evidence already evaluated. With regard to the GSPRs that are not yet met but will be covered by the investigation, please identify them clearly and indicate how every precaution has been taken to protect the health and safety of the subjects and other users. If some GSPRs are not relevant for the investigational device, this should be indicated and briefly justified. All of the information above is preferably presented in the format of the checklist of GSPRs, standards, common specifications and scientific advice, which can be found as an annex in the MDCG 2021-8 guidance55. This template has two sections: Section A where standards, common specifications and scientific advice can be listed, and the level of compliance is indicated. Section B is a matrix for documenting the fulfilment of the GSPRs, referencing the applied standards or common specifications, as well as the evidence of conformance, documentation and justification/comment in case of deviation. If documenting the conformance with a particular requirement is the purpose of the current clinical investigation, this should be clearly indicated in the matrix. In case CE-marked devices are investigated in the clinical investigation, fulfilment of the GSPRs for the intended purpose(s) covered by the CE-mark should be confirmed by providing the EU Declaration of Conformity56 issued by the manufacturer and the certificate issued by the Notified Body57 (if applicable, depending on device classification). 2.8. Procedures According to section 2.8, chapter II, Annex XV of the MDR, the IB should include 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. All involved procedures may impact the overall risk assessment of the clinical investigation and the sponsor needs to ensure that risks associated with the planned use of the investigational device have been included in the risk assessment. If the use of the investigational device deviates from normal clinical practice this should be highlighted. Note that it is appropriate to describe what is considered normal clinical practice in this section. 55 MDCG 2021-08 Clinical investigation application/notification documents. 56 Article 19 and Annex IV of the MDR. 57 Article 56 and Annex XII of the MDR. https://ec.europa.eu/health/system/files/2021-05/mdcg_2021-8_en_0.pdf Medical Device Medical Device Coordination Group Document MDCG 2024-5 29 Specify any other devices or medicinal products to be used in combination with the investigational device and comment on their regulatory status. It is necessary to describe any potential new risks with such combinations and how these are managed. In addition, it is necessary to ensure that the combined use planned in the investigation does not impact the regulatory status of the other devices or medicinal products. Medical Device Medical Device Coordination Group Document MDCG 2024-5 Appendix A Cross-references between requirements in Annex XV chapter II of the MDR and the Clinical Investigation submission package Prior to submission of the IB, sponsor may complete this checklist to ensure the IB meets the minimum requirements for validation of the application per article 70 of the MDR. The checklist, if used, should be included together with the IB in the submission to facilitate the validation by the competent authority. Cross-references between requirements in Chapter II Annex XV of the MDR and the Clinical Investigation submission package Requirement Description of requirement Location within submission package Annex XV Chapter II (2): Investigators Brochure (information in IB or enclosed as separate documents with a summary provided in the IB. 2.1 Identification and description of the device Document Page 2.1 Identification of the device Document Page 2.1 Information on the intended purpose Document Page 2.1 The risk classification and applicable classification rule pursuant to Annex VIII Document Page 2.1 Design of the device Document Page 2.1 Manufacturing of the device Document Page Medical Device Medical Device Coordination Group Document MDCG 2024-5 31 Cross-references between requirements in Chapter II Annex XV of the MDR and the Clinical Investigation submission package Requirement Description of requirement Location within submission package If enclosed as separate documents, a clear reference within the IB should be made to the enclosed documents) 2.1 Reference to previous and similar generations of the device. Document Page 2.2 Manufacturer's instructions for installation, maintenance, maintaining hygiene standards and for use, including storage and handling requirements Document Page 2.2 Information to be placed on the label Document Page 2.2 Instructions for use to be provided with the device. Document Page 2.2 Information relating to any relevant training required. Document Page Medical Device Medical Device Coordination Group Document MDCG 2024-5 32 Cross-references between requirements in Chapter II Annex XV of the MDR and the Clinical Investigation submission package Requirement Description of requirement Location within submission package 2.3 Pre-clinical evaluation based on pre-clinical testing and experimental data in particular as applicable; in-design calculations, in-vitro test, ex-vivo test, animal test, mechanical test, electrical test, reliability test, sterilization validation, software verification and validation, performance test, evaluation of biocompatibility and biological safety. Summary and evaluation of pre-clinical/ non-clinical data Document(s) Page 2.4 Existing clinical data, in particular available literature or other clinical data available relating to safety, performance and clinical benefit Document Page 2.5 Summary of the benefit risk analysis and risk management Document Page 2.5 Information regarding known or foreseeable risks, any undesirable side effects, contraindications and warnings Document Page Medical Device Medical Device Coordination Group Document MDCG 2024-5 33 Cross-references between requirements in Chapter II Annex XV of the MDR and the Clinical Investigation submission package Requirement Description of requirement Location within submission package 2.6 In case of devices that contains: medicinal substance Detailed information om the substance, and the risk management in relation to the substance, and evidence for the added value of incorporation of such constituents in relation to the clinical benefit and safety of the device Document Page 2.6 In case of devices that contains: human blood / plasma or derivate Detailed information om the substance, and the risk management in relation to the substance, and evidence for the added value of incorporation of such constituents in relation to the clinical benefit and safety of the device Document Page 2.6 In case of devices that contains non-viable tissues or cells of human or animal origin, or their derivatives Detailed information on the tissue/cell their derivate, and the risk management in relation to the tissue, cell or their derivate, and evidence for the added value of incorporation of such constituents in relation to the clinical benefit and safety of the device Document Page 2.7 List of fulfilment of the General Safety and Performance Requirements (GSPR). Document Page Medical Device Medical Device Coordination Group Document MDCG 2024-5 34 Cross-references between requirements in Chapter II Annex XV of the MDR and the Clinical Investigation submission package Requirement Description of requirement Location within submission package 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. Document Page Abbreviations 1. Introduction 2. Content of the Investigator’s Brochure Administrative details 2.1. Investigational device information 2.1.1. Identification of the device 2.1.2. Intended purpose 2.1.3. Intended clinical performance9F 2.1.4. Qualification and classification 2.1.5. Literature and evaluation supporting the rationale for the design and intended use of the investigational device 2.1.6. General description of the device: 2.1.6.1. Design 2.1.6.1.1. Description of the key functional elements 2.1.6.1.2. Overview of materials used 2.1.6.1.3. Technical specifications 2.1.7. Summary of relevant manufacturing processes 2.1.8. Reference to previous and similar generations of the device 2.1.9. Overview of identified equivalent or, if any, similar devices available 2.2. Labels and instructions for use 2.2.1. Instructions for use 2.2.2. Labels 2.2.3. Training 2.2.4. Implant card 2.3. Pre-clinical evaluation 2.3.1. General recommendations regarding pre-clinical evaluation 2.3.2. Specific recommendations regarding pre-clinical evaluation 2.3.2.1. In design calculations 2.3.2.2. Bench testing - “horizontal” tests (valid for any device) 2.3.2.2.1. Performance tests 2.3.2.2.2. Reliability tests 2.3.2.2.3. Interoperability and compatibility tests 2.3.2.2.4. Usability tests 2.3.2.3. Bench testing - “Vertical”tests (depending on the device type) 2.3.2.3.1. Mechanical, electrical safety and electromagnetic compatibility tests 2.3.2.3.2. Biocompatibility and biological safety 2.3.2.3.3. Software verification and validation 2.3.2.3.4. Cybersecurity tests 2.3.2.3.5. Validation of cleaning, disinfection and sterilization 2.3.2.3.6. Packaging validation 2.3.3. Animal tests 2.4. Existing clinical data 2.5. Risk management of the investigational device 2.5.1. Anticipated Serious Adverse Events (SAEs) and Serious Adverse Device Effects (SADEs) 2.6. 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 2.6.1. General requirements 2.6.2. Quality aspects 2.6.2.1. Information on incorporation of the medicinal substance in the device 2.6.2.2. Information on the final investigational device51F 2.6.2.3. Specific requirements for starting materials, intermediates or substances of biological origin 2.6.2.4. Specific requirements for adventitious agents 2.6.2.5. Additional information required for substances from human plasma 2.6.2.6. Substance of animal origin 2.7. Fulfilment of General Safety and Performance Requirements 2.8. Procedures Appendix A

Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 1 of 23 MDCG 2024-4 Safety reporting in performance studies of in vitro diagnostic medical devices under Regulation (EU) 2017/746 April 2024 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 2024-4 Page 2 of 23 Table of contents 1 INTRODUCTION ................................................................................................... 4 2 SCOPE .................................................................................................................. 5 2.1 PERFORMANCE STUDIES OF IN VITRO DIAGNOSTIC MEDICAL DEVICES ........................................................................... 5 3 ABBREVIATIONS ................................................................................................. 5 4 DEFINITIONS ........................................................................................................ 6 4.1 ADVERSE DEVICE EFFECT (ADE) .......................................................................................................................... 6 4.2 ADVERSE EVENT (AE) ........................................................................................................................................ 6 4.3 ANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (ASADE) ....................................................................................... 6 4.4 COMPANION DIAGNOSTIC (CDX) ......................................................................................................................... 6 4.5 DEVICE FOR PERFORMANCE STUDY ....................................................................................................................... 6 4.6 DEVICE DEFICIENCY (DD) ................................................................................................................................... 6 4.7 INCIDENT ........................................................................................................................................................ 7 4.8 IN-HOUSE IVD ................................................................................................................................................. 7 4.9 INTERVENTIONAL CLINICAL PERFORMANCE STUDY .................................................................................................... 7 4.10 INVESTIGATOR ................................................................................................................................................. 7 4.11 LEFT-OVER SAMPLE ........................................................................................................................................... 7 4.12 MALFUNCTION ................................................................................................................................................. 7 4.13 MANUFACTURER .............................................................................................................................................. 7 4.14 NEW FINDING .................................................................................................................................................. 7 4.15 PERFORMANCE STUDY (PS) ................................................................................................................................ 7 4.16 PERFORMANCE STUDY PLAN (PSP) ....................................................................................................................... 7 4.17 SERIOUS ADVERSE DEVICE EFFECT (SADE) ............................................................................................................ 7 4.18 SERIOUS ADVERSE EVENT (SAE) .......................................................................................................................... 8 4.19 SPECIMEN ....................................................................................................................................................... 8 4.20 SPONSOR ........................................................................................................................................................ 8 4.21 STUDY PROCEDURE ........................................................................................................................................... 8 4.22 SUBJECT.......................................................................................................................................................... 8 4.23 UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) .................................................................................... 8 5 REPORTING METHOD ......................................................................................... 8 5.1 REPORTABLE EVENTS IN PRE-MARKET PS INITIATED UNDER DIRECTIVES LEGISLATION ...................................................... 9 5.2 TRANSITION TO REPORTING VIA EUDAMED............................................................................................................. 9 5.3 OVERVIEW OF FORMATS TO BE USED BY SPONSORS WHEN REPORTING TO NCAS ........................................................... 9 5.4 COLLECTING REPORTS FROM INVESTIGATORS .......................................................................................................... 9 6 REPORTABLE EVENTS ....................................................................................... 9 6.1 EXCEPTIONS FOR PMPF STUDIES FALLING UNDER IVDR ARTICLE 70(1) .................................................................... 11 6.2 REPORTABLE EVENTS OCCURRING IN OTHER MSS / THIRD COUNTRIES ...................................................................... 11 7 REPORT BY WHOM ........................................................................................... 12 8 REPORT TO WHOM ........................................................................................... 12 Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 3 of 23 9 REPORTING TIMELINES ................................................................................... 12 9.1 REPORT BY SPONSOR TO NCAS. ......................................................................................................................... 12 9.2 REPORT BY THE INVESTIGATOR TO THE SPONSOR ................................................................................................... 12 10 CAUSALITY ASSESSMENT ............................................................................... 13 11 REPORTING FORM ............................................................................................ 14 11.1 COMPLETION GUIDELINES: FORM HEADER ........................................................................................................... 15 11.2 COMPLETION GUIDELINES: EVENT DETAILS ........................................................................................................... 16 12 REFERENCES .................................................................................................... 20 13 APPENDIX – PERFORMANCE STUDY SUMMARY SAFETY REPORTING FORM ............................................................................................................................ 20 Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 4 of 23 1 Introduction Safety reporting in performance studies of in vitro diagnostic medical devices (IVDs) shall be performed in line with the requirements of Article 76(2) of Regulation (EU) 2017/746 – In Vitro Diagnostic Medical Device Regulation (IVDR): The sponsor shall report without delay to all Member States in which a performance study is being conducted all of the following by means of the electronic system referred to in IVDR Article 69: a) any serious adverse event that has a causal relationship with the device, the comparator or the study 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 performance study is being conducted, the sponsor shall provide all information referred to in paragraph 1 of IVDR Article 76(1). For post-market performance follow-up (PMPF) studies of CE marked devices1 used within the intended purpose covered by the CE marking, reporting requirements of IVDR Articles 76(5-6) apply. This means that the vigilance provisions laid down in IVDR Articles 82 to 85 and in the acts adopted pursuant to IVDR Article 86 apply to PMPF studies. However, this guidance document is still relevant for PMPF studies as the reporting of serious adverse events (SAEs) where a causal relationship to the preceding PMPF study has been established follow the reporting procedures of performance studies as outlined in IVDR Article 76. Since the electronic system referred to in IVDR Article 69 (Eudamed and its module for clinical investigations and performance studies) is not yet available and fully functional from the date of application of the IVDR, this guidance outlines the procedures for safety reporting in performance studies in the absence of the Eudamed module or when Eudamed is not yet fully functional (see also sections 5.1 and 5.2 in this guidance). This document defines SAE reporting modalities and includes a summary tabulation reporting format. 1 The PMPF studies referred to in IVDR Article 70(1). Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 5 of 23 2 Scope 2.1 Performance studies of in vitro diagnostic medical devices The reporting modalities and format set out in this guidance apply to: • Performance studies covered by IVDR Article 58(1): • in which surgically invasive sample-taking is done only for the purpose of the performance study; • that is an interventional clinical performance study as defined in IVDR Article 2(46); • where the conduct of the study involves additional invasive procedures or other risks for the subjects of the studies; • performance studies covered by IVDR Article 58(2) involving companion diagnostics (except when only using left-over samples); • PMPF studies covered by IVDR Article 70(1) that involve procedures additional to those performed under the normal conditions of use of the IVD and where those additional procedures are invasive or burdensome, in case a causal relationship between a SAE and the preceding performance study has been established; • performance studies covered by IVDR Article 70(2) that are conducted to assess, outside the scope of its intended purpose, an IVD that already bears the CE marking.2 • combined studies of medicinal products and IVDs. When the study satisfies the definition of a performance study of an IVD, regardless of whether it is conducted in the context of a clinical trial of a medicinal product, the requirements of the IVDR and including its safety reporting obligations apply to the study. This guidance document is then relevant for compliance with the IVDR regarding safety reporting. MDCG 2022-10 provides further guidance on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and the IVDR. 3 Abbreviations ADE Adverse Device Effect AE Adverse Event ASADE Anticipated Serious Adverse Device Effect CDx Companion diagnostic 2 The performance study sponsor is responsible for reporting per IVDR Article 76. However, the device manufacturer remains responsible for postmarket surveillance and vigilance obligations for the CE Mark device per IVDR Articles 82-83. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 6 of 23 DD Device deficiency IVD In Vitro diagnostic medical device IVDR Regulation (EU) 2017/746 on in vitro diagnostic medical devices MDR Regulation (EU) 2017/745 on medical devices MS Member State NCA national competent authority PS Performance study PSP Performance study plan SADE Serious Adverse Device Effect SAE Serious Adverse Event USADE Unanticipated serious adverse device effect 4 Definitions 4.1 Adverse Device Effect (ADE) Any adverse event related to the use of a device for performance study or a comparator3. See ISO 20916 section 3.1. 4.2 Adverse Event (AE) Any untoward medical occurrence, inappropriate patient management decision, 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 performance study, whether or not related to the device for performance study. See IVDR Article 2(60). 4.3 Anticipated Serious Adverse Device Effect (ASADE) Any serious adverse device effect which by its nature, incidence, severity or outcome has been identified in the risk assessment. See ISO 20916 section 3.5. 4.4 Companion diagnostic (CDx) A device which is essential for the safe and effective use of a corresponding medicinal product to: (a) identify, before and/or during treatment, subjects who are most likely to benefit from the corresponding medicinal product; or 3 A comparator might be: other CE-marked IVD, reference method, gold standard,… Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 7 of 23 (b) identify, before and/or during treatment, subjects likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product. See IVDR Article 2(7). 4.5 Device for performance study A device intended by the manufacturer to be used in a performance study. A device intended to be used for research purposes, without any medical objective, shall not be deemed to be a device for performance study. See IVDR Article 2(45). 4.6 Device deficiency (DD) Any inadequacy in the identity, quality, durability, reliability, usability, safety or performance of a device for performance study, including malfunction, use errors or inadequacy in information supplied by the manufacturer. See IVDR Article 2(62). 4.7 Incident 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 harm as a consequence of a medical decision, action taken or not taken on the basis of information or result(s) provided by the device. See IVDR Article 2(67). 4.8 In-house IVD An IVD manufactured and used within the same health institution as outlined in IVDR Article 5(5). Health institution is defined in IVDR Article 2(29). 4.9 Interventional clinical performance study A clinical performance study where the test results may influence patient management decisions and/or may be used to guide treatment. See IVDR Article 2(46). 4.10 Investigator An individual responsible for the conduct of a performance study at a performance study site. See IVDR Article 2(48). 4.11 Left-over sample Unadulterated remainder of human derived samples collected as part of routine clinical practice and after all standard analysis has been performed. Such specimens/samples would be otherwise discarded as there is no remaining clinical need for them. This can include specimens collected for research or other purposes not connected to the clinical performance study in question. Left- over samples include “specimen or sample that are collected in the past and obtained from repositories (e.g. tissue banks, commercial vendor collections). See ISO 20916 section 3.25. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 8 of 23 4.12 Malfunction Any failure of an device for performance study to perform in accordance with its intended use when used in accordance with the instructions for use or performance study plan. See ISO 20916 section 3.27. 4.13 Manufacturer 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 trade mark. See IVDR Article 2(23). 4.14 New Finding New information discovered as the result of an inquiry/investigation/test based on the occurrence of the event. Follow-up from the event. See MDCG 2020-10/1. 4.15 Performance study (PS) A study undertaken to establish or confirm the analytical or clinical performance of a device. See IVDR Article 2(42). 4.16 Performance study plan (PSP) A document that describes the rationale, objectives, design methodology, monitoring, statistical considerations, organisation and conduct of a PS. See IVDR Article 2(43). 4.17 Serious Adverse Device Effect (SADE) Any ADE that has resulted in any of the consequences characteristic of a serious adverse event. See ISO 20916 section 3.43. 4.18 Serious Adverse Event (SAE) Any AE that led to any of the following: a) a patient management decision resulting in death or an imminent life-threatening situation for the individual being tested, or in the death of the individual's offspring, b) death, c) serious deterioration in the health of the individual being tested or the recipient of tested donations or materials, 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 subject 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, d) foetal distress, foetal death or a congenital physical or mental impairment or birth defect. See IVDR Article 2(61). Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 9 of 23 4.19 Specimen Any discrete portion of a body fluid or tissue taken for examination, study, or analysis of one or more quantities or characteristics to determine the character of the whole body fluid or tissue. See ISO 20916 section 3.47. 4.20 Sponsor Any individual, company, institution or organisation which takes responsibility for the initiation, for the management and setting up of the financing of the PS. See IVDR Article 2(57). 4.21 Study procedure Any procedure foreseen in the PS (e.g. specimen collection) with the aim of investigating the device. 4.22 Subject An individual who participates in a PS and whose specimen(s) undergo in vitro examination by a device for PS and/or by a device used for control purposes. See IVDR Article 2(47). 4.23 Unanticipated serious adverse device effect (USADE) Any SADE, the nature, severity or outcome of which is not consistent with the reference safety information. See ISO 20916 section 3.52. 5 Reporting method The template of the Summary Reporting Form4 in the appendix should be used for all studies from 26 May 2022. The tabular form 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 transmitted to all national competent authorities (NCAs) where the PS is being performed. For a new finding or update, the line of the SAE needs to be updated and the first column set to “m”. Write the new findings in the free description of event column and highlight the additions. When applicable, update the others columns as well. For more details on how to complete the form, see section 11. Reporting form. 5.1 Reportable events in pre-market PS initiated under directives legislation Any SAE or DD that may (have) lead to a SAE occurring in a PS after 26 May 2022, regardless of when the PS started, should be reported in accordance with Article 76 of the IVDR.5 5.2 Transition to reporting via Eudamed Once Eudamed is fully functional, the obligations and requirements that relate to safety reporting via Eudamed shall apply. Full functionality of Eudamed shall start from six months after the date of publication of the notice referred to in IVDR Article 34(3) of the MDR. 4 National provisions can apply 5 National requirements may apply to PS that commenced under the IVDD. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 10 of 23 5.2.1 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 reports have been made according to the procedures described in this document. For these reportable events, follow-up and final reports will be submitted to the NCAs by the same procedure, but all new reportable events shall be entered in Eudamed. Whether retrospective uploading of previous event reports to Eudamed will be possible is not clear at the time this guidance is issued. 5.3 Overview of formats to be used by sponsors when reporting to NCAs From 26 May 2022 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 specific PS, Eudamed should continue to be used for reporting all new events and updates to those events throughout the remainder of the study. When Eudamed is mandatory, i.e. from the date corresponding to six months after the date of publication of the notice referred to in MDR Article 34(3). Web form via Eudamed shall be used for all new events, and updates to those events. The tabular format of this guidance (Appendix- Summary Reporting Form) can be used only to transmit follow-up reports/final reports to the NCAs on events which were initially reported in this format. 5.4 Collecting reports from investigators The format in which sponsors wish to receive single event reports from investigators will be up to the sponsor to design and they may be adapted to an individual PS. When sponsors design such reporting forms, they should consult this guidance document to ensure all relevant details are captured in the reports from the investigator, so that the sponsors can fulfil their reporting obligations. 6 Reportable events For the purpose of this guidance and based on the definitions above, the following events are considered reportable events in accordance with IVDR Article 76(2): a) any SAE that has a causal relationship with the device6, the comparator7 or the study procedure or where such causal relationship is reasonably possible; 6 Device= device for performance study. 7 A comparator might be: other CE-marked IVD, reference method, gold standard,… Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 11 of 23 b) any DD that might have led to a SAE 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). From the definition above, it also follows that SAEs related to a CE marked IVD which is part of a PS with an IVD for PS (for example a CE marked comparator IVD or a CE marked IVD that is used during the study procedure) are reportable if there is a causal (or reasonably possible) relationship to that IVD. The reporting procedures described in this guide should then be followed by the PS sponsor, in addition to the normal vigilance reporting for CE marked devices by the manufacturer (double reporting is certainly possible). All causality assessments should be made using section 10 of this guidance. Only causality level 1 (i.e. “not related”) is excluded from reporting. If either the sponsor or the investigator has assigned a higher causality level than "not related", the event should be reported. As not all safety provisions in the IVDR are applicable to all types of IVD PS, the following table depicts the safety provisions laid out in the IVDR that are applicable per type of IVD PS. Type of PS IVDR safety reporting provisions PS referred to in IVDR Article 58(1-2): Any PS or any combined IVD study (a clinical study of a medicinal product, medical device, in which an IVD is also studied): a. in which surgically invasive sample-taking is done only for the purpose of the PS; b. that is an interventional clinical PS as defined in IVDR Article 2(46); c. where the conduct of the study involves additional invasive procedures or other risks for the subjects of the studies; d. involving CDx (except when only using left-over samples). IVDR Article 76(2-3) PMPF study referred to in IVDR Article 70(1) with additional burdensome and/or invasive procedures. IVDR Article 76(5) AND IVDR Article 76(6) For more information, see section 6.1: Exceptions for PMPF studies falling under IVDR Article 70(1) and Section 10: causality Assessment. PS referred to IVDR Article 70(2) conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking. IVDR Article 76(2-3) Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 12 of 23 PS with an in-house IVD referred to in IVDR Article 5(5). No provisions on safety reporting according to the IVDR. However, safety reporting may be regulated by national legislation. 6.1 Exceptions for PMPF studies falling under IVDR Article 70(1) SAE reporting for PMPF studies falling under Article 70(1) is governed by Articles 76(5) and 76(6). This means that the provisions on vigilance apply and need to by the manufacturer of the CE marked device(s). However, when a causal relationship between the SAE and the preceding PS has been established, reporting procedures for PS should be followed by the PS sponsor. This means that: • For the purpose of this guidance (safety reporting in PS), reportable events in PMPF studies are those SAEs where a causal relationship between the SAE and the preceding PS has been established. The other relationship categories i.e. ‘not related’, ‘possible’ and ‘probable’ do not need to be reported. • In the context of vigilance, IVDR Articles 82-85 need to be taken into account and this concerns the serious incidents where a relationship between the incident and the device is at least reasonably possible. It is thus possible that events occurring in such PS need to be reported to both the competent authorities in charge of PS AND to the competent authorities in charge of vigilance. 6.2 Reportable events occurring in other MSs / Third Countries 6.2.1 Reportable events occurring in other MSs (MS) The sponsor shall report the reportable SAEs per PS. If several PS are conducted (e.g. specimen collection in multiple sites) with the same device, only those SAEs that happen in PS that have the same PSP code should be reported for those PS, and only to those MS where a PS with that specific PSP code is being conducted8. It is acknowledged that the same PS can be conducted under different versions of the same PSP code in different MS, e.g. with country specific adaptations, and in those cases the SAE reporting can normally be combined for all the versions of the PSP for the same PS. Reportable events occurring before the PS is authorised to start in a MS will be reported to this MS upon authorization in this MS. 8 “Is being conducted” has to be interpreted as “has been approved or have been notified to the NCA”. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 13 of 23 6.2.2 Reportable events occurring in third countries Reportable events occurring in third countries9 in which a PS is conducted (e.g. specimen collection in that country) under the same PSP (see section 6.2.1 for what is meant with same PSP) have to be reported in accordance with this guidance to the NCA(s) of the European MS(s) in which the PS is being conducted. • The NCA will start receiving the reportable events occurring in third countries as soon as the PS is authorised to start in that MS. • Reportable events occurring in third countries after the participating European sites have closed, shall continue to be reported to the MSs in which the PS was conducted. Reportable events occurring before the PS is authorized to start in a MS will be reported to this MS upon authorization in this MS. 7 Report by whom Reportable events have to be reported by the sponsor of the PS (or the PS sponsor’s delegate), which could be the manufacturer, the legal representative or another person10 or entity. 8 Report to whom Reportable events must be reported at the same time to all NCAs where the PS has commenced, using the summary table featured in the appendix. A list of PS contact points within the NCAs is published at the European Commission's webpage. For the purpose of this guidance, a PS is considered to have commenced in an individual MS when the sponsor is authorised to start the study in that MS in accordance with the provisions laid down in the IVDR. MSs may also require separate reporting to the Ethics Committee(s). 9 Reporting timelines 9.1 Report by sponsor to NCAs. The sponsor must report to all NCAs where the PS is authorised to start: • For all reportable events as described in section 6 which indicate an imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other patients/subjects, users or other persons or a new finding to it: immediately, but 9 Countries other than Switzerland, Turkey and those belonging to the EEA. 10 Contact person established by the sponsor in line with IVDR Article 58(4) if accepted by MS. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 14 of 23 not later than 2 calendar days after awareness by sponsor of a new reportable event or of new information in relation with an already reported event. This includes events that are of significant and unexpected nature such that they become alarming as a potential public health hazard. It also includes the possibility of multiple deaths occurring at short intervals. These concerns may be identified by either the NCA or the sponsor. • Any other reportable events as described in section 6 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 reportable event or of new information in relation with an already reported event. In some cases, a different periodicity or different modalities may be agreed between the participating NCAs and the sponsor according to the study’s design and to the pathology studied in the PS. This would allow implementation of adequate provision for PS in which SAE frequency is expected to be high due to the natural progression of the disease (e.g. palliative oncology). 9.2 Report by the investigator to the sponsor The sponsor must implement and maintain a system to ensure that the reporting of the reportable events as defined under section 6 will be provided by the investigator to the sponsor immediately, but not later than 3 calendar days after awareness of the event. 10 Causality assessment The relationship between the use of the in vitro diagnostic medical device11 (including the study procedure) and the occurrence of each SAE must be assessed and categorized. During causality assessment activity, clinical judgement must be used and the relevant documents, such as the Investigator’s Brochure, the PSP or the Risk Analysis Report must be consulted, as all the foreseeable SAEs and the potential risks are listed and assessed there12. The presence of confounding factors, such as concomitant medication/treatment, the natural history of the underlying disease, other concurrent illness or risk factors must also be considered. The above considerations also apply to the SAEs occurring in the comparison group. For the purpose of harmonizing reports, each SAE will be classified according to four different levels of causality: 1. Not related 2. Possible 3. Probable 11 Intended as both device for PS and comparator. 12 For a comparator device, the instructions for use could be a relevant document. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 15 of 23 4. Causal relationship The sponsor and the investigators will use the following definitions to assess the relationship of the SAE to the device for PS, the comparator or the study procedure. 1. Not related: the relationship to the device for PS, the comparator or to study procedures can be excluded when: - the event has no temporal relationship with the use of the device for PS, or the procedures related to use of the device for PS; - the relationship between the SAE and the device for PS is biologically implausible; - the discontinuation of device use or the reduction of the level of activation/exposure - when clinically feasible - and reintroduction of its use (or increase of the level of activation/exposure), do not impact on the SAE; - the event involves a body-site or an organ that cannot be affected by the device for PS or procedure; - the SAE can clearly 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 SAE does not depend on a false result given by the device for PS ; In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, depending on the type of device/procedures and the SAE. 2. Possible: the relationship with the use of the device for PS or the comparator, or the relationship with study procedures, is weak but cannot be ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/clinical condition or/and an effect of another device, drug or treatment). Cases where relatedness cannot be assessed, or no information has been obtained, should also be classified as possible. 3. Probable: the relationship with the use of the device for PS or the comparator, or the relationship with study procedures, seems relevant and/or the event cannot be reasonably explained by another cause. 4. Causal relationship: the SAE is associated with the device for PS, comparator or with study procedures beyond reasonable doubt when: - the product category the device for PS belongs to or similar IVDs and study procedures are known to have this event; - the event has a temporal relationship with the device for PS or study procedures; - other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or treatment) have been adequately ruled out; - harm to the subject is due to error in use; Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 16 of 23 - the event depends on a false result given by the device for PS used for diagnosis13, when applicable; In order to establish the relatedness, not all the criteria listed above might be met at the same time, depending on the type of device/procedures and the SAE. The sponsor and the investigators will distinguish between the SAEs related to the device for PS and those related to the procedures (any procedure specific to the PSP). Complications caused by concomitant treatments not imposed by the PSP are considered not related. Similarly, several routine diagnostic or patient management procedures are applied to subjects regardless of the PSP. If routine procedures are not imposed by the PSP, complications caused by them are also considered not related. The relationship between a SAE and the procedure or the device needs to be assessed separately. This does however not mean that they are mutually exclusive; a SAE can be related to both the procedure and the device, or it can be related only to the procedure or only to the device. When it is unclear whether an event is related to the device or to the procedure, the investigator should: • set the relationship to device to possible (or higher) AND • set the relationship to procedure to possible (or higher) When the healthcare provider performs the procedures and uses the device(s) for PS, the causality assessment of this healthcare provider should prevail. In case of self-tests, the assessment by the sponsor and the one by the user are equally weighted. In some particular cases the event may not be adequately assessed 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 and avoid these situations. Where an investigator assessment is not available and/or the sponsor remains uncertain about classifying the SAE, the sponsor should not exclude the relatedness; the event should be classified as “possible”, and the reporting is not to be delayed. Particular attention shall be given to the causality evaluation of unanticipated SAEs. The occurrence of unanticipated events could suggest that the PS places subjects at increased risk of harm than was to be expected beforehand. 11 Reporting form The reporting form template for the summary SAE tabulation is given in the Appendix of this document. 13 If a device for performance study gives an incorrect diagnosis, the subject might, for example, receive an unnecessary treatment and incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious disease. In other cases, the subject might not receive an effective treatment (thereby missing out on the benefits that treatment would confer), or might not be diagnosed with the correct disease or condition. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 17 of 23 The reporting form is study specific and covers only a given PS, defined by a distinct PSP. English is the recommended language for the reporting form. The reporting form can be modified in any applicable software (not only Microsoft Excel), but the file needs to be compatible with Microsoft Excel when sent to the participating NCAs. Sponsors who generate the excel report file by automated processes may implement other technical features in their systems for excel file generation to ensure the preferred terms listed in metadata are used. The template form contains inserted filters and functionalities to facilitate the use of preferred terminology in the reporting. These are important for the analysis and should be maintained. The table gives a cumulative overview of the reportable events per PS and will be updated and transmitted to participating NCAs each time a new reportable event or a new finding to an already reported event is to be reported. If more detailed information has to be provided on request of an NCA, the individual study specific reporting form should be used. 11.1 Completion guidelines: Form header 11.1.1 EUDAMED/CIV-ID It will not be possible to generate the Union-wide unique single identification number mentioned in IVDR Article 66 (1) before Eudamed is fully functional. Until Eudamed is fully functional, PS will get tracking numbers (CIV-ID) upon registration in the Eudamed2 database which is performed by the NCA upon receipt of an application. This CIV-ID is provided to the sponsor during the NCA’s handling of the initial application for the PS and should be entered on the safety reporting form. 11.1.2 Title of PS The identifying title of the PS. The title indicated here should be consistent with other title entries (such as in PS application form, PSP cover page etc). 11.1.3 PSP number/code The unique identification code or short name assigned to the specific PSP by the sponsor (numeric, alphanumeric or acronym) should be indicated. 11.1.4 Contact person Name, address, e-mail and telephone number should be provided for the person who is the sponsor’s point of contact in case the NCA has follow-up questions regarding submitted safety report forms. 11.1.5 MS+NCA Reference numbers For each participating MS, indicate the country code14 and the NCA’s national reference number for the PS. Example: SE 5.1-20YY-XXXXXX 14 Use ISO-3166-1 alpha-2 codes, i.e. two-letter country codes as defined in ISO 3166-1 Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 18 of 23 DK 20YYXXXXXX 11.1.6 No. of subjects enrolled to date total & No. of specimens tested with the IVD to date total Indicate the total number of subjects who have been enrolled and number of specimens that have been tested with the IVD (per date of report) in the PS globally. 11.1.7 No. of subjects enrolled to date per country & No. of specimens collected to date per country List all countries where the PS has been authorised by the report date and indicate the number of enrolled subjects and number of obtained specimens in the PS (per date of report) in each country. 11.1.8 Device type Indicate the type of device(s) assessed in the PS according to EMDN categories (use the level as specialised as possible). The EMDN can be accessed and downloaded in pdf and excel format at webgate.ec.europa. eu/dyna2/emdn and the European Commission’s website page for MDCG documents. 11.1.9 Reference MS Indicate the name of the MS which drew the unique EUDAMED ID (normally the first MS receiving an application for the PS). Once the coordinated assessment procedure (per IVDR Article 74) is up and running, the coordinating MS should be indicated here. 11.1.10 No. of devices for PS used to date total Indicate the total number of devices for PS (e.g. reagent kits) which have been used (per date of report) in the PS globally. The number of devices used could be indicative of a quality issue. Therefore, if not applicable to the device used, please provide justification and add another parameter to assess quality issues with the IVD. 11.1.11 No. of devices for PS used to date per country List all countries where the PS has been authorised by the report date and indicate the number of devices for PS (e.g. reagent kits) which have been used in the PS (per date of report) in each country. The number of devices used could be indicative of a quality issue. Therefore, if not applicable to the device used, please provide justification and add another parameter to assess quality issues with the IVD. 11.1.12 Date of report Indicate the date when the report is compiled for transmission to NCAs. Format DD/MM/YYYY. 11.2 Completion guidelines: Event details Each unique reportable event is presented in a separate line. Updates to a previously reported event should be made by changing the information in the same line, and clearly identified according to the principles described below. https://webgate.ec.europa.eu/dyna2/emdn/ https://ec.europa.eu/health/md_sector/new_regulations/guidance_en https://ec.europa.eu/health/md_sector/new_regulations/guidance_en Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 19 of 23 Any new information added in the form should be highlighted in bold and/or colour. This includes any new lines added and any changes made to the information in an already existing line. In the initial report, in any given line, no fields shall be left intentionally blank. To meet this requirement, preliminary information should be filled in, despite the need of further updating. 11.2.1 Status The sponsor shall identify the new/updated information in the status column as: A = added = new reportable event; D = deleted = already reported event that has been deleted due to downgrading to non- serious, due to integration in another event, or … Add the reason for deletion in the corresponding cell in column “Free description of event”. M = modified = new finding/update to an already reported event; U = unchanged. Do not add other options. 11.2.2 Date Sponsor received report of SAE/DD Indicate the date when the sponsor was first notified by the study site about the event. This date is checked for compliance with reporting timelines as outlined in section 9 Reporting timelines. Format DD/MM/YYYY. 11.2.3 Country code Indicate the country code14 for the country in which the subject associated with the event has been enrolled. Choose from dropdown menu or enter manually if code is not available. 11.2.4 Study site 11.2.4.1 Specimen collection Name identifying the institution or site where the specimen was collected. 11.2.4.2 Specimen analysis Name identifying the institution or site where the specimen was analysed. 11.2.5 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 provided in this form). 11.2.6 SAE or DD ID code The investigator, sponsor or manufacturer should assign a unique ID to each SAE or DD that has occurred. This number shall remain unchanged throughout all other alterations of the particular SAE reporting due to ongoing assessment. 11.2.7 Date of specimen collection Indicate the date of the relevant collection of the specimen. Format DD/MM/YYYY. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 20 of 23 11.2.8 Date of event onset The date when the first signs of an event were noticed may be different (earlier) than the date when the event fulfilled the seriousness criteria (see further the definition in section 4.15). The date when the event became an SAE should be reported as Date of event onset. In case of DDs which did not lead to an SAE, the date the DD was discovered should be indicated. Format DD/MM/YYYY. 11.2.9 SAE or DD Choose one option from SAE or DD. When a DD lead to a SAE, both need to be reported on separate lines. In the line of the DD/SAE, refer to the associated SAE/DD. Complete all possible information in both lines. This might mean double reporting of some information, but it is necessary that both the DD and the SAE have all information and can be analysed separately. Do not add other options. 11.2.10 Subject gender Choose one option from the following list (do not add other options): • Female • Male • Other • Unknown 11.2.11 Classification of event Choose one option from the following list of consequence characteristics (do not add other options): • Patient management decision resulting in death or an imminent life-threatening situation for the individual being tested or in the death of the individual’s offspring • Death • Life-threatening illness or injury • Permanent impairment of body structure or body function • Hospitalization or prolongation of hospitalization • Medical or surgical intervention • Chronic disease • Foetal distress, foetal death or congenital physical or mental or birth defect • Not applicable (Note that this option is only to be selected in case of reportable DDs that did not lead to an SAE) 11.2.12 SAE connected to specimen collection or to specimen analysis Choose one option from the following list (do not add other options): Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 21 of 23 • Specimen collection • Specimen analysis (including pre-analytical, analytical and post-analytical phase) 11.2.13 Free description of event Provide a description of the event in free text. Please provide other relevant information not already captured in this report. 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 SAE) • Medical background of the subject • Medical care of the subject • Comments on the event in relation to already known safety data 11.2.14 Device issue (if applicable) The IMDRF codes applicable to device issues can be found in annex A on the IMDRF webpage related to AE terminology. You can use this worksheet to look up the appropriate codes. Please report all the appropriate codes applicable for the SAE or DD reported. Please separate each code only by “;”. Please do not use the terminology, but only the codes. 11.2.15 Clinical signs/symptoms The IMDRF codes applicable to clinical signs/symptoms can be found in annex E on the IMDRF webpage related to AE terminology. Please report all the appropriate codes applicable for the SAE or DD reported. Please separate each code only by “;”. Please do not use the terminology, but only the codes. 11.2.16 Clinical impact The IMDRF codes applicable to clinical impact of the SAE or DD can be found in annex F on the IMDRF webpage related to AE terminology. Please report all the appropriate codes applicable for the SAE or DD reported. Please separate each code only by “;”. Please do not use the terminology, but only the codes. 11.2.17 Action / treatment / outcome Provide information in free text on actions taken, treatment(s) administered and the outcome. “Outcome” is a broader term then “event status” and the value to be entered here is considered to be more specific than the options given for “event status” (see 11.4.13). 11.2.18 Relationship to procedure Choose one option from the following list of causality levels (for explanatory texts see section 10 Causality assessment) (do not add other options): • Not related https://www.imdrf.org/working-groups/adverse-event-terminology https://www.imdrf.org/working-groups/adverse-event-terminology https://www.imdrf.org/working-groups/adverse-event-terminology https://www.imdrf.org/working-groups/adverse-event-terminology https://www.imdrf.org/working-groups/adverse-event-terminology https://www.imdrf.org/working-groups/adverse-event-terminology Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 22 of 23 • Possible • Probable • Causal • Not applicable (please justify) Please report the assessments by sponsor and investigator in the respective columns. The investigator could mean the specimen collection site investigator or the specimen analysis site investigator. 11.2.19 Relationship to device Choose one option from the following list of causality levels (for explanatory texts see section 10 Causality assessment) (do not add other options): • Not related • Possible • Probable • Causal • Not applicable (please justify) Please report the assessments by sponsor and investigator in the respective columns. The investigator could mean the specimen collection site investigator or the specimen analysis site investigator. 11.2.20 Study arm Choose one option from the following list: • Test group (described in the PSP) • Comparison group (described in the PSP) • Blinded • Not applicable Note: For some study designs it might be more relevant to add name of device; i.e. in a PS with several test groups it might be useful to differentiate which study device was used for testing the subject. 11.2.21 Event status (only applicable for SAE) Choose one option from the following list (do not add other options): • Resolved • Resolved with Sequelae • Ongoing • Death Doesn’t need to be completed for DD. Medical Devices Medical Device Coordination Group Document MDCG 2024-4 Page 23 of 23 11.2.22 Date of event resolution (only applicable for SAE) Add date in format DD/MM/YYYY. If event status is “Ongoing” enter Not Applicable. 12 References 1. 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. 2. Council Directive 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices. 3. Commission Decision 2010/227/EU of 19 April 2010 on the European Databank on Medical Devices (Eudamed). 4. Codes for the representation of names of countries and their subdivisions – Part 1: Country codes (ISO 3166-1) published by International Organisation for Standardization (ISO). 5. In vitro diagnostic medical devices — Clinical performance studies using specimens from human subjects — Good study practice (ISO 20916) published by International Organisation for Standardization (ISO). 6. Documents by the International Medical Device Regulators Forum (IMDRF) to support regulatory harmonization: https://www.imdrf.org/documents. 7. MDCG 2022-10: Q&A on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR). 13 Appendix – Performance Study Summary Safety Reporting Form https://www.imdrf.org/documents 1 Introduction 2 Scope 2.1 Performance studies of in vitro diagnostic medical devices 3 Abbreviations 4 Definitions 4.1 Adverse Device Effect (ADE) 4.2 Adverse Event (AE) 4.3 Anticipated Serious Adverse Device Effect (ASADE) 4.4 Companion diagnostic (CDx) 4.5 Device for performance study 4.6 Device deficiency (DD) 4.7 Incident 4.8 In-house IVD 4.9 Interventional clinical performance study 4.10 Investigator 4.11 Left-over sample 4.12 Malfunction 4.13 Manufacturer 4.14 New Finding 4.15 Performance study (PS) 4.16 Performance study plan (PSP) 4.17 Serious Adverse Device Effect (SADE) 4.18 Serious Adverse Event (SAE) 4.19 Specimen 4.20 Sponsor 4.21 Study procedure 4.22 Subject 4.23 Unanticipated serious adverse device effect (USADE) 5 Reporting method 5.1 Reportable events in pre-market PS initiated under directives legislation 5.2 Transition to reporting via Eudamed 5.2.1 Ongoing events at time of transition to Eudamed 5.3 Overview of formats to be used by sponsors when reporting to NCAs 5.4 Collecting reports from investigators 6 Reportable events 6.1 Exceptions for PMPF studies falling under IVDR Article 70(1) 6.2 Reportable events occurring in other MSs / Third Countries 6.2.1 Reportable events occurring in other MSs (MS) 6.2.2 Reportable events occurring in third countries 7 Report by whom 8 Report to whom 9 Reporting timelines 9.1 Report by sponsor to NCAs. 9.2 Report by the investigator to the sponsor 10 Causality assessment 11 Reporting form 11.1 Completion guidelines: Form header 11.1.1 EUDAMED/CIV-ID 11.1.2 Title of PS 11.1.3 PSP number/code 11.1.4 Contact person 11.1.5 MS+NCA Reference numbers 11.1.6 No. of subjects enrolled to date total & No. of specimens tested with the IVD to date total 11.1.7 No. of subjects enrolled to date per country & No. of specimens collected to date per country 11.1.8 Device type 11.1.9 Reference MS 11.1.10 No. of devices for PS used to date total 11.1.11 No. of devices for PS used to date per country 11.1.12 Date of report 11.2 Completion guidelines: Event details 11.2.1 Status 11.2.2 Date Sponsor received report of SAE/DD 11.2.3 Country code 11.2.4 Study site 11.2.4.1 Specimen collection 11.2.4.2 Specimen analysis 11.2.5 Subject ID code 11.2.6 SAE or DD ID code 11.2.7 Date of specimen collection 11.2.8 Date of event onset 11.2.9 SAE or DD 11.2.10 Subject gender 11.2.11 Classification of event 11.2.12 SAE connected to specimen collection or to specimen analysis 11.2.13 Free description of event 11.2.14 Device issue (if applicable) 11.2.15 Clinical signs/symptoms 11.2.16 Clinical impact 11.2.17 Action / treatment / outcome 11.2.18 Relationship to procedure 11.2.19 Relationship to device 11.2.20 Study arm 11.2.21 Event status (only applicable for SAE) 11.2.22 Date of event resolution (only applicable for SAE) 12 References 13 Appendix – Performance Study Summary Safety Reporting Form

Ausgabe 146/2025 31. Juli 2025 Persönliches Exemplar für Pharma Deutschland Presse Inhaltsverzeichnis Arzneimittelsicherheit In eigener Sache: Umfrage zu sozialen Medien in Consumer Healthcare Friendly Reminder zur Teilnahme an einer Umfrage zu sozialen Medien im Bereich Consumer Healthcare, die im Rahmen der Masterarbeit von Nora Krogull (Referentin Arzneimittelsicherheit) verwendet wird. Arzneimittelversorgung G-BA: Stellungnahmeverfahren zur Anlage XII (Nutzenbewertung nach § 35a SGB V) – Belumosudil (chronische Graft-versus-Host-Krankheit); Beschränkung der Versorgungsbefugnis Der Gemeinsame Bundesausschuss (G-BA) hat in einem Schreiben an die Verbände über die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie informiert. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 1/25 Arzneimittelversorgung G-BA: Aufforderung zum Vorschlag geeigneter digitaler medizinischer Anwendungen – DMP Diabetes Mellitus Typ 2 Der Unterausschuss DMP hat mit der Aktualisierung der Anforderungen an das DMP Diabetes mellitus Typ 2 begonnen. Arzneimittelzulassung Bericht zur CMDh-Sitzung im Juli 2025 Die Koordinierungsgruppe für das Verfahren der gegenseitigen Anerkennung und das dezentrale Verfahren – human (CMDh), trifft sich monatlich zu einer mehrtägigen Sitzung. Der Bericht zur Sitzung im Juli 2025 wurde nun veröffentlicht. Chemikalien Öffentliche Konsultation zum überarbeiteten Rahmen für „inhärent sichere und nachhaltige“ Chemikalien und Materialien Der überarbeitete Rahmen für „inhärent sichere und nachhaltige“ Chemikalien und Materialien (Framework for ‘Safe and Sustainable by Design (SSbD)' Chemicals and Materials) wurde am 25. Juli 2025 veröffentlicht. Gleichzeitig wurde auch die öffentliche Konsultation eröffnet, eine Teilnahme ist bis zum 15. September 2025 möglich. Europa & Internationales Protokoll der Sitzung der SPOC Working Group veröffentlicht Auf der Webseite der Europäischen Arzneimittel-Agentur (EMA) wurde das Protokoll der Sitzung der Medicine Shortages Single Point of Contact (SPOC) Working Party vom 17. Juni 2025 veröffentlicht. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 2/25 Medizinprodukte EUDAMED: Aktuelle Planung für die schrittweise Einführung Die Europäische Kommission hat die Übersicht zur aktuellen Planung für die schrittweise Einführung der Europäischen Datenbank für Medizinprodukte (EUDAMED) im Juli 2025 aktualisiert und die neue Version auf ihrer Webseite veröffentlicht. Medizinprodukte Harmonisierte Normen für Medizinprodukte: Entwurf einer weiteren Änderung des Durchführungsbeschlusses (EU) 2021/1182 Der Entwurf eines Durchführungsbeschlusses der Kommission zur Änderung des Durchführungsbeschlusses (EU) 2021/1182 hinsichtlich harmonisierter Normen für Operationskleidung und -abdecktücher sowie medizinische Gesichtsmasken ist am 31. Juli 2025 veröffentlicht worden. Medizinprodukte Meldung von Risiken aus Medizinprodukten „außerhalb der Dienstzeit“ Auf der Webseite des Bundesinstituts für Arzneimittel und Medizinprodukte (BfArM) wurde am 30. Juli 2025 die aktualisierte Übersicht der Adressen zur Meldung von Risiken im Zusammenhang mit Medizinprodukten „außerhalb der Dienstzeit“ veröffentlicht. Nachhaltigkeit EU-Kommission: Vorschlag für Nachhaltigkeitsberichterstattung von KMU Am 30. Juli 2025 hat die EU-Kommission einen Vorschlag für eine vereinfachte Nachhaltigkeitsberichterstattung von kleinen und mittleren Unternehmen (KMU) veröffentlicht Recht 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 3/25 BGH bestätigt unzulässige Werbung mit Vorher- Nachher-Bildern für Nasen- oder Kinnkorrektur durch Unterspritzung mit Hyaluron In seinem heutigen Urteil (31. Juli 2025, Az.: I ZR 70/24) hat der Bundesgerichtshof (BGH) das Urteil des Oberlandesgerichts (OLG) Hamm vom 29. August 2024 (Az.: I-4 UKl 2/24) bestätigt, welches die Werbung von verschiedenen ästhetische Gesichtsbehandlungen durch Vorher-Nachher-Bilder untersagt hatte.  Recht Grundstoffüberwachung: Unterstellung von 2 weiteren Stoffen unter die gesetzliche Grundstoffüberwachung Im Amtsblatt der Europäischen Union ist die Delegierte Verordnung (EU) 2025/1475 zur Änderung der Verordnung (EG) Nr. 273/2004 und der Verordnung (EG) Nr.111/2005 betreffend der Aufnahme bestimmter Drogenausgangsstoffe veröffentlicht worden. Pharma Deutschland in den Medien Pharma Deutschland warnt vor Folgen des neuen EU-USA- Handelsabkommens monitor VERSORGUNGSFORSCHUNG Online am 30.07.2025 und in 2 weiteren Quellen Pharma Deutschland reagiert mit Sorge auf das neu geschlossene Handelsabkommen zwischen der EU und den USA. "Was gegebenenfalls Planbarkeit für viele Branchen bedeutet, ist im Arzneimittelbereich eine strategische Belastung für europäische Pharma-Hersteller", sagt Dorothee Brakmann, Hauptgeschäftsführerin von Pharma Deutschland. Pharma Deutschland fordert Transparenz bei Spurenstoffen im Abwasser W & A Wasser & Abwasser Technik online (DE) am 31.07.2025 Im Zuge der vom Europäischen Parlament angestrebten neuen Folgenabschätzung der Kommunalabwasserrichtlinie durch die Europäische Kommission fordert Pharma Deutschland vollständige Informationen über die Spurenstoffe und deren Mengen im kommunalen Abwasser in Deutschland. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 4/25 https://links.pharmadeutschland.de/c/109675311/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675311/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675312/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675312/cd51ed011-t09oes   Arzneimittelsicherheit In eigener Sache: Umfrage zu sozialen Medien in Consumer Healthcare Friendly Reminder zur Teilnahme an einer Umfrage zu sozialen Medien im Bereich Consumer Healthcare, die im Rahmen der Masterarbeit von Nora Krogull (Referentin Arzneimittelsicherheit) verwendet wird. Im Februar 2025 hat Pharma Deutschland eine erste Umfrage zur Nutzung sozialer Medien in der Pharmakovigilanz innerhalb eines kleineren Verteilerkreises durchgeführt. Aufgrund der großen Relevanz des Themas startet unser europäischer Dachverband AESGP nun ebenfalls eine Umfrage dazu. Durch die zahlreichen Rückmeldungen und das positive Feedback zur ersten Umfrage möchten wir das Thema mit dieser neuen Erhebung vertiefen. Die Ergebnisse werden in Kooperation mit der AESGP sowie zusätzlich im Rahmen der Masterarbeit von Nora Krogull verwendet. Ihre Erfahrungen und Einschätzungen leisten einen wichtigen Beitrag zum besseren Verständnis dieses zunehmend relevanten Themas und helfen dabei, künftig gezieltere Hilfestellungen und Empfehlungen für unsere Mitgliedsunternehmen entwickeln zu können. Bitte beachten Sie, dass sich die Umfrage ausschließlich auf Arzneimittel bezieht. Sie ist in englischer Sprache verfasst, kann bei Bedarf aber auch gerne auf Deutsch beantwortet werden. Die Umfrage ist bis zum 25. August 2025 geöffnet. Senden Sie die ausgefüllte Tabelle gerne an Nora Krogull (krogull@pharmadeutschland.de). 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 5/25 https://links.pharmadeutschland.de/c/109675313/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675313/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675313/cd51ed011-t09oes mailto:krogull@pharmadeutschland.de mailto:krogull@pharmadeutschland.de Für eventuelle Rückfragen stehen wir Ihnen jederzeit zur Verfügung. Herzlichen Dank für Ihre Unterstützung! Die entsprechende Excel-Tabelle zum Ausfüllen finden sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Nora Krogull krogull@pharmadeutschland.de   Arzneimittelversorgung G-BA: Stellungnahmeverfahren zur Anlage XII (Nutzenbewertung nach § 35a SGB V) – Belumosudil (chronische Graft-versus-Host- Krankheit); Beschränkung der Versorgungsbefugnis Der Gemeinsame Bundesausschuss (G-BA) hat in einem Schreiben an die Verbände über die Einleitung eines Stellungnahmeverfahrens zur Änderung der Arzneimittel-Richtlinie informiert. Themen Arzneimittelsicherheit Verschiedenes 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 6/25 mailto:krogull@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675314/cd51ed011-t09oes Der Unterausschuss Arzneimittel des Gemeinsamen Bundesausschusses (G-BA) hat in seiner Sitzung am 29. Juli 2025 beschlossen, ein Stellungnahmeverfahren zur Änderung der Arzneimittel-Richtlinie (AM- RL) einzuleiten: Im Rahmen des Stellungnahmerechts nach § 92 Absatz 3a SGB V besteht bis zum 28. August 2025 die Gelegenheit zur Abgabe einer Stellungnahme. Später eingegangene Stellungnahmen werden nicht berücksichtigt. Die Stellungnahme zum Richtlinienentwurf ist durch Literatur (z. B. relevante Studien) zu begründen und die zitierte Literatur ist obligat im Volltext inklusive eines standardisierten und vollständigen Literatur- bzw. Anlagenverzeichnisses der Stellungnahme beizufügen und das entsprechende Begleitblatt „Literaturverzeichnis" zu verwenden. Es wird darauf hingewiesen, dass nur Literatur, die im Volltext vorliegt, berücksichtigt werden kann. Mit Abgabe einer Stellungnahme erklärt man sich einverstanden, dass diese in den Tragenden Gründen bzw. in der Zusammenfassenden Dokumentation wiedergegeben werden kann. Diese Dokumente werden jeweils mit Abschluss der Beratungen im Gemeinsamen Bundesausschuss erstellt und in der Regel der Öffentlichkeit via Internet zugänglich gemacht.  Die Stellungnahme einschließlich Literatur sowie Literatur- bzw. Anlagenverzeichnis ist in elektronischer Form (z. B. per CD/DVD oder per E-Mail) als Word-Datei bzw. die Literatur als PDF-Datei zu richten an:  Gemeinsamer Bundesausschuss Abteilung Arzneimittel Gutenbergstraße 13 10587 Berlin Per E-Mail (Nutzenbewertung35a@g-ba.de) mit der Betreffzeile „2024-AbD-008 Belumosudil – Versorgungsbefugnis" oder über das AMNOG-Portal: https://extern.portal.g-ba.de/ Zudem besteht für Mitgliedsunternehmen die Möglichkeit, die Stellungnahme über Pharma Deutschland einzureichen. In diesem Fall sollten die erforderlichen Unterlagen bis spätestens 21. August 2025 per Mail an Pharma Deutschland (stellungnahme@pharmadeutschland.de) gesendet werden. Anlage XII (Nutzenbewertung nach § 35a SGB V) – Belumosudil (chronische Graft-versus-Host-Krankheit); Beschränkung der Versorgungsbefugnis 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 7/25 https://links.pharmadeutschland.de/c/109675315/cd51ed011-t09oes mailto:Nutzenbewertung35a@g-ba.de?subject=2024-AbD-008%20Belumosudil%20%E2%80%93%20Versorgungsbefugnis https://links.pharmadeutschland.de/c/109675316/cd51ed011-t09oes mailto:stellungnahme@pharmadeutschland.de mailto:stellungnahme@pharmadeutschland.de Die vollständigen Unterlagen zum o. g. Stellungnahmeverfahren mit Literaturverzeichnisvorlage finden Sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Bernhard Liebenhoff liebenhoff@pharmadeutschland.de   Arzneimittelversorgung G-BA: Aufforderung zum Vorschlag geeigneter digitaler medizinischer Anwendungen – DMP Diabetes Mellitus Typ 2 Der Unterausschuss DMP hat mit der Aktualisierung der Anforderungen an das DMP Diabetes mellitus Typ 2 begonnen. Themen Arzneimittelversorgung Arzneimittel-Richtlinie Frühe Nutzenbewertung (Anlage XII der AM-RL) Dokumente Belumosudil 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 8/25 mailto:liebenhoff@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675317/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675317/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675317/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675317/cd51ed011-t09oes Der Gemeinsame Bundesausschuss (G-BA) hat die DMP-Richtlinien nach § 137f Absatz 2 SGB V regelmäßig zu prüfen und ggf. zu aktualisieren. Der Unterausschuss DMP hat mit der Aktualisierung der Anforderungen an das DMP Diabetes mellitus Typ 2 begonnen. In diesem Zusammenhang ist gemäß 6. Kapitel Verfahrensordnung (VerfO) des G-BA auch die medizinisch- inhaltliche Prüfung auf Eignung digitaler medizinscher Anwendungen (dimA) zur Aufnahme in das jeweilige DMP durch den G-BA vorgesehen. Das nähere zum Verfahren sowie den Kriterien zur Feststellung der Eignung der dimA ist in der Verfahrensordnung beschrieben. Pharma Deutschland ist im Rahmen der Feststellung geeigneter DiMA nach § 137f Absatz 8 SGB V vorschlagsberechtigt. Vor diesem Hintergrund sind wir gebeten, für die Indikation Diabetes mellitus Typ 2 geeignete digitale medizinische Anwendungen vorzuschlagen. Die Aufforderung soll dazu dienen, dem G-BA frühzeitig geeignete dimA zur Kenntnis zu geben, damit er den Prüfauftrag gemäß § 137f Absatz 8 Satz 1 SGB V umsetzen kann. Wir bitten um Ihre Vorschläge für geeignete dimA bis einschließlich 22. August 2025 per E-Mail an Dr. Karl Sydow (sydow@pharmadeutschland.de) und Petra ten Haaf (tenhaaf@pharmadeutschland.de) zu schicken.  Das Schreiben des G-BA finden Sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Petra ten Haaf tenhaaf@pharmadeutschland.de Dr. Karl Sydow sydow@pharmadeutschland.de Themen Arzneimittelversorgung Arzneimittelversorgungsverträge DMP Dokumente Vorschlagsverfahren digitaler medizinischer Anwendungen für DMP Diabetes mellitus Typ 2 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c45f… 9/25 https://links.pharmadeutschland.de/c/109675318/cd51ed011-t09oes mailto:sydow@pharmadeutschland.de mailto:sydow@pharmadeutschland.de mailto:tenhaaf@pharmadeutschland.de mailto:tenhaaf@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675319/cd51ed011-t09oes mailto:tenhaaf@pharmadeutschland.de mailto:sydow@pharmadeutschland.de   Arzneimittelzulassung Bericht zur CMDh-Sitzung im Juli 2025 Die Koordinierungsgruppe für das Verfahren der gegenseitigen Anerkennung und das dezentrale Verfahren – human (CMDh), trifft sich monatlich zu einer mehrtägigen Sitzung. Der Bericht zur Sitzung im Juli 2025 wurde nun veröffentlicht. Die Sitzung der CMDh fand am 22. und 23. Juli 2025 statt. Folgende Punkte wurden im Bericht zur Sitzung festgehalten und näher erläutert.   Geänderter Rechtsrahmen für Variations Die aktualisierte Classification Guideline ist ab dem 15. Januar 2026 anzuwenden. Damit sich die pharmazeutischen Unternehmer frühzeitig darauf vorbereiten können, wurde der finale Entwurf der Guideline, welcher als Basis für die Übersetzungen in die EU-Landessprachen dient, frühzeitig publiziert. Typ IA-Variations, welche vor dem Geltungsbeginn implementiert wurden, sollten im Rahmen eines Annual Updates bis Dezember 2025, spätestens aber vor dem 15. Januar 2026 eingereicht werden. Für Änderungen des Typs IA, die nach der Einreichung des Annual Updates umgesetzt werden, kann in Ausnahmefällen eine Einreichung als singuläre Notifizierungen erfolgen. Weitere Hinweise werden auf der Webseite der CMDh zum Revised Variations Framework veröffentlicht. Ergebnisse des Art. 31-Verfahrens zu Azithromycin-haltigen Arzneimitteln (systemische Anwendung) Die CMDh rät, mit der Umsetzung der Ergebnisse des Artikel 31-Referrals und den zugehörigen Einreichungen als Variations auf die Kommissionsentscheidung zu warten. Anpassungen der Formulierung der Indikationsgebiete werden nur für diejenigen Indikationen erwartet, über die das jeweilige Arzneimittel bereits verfügt. Weiterhin wird empfohlen, die Änderungen im Rahmen einer Variation vom Typ IB einzureichen, da in einigen Fällen die Implementierung weiterer Prüfung bedarf (Kategorie C.I.1.a für alle Produkte, die Teil des Verfahrens waren). 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 10/25 https://links.pharmadeutschland.de/c/109675320/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675321/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675322/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675323/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675323/cd51ed011-t09oes Sollten zusätzliche Daten eingereicht werden, so wird eine Einreichung vom Typ II, Kategorie C.I.1.c erwartet. In diesem Zusammenhang erinnert die CMDh daran, dass die Nutzung von Worksharing-Verfahren inzwischen verpflichtend ist. Folgende Möglichkeiten kommen hierbei in Betracht: Kriterien für die Auswahl von Produkten zur SmPC-Harmonisierung Im Rahmen ihrer Sitzung einigte sich die CMDh darauf, die Kriterien zur Auswahl von Produkten, deren SmPC harmonisiert werden soll, wie folgt zu aktualisieren: Nur Produkte eines Zulassungsinhabers können in ein Artikel 30-Verfahren eingeschlossen werden. Das aktualisierte Dokument wird in Kürze auf der Webseite der CMDh unter „Product Information > Referral Art. 30 and 31 (non-pharmacovigilance) > Harmonisation of SmPC – Article 30 Referrals“ publiziert. Anleitung zur Erstellung von öffentlichen Beurteilungsberichten  Die CMDh verständigte sich auf eine Verfahrensverbesserung bei der Erstellung von öffentlichen Beurteilungsberichten (Public Assessment Reports, PAR). Neue Anleitungen wurden entwickelt, wie der finale Assessment Report in den PAR umgewandelt werden kann. Diese Informationen werden in einem neuen Template abgebildet, welches auf dem Template zum aktualisierten Overview Assessment Report basiert. Der jeweilige RMS kann entscheiden, ob er diesen neuen Weg wählen oder das „leere“ Template nutzen möchte. Das neue Template wird in Kürze unter „Templates > Assessment Reports > Public AR“ auf der Webseite der CMDh zu finden sein. Aktualisierung des Overview Assessment Report Templates Auch das im vorherigen Abschnitt erwähnte Overview Assessment Report Template wurde aktualisiert. Zum einen, um die oben beschriebene Änderung abzubilden und zum anderen, um es an die geänderten Anforderungen an das Environmental Risk Assessment anzupassen. Einreichung eines Worksharings für die Anpassung der Abschnitte 4.3 bis 4.9 und 5.2 bis 5.3 der SmPC und separate Einreichung der Anpassung von Indikation und Dosierungsanleitung – dies insbesondere dann, wenn die notwendigen Anpassungen in den Abschnitten 4.1, 4.2 und 5.1 in den einzelnen Mitgliedstaaten unterschiedlich sind. Einreichung eines Worksharings für alle Abschnitte unter 4. und 5. der SmPC, allerdings nur in den Mitgliedstaaten, in denen die Indikationen gleich formuliert oder sehr ähnlich sind, d.h. wenn die gleiche Indikation im Antrag angegeben werden kann. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 11/25 Das aktualisierte Template (mit und ohne Anmerkungen) wird in Kürze auf der Webseite der CMDh unter „Templates > Assessment Reports > DCP (AR/Comments)“ veröffentlicht. Streichung der eCTD-Sequenz Nummern aus dem Template für den Cover Letter Die Templates für die Cover Letter (Anschreiben) für Neuzulassungsverfahren, Variations und Renewal-Verfahren wurden aktualisiert, ebenso wie die Empfehlungen der Mitgliedstaaten zur Gestaltung von Anschreiben für Neuanträge im Rahmen von MRP bzw. DCP-Verfahren. Im Rahmen der Sitzung einigten sich die CMDh-Mitglieder darauf, dass die eCTD-Sequenznummern nicht mehr in den Anschreiben aufgeführt werden müssen, da die Nutzung von Tracking Tables ohnehin verpflichtend sei. Die überarbeiteten Dokumente werden in Kürze unter „Templates > Application for MA“, „Procedural Guidance > Variations“, „Templates > Renewal“ und „Procedural Guidance > Application for MA > Validation Procedure“ veröffentlicht. Öffentliche Beurteilungsberichte zu Worksharings nach Art. 45 und 46 der Paediatric Regulation Die CMDh stimmte einem öffentlichen Beurteilungsbericht zu pädiatrischen Studien im Rahmen von Art. 46 der Verordnung über Kinderarzneimittel für zu. Der Bericht wird auf der Webseite der CMDh unter „Paediatric Regulation > Assessment Reports“ veröffentlicht. CMDh-Position zu PSUSA-Verfahren  Auf Grundlage der PRAC-Empfehlungen und des PRAC-Bewertungsberichts im Anschluss an die Prüfung der PSURs stimmte die CMDh den Schlussfolgerungen der PSUR-Bewertung für die nachfolgenden Wirkstoffe zu (by consensus), die eine Anpassung der jeweiligen Zulassungen (Variation) vorsieht: Repevax, Adacel-Polio, Traxis-Polio (Tetanus-Diphtherie-Pertussis (azellulär)-Poliomyelitis (inaktiviert)-Impfstoff (adsorbiert, mit reduziertem Antigengehalt (Tdap-IPV) Acetylsalicylsäure/Bisoprolol Bisoprolol/Hydrochlorothiazid Diamorphin Domperidon Hydromorphon Nicotin 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 12/25 Weitere Informationen zu diesen Verfahren, einschließlich der Informationen bezüglich der Implementierung, werden in Kürze auf der Webseite der EMA publiziert. HaRP (Harmonisation of RMP-Projekt) Die HaRP-Peer-Review-Gruppe hat im Rahmen des HaRP-Projekts 16 neue Bewertungsberichte fertiggestellt, die als Ergebnis eine harmonisierte Liste von Sicherheitsbedenken pro Wirkstoff enthalten. Die CMDh hat diese Berichte angenommen. Weiterhin wird die „Liste der Sicherheitsbedenken pro genehmigten RMP von Wirkstoffen pro Produkt“ aktualisiert, um die derzeit veröffentlichten Listen der Sicherheitsbedenken von Produkten, die diese Wirkstoffe enthalten, zu löschen, und es werden Links zu den Bewertungsberichten mit der harmonisierten Liste der Sicherheitsbedenken hinzugefügt. Die Bewertungsberichte werden in Kürze auf der Webseite der CMDh unter „Pharmacovigilance > RMP > HaRP Assessment Reports“ veröffentlicht. Darüber hinaus enthält der Bericht die üblichen Statistiken zu Neuzulassungsanträgen im MR- und DC-Verfahren. Weiterhin wurden auf der CMDh-Webseite die Statistiken für das Jahr 2024 veröffentlicht. Die nächste Sitzung der CMDh findet vom 19. bis zum 21. August 2025 statt. Kontakt Stephanie Pick pick@pharmadeutschland.de Marit Heimbürger heimbuerger@pharmadeutschland.de   Chemikalien Öffentliche Konsultation zum überarbeiteten Rahmen für „inhärent Phosphocreatin Tapentadol 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 13/25 https://links.pharmadeutschland.de/c/109675324/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675325/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675325/cd51ed011-t09oes mailto:pick@pharmadeutschland.de mailto:heimbuerger@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675326/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675326/cd51ed011-t09oes sichere und nachhaltige“ Chemikalien und Materialien Der überarbeitete Rahmen für „inhärent sichere und nachhaltige“ Chemikalien und Materialien (Framework for ‘Safe and Sustainable by Design (SSbD)' Chemicals and Materials) wurde am 25. Juli 2025 veröffentlicht. Gleichzeitig wurde auch die öffentliche Konsultation eröffnet, eine Teilnahme ist bis zum 15. September 2025 möglich. Die Empfehlung der Kommission zur Schaffung eines europäischen Bewertungsrahmens für „inhärent sichere und nachhaltige“ Chemikalien und Materialien (C/2022/8854) wurde im Dezember 2022 angenommen. Sie enthält einen umfassenden Rahmen zur Unterstützung der Konzeption, Entwicklung, Herstellung und Verwendung von Chemikalien und Materialien, deren Funktion oder Leistung wünschenswert ist und die dabei sicher und nachhaltig sind. Dadurch soll ein besserer Schutz der menschlichen Gesundheit und der Umwelt über den gesamten Lebenszyklus hinweg gewährleistet werden. Die Empfehlung der Kommission aus dem Jahr 2022 sah einen Testzeitraum vor, in dem Mitgliedstaaten, die Industrie, Hochschulen sowie Forschungs- und Technologieorganisationen die Möglichkeit hatten, den Bewertungsrahmen über einen freiwilligen Berichtsmechanismus zu erproben und Rückmeldungen zu geben. Dieser Testzeitraum umfasste zwei Konsultations- und Berichtszyklen – einen im Jahr 2023 und einen zweiten im Jahr 2024. Während der zweijährigen Testphase wurden mehr als 80 Fallstudien eingereicht, analysiert und diskutiert. Darüber hinaus wurden zwei Stakeholder-Workshops mit jeweils über 500 Teilnehmenden durchgeführt. Ziel der Testphase war es, Informationen und Praxiserfahrungen zu sammeln, um den Rahmen zu überarbeiten und seine Relevanz, Verlässlichkeit und Anwendbarkeit zu verbessern. Die überarbeitete Rahmenregelung für „inhärent sichere und nachhaltige“ Chemikalien und Materialien, die nun zur öffentlichen Konsultation vorliegt, basiert auf den Erkenntnissen der zweijährigen Testphase. Sie wird als Grundlage für die Überarbeitung der Empfehlung der Kommission bis Ende 2025 dienen. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 14/25 https://links.pharmadeutschland.de/c/109675326/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675326/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675327/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675328/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675329/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675329/cd51ed011-t09oes Eine Teilnahme an dieser öffentlichen Konsultation bis zum 15. September 2025 möglich. Kontakt Marie Anton anton@pharmadeutschland.de Dr. Heike Wollersen wollersen@pharmadeutschland.de   Europa & Internationales Protokoll der Sitzung der SPOC Working Group veröffentlicht Auf der Webseite der Europäischen Arzneimittel- Agentur (EMA) wurde das Protokoll der Sitzung der Medicine Shortages Single Point of Contact (SPOC) Working Party vom 17. Juni 2025 veröffentlicht. Die SPOC Working Group hat aktuelle und kritische Arzneimittelengpässe in der EU diskutiert. Die Inhalte der Sitzung betrafen u.a. die internationale Lage und die Versorgungssicherheit. Es wurden keine akuten Risiken durch geopolitische Entwicklungen festgestellt, aber die EMA beobachtet weiterhin die Lage. Die Antibiotika-Verfügbarkeit hat sich gebessert. Die Mitglieder der SPOC Working Group tauschten Informationen über die Verfügbarkeit von Antibiotika in ihren Ländern aus und stellten fest, dass es in ihren Gebieten keine Verfügbarkeitsprobleme gibt. Die EMA schließt den Eintrag im Mangelkatalog für Amoxicillin und Amoxicillin/Clavulansäure. Die Mitglieder der SPOC- Arbeitsgruppe überwachen weiterhin die Versorgungslage mit Antibiotika in ihren Gebieten. Weitere Themen waren die Weiterentwicklung der Methodik zur Bewertung von Lieferkettenrisiken und die Evaluierung des Solidaritätsmechanismus (VSM) 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 15/25 mailto:anton@pharmadeutschland.de mailto:wollersen@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675330/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675330/cd51ed011-t09oes und mögliche Integration von rescEU als Notfallreserve. Weitere Inhalte der Sitzung können dem Protokoll entnommen werden.  Kontakt Andrea Schmitz schmitz@pharmadeutschland.de Anna Wehage wehage@pharmadeutschland.de   Medizinprodukte EUDAMED: Aktuelle Planung für die schrittweise Einführung Die Europäische Kommission hat die Übersicht zur aktuellen Planung für die schrittweise Einführung der Europäischen Datenbank für Medizinprodukte (EUDAMED) im Juli 2025 aktualisiert und die neue Version auf ihrer Webseite veröffentlicht. Wie im Pharma Deutschland aktuell 36/2024 vom 9. Juli 2024 berichtet, ist die Verordnung (EU) 2024/1860 zur Änderung der Verordnung (EU) 2017/745 über Medizinprodukte (MDR) und der Verordnung (EU) 2017/746 über In-vitro-Diagnostika (IVDR) im Amtsblatt der Europäischen Union veröffentlicht worden. Sie ermöglicht eine schrittweise Einführung der einzelnen elektronischen Systeme von EUDAMED, sobald ihre Funktionsfähigkeit gemäß dem in der MDR festgelegten Verfahren überprüft wurde. Sie sieht ebenfalls vor, dass der Geltungsbeginn der Pflichten und Anforderungen im Zusammenhang mit EUDAMED und das Datum der Anwendung der entsprechenden nationalen Registrierungsanforderungen auf der Grundlage der Richtlinien 90/385/EWG, 93/42/EWG und 98/79/EG angeglichen werden. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 16/25 https://links.pharmadeutschland.de/c/109675331/cd51ed011-t09oes mailto:schmitz@pharmadeutschland.de mailto:wehage@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675332/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675332/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675333/cd51ed011-t09oes Angesichts des laufenden Konsultationsprozesses mit der Koordinierungsgruppe Medizinprodukte (MDCG) und den jüngsten politischen Entwicklungen werden die Zeitpläne für EUDAMED derzeit revidiert. Die Europäische Kommission hat die Übersicht zur aktuellen Planung für die schrittweise Einführung von EUDAMED mit der Ansicht der Funktionalität der Module überarbeiten müssen und die neuste Version im Juli 2025 auf ihrer Webseite veröffentlicht. Das Audit der ersten vier Module „Registrierung von Wirtschaftsakteuren“, „UDI/Produkte“, „Benannte Stellen und Bescheinigungen“ und „Marktüberwachung“ ist abgeschlossen. Die Veröffentlichung der Bekanntmachung der Funktionsfähigkeit dieser vier Module im Amtsblatt der Europäischen Union ist spätestens im 3. Quartal 2025 geplant. Für das Modul „Vigilanz“ wird die Veröffentlichung der Bekanntmachung der Funktionsfähigkeit im Amtsblatt für das erste oder zweite Quartal 2026 erwartet. Die Übersicht finden Sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Marie Anton anton@pharmadeutschland.de Dr. Heike Wollersen wollersen@pharmadeutschland.de   Medizinprodukte Themen Medizinprodukte EUDAMED, DMIDS und UDI Dokumente EUDAMED Übersicht zur aktuellen Planung für die schrittweise Einführung der Europäischen Datenbank für Medizinprodukte (EUDAMED) (Juli 2025) 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 17/25 https://links.pharmadeutschland.de/c/109675334/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675335/cd51ed011-t09oes mailto:anton@pharmadeutschland.de mailto:wollersen@pharmadeutschland.de Harmonisierte Normen für Medizinprodukte: Entwurf einer weiteren Änderung des Durchführungsbeschlusses (EU) 2021/1182 Der Entwurf eines Durchführungsbeschlusses der Kommission zur Änderung des Durchführungsbeschlusses (EU) 2021/1182 hinsichtlich harmonisierter Normen für Operationskleidung und -abdecktücher sowie medizinische Gesichtsmasken ist am 31. Juli 2025 veröffentlicht worden. Wie im BAH um Vier 137/2021 vom 19. Juli 2021 berichtet, wurde der Durchführungsbeschluss (EU) 2021/1182 der Europäischen Kommission vom 16. Juli 2021 über die harmonisierten Normen für Medizinprodukte zur Unterstützung der MDR im Amtsblatt der Europäischen Union veröffentlicht. Am 31. Juli 2025 wurde der Entwurf eines Durchführungsbeschlusses der Kommission zur Änderung des Durchführungsbeschlusses (EU) 2021/1182 hinsichtlich harmonisierter Normen für Operationskleidung und -abdecktücher sowie medizinische Gesichtsmasken veröffentlicht. Die Liste der harmonisierten Normen im Rahmen der MDR würde damit um drei weitere Referenzen erweitert werden: Insgesamt würde es mit diesem Entwurf 35 harmonisierte Normen im Rahmen der MDR geben. EN 13795-1:2025 Surgical clothing and drapes - Requirements and test methods - Part 1: Surgical drapes and gowns EN 13795-2:2025 Surgical clothing and drapes - Requirements and test methods - Part 2: Clean air suits EN 14683:2025 Medical face masks - Requirements and test methods 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 18/25 https://links.pharmadeutschland.de/c/109675336/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675336/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675336/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675336/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675336/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675337/cd51ed011-t09oes Den Entwurf des Durchführungsbeschlusses finden Sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Marie Anton anton@pharmadeutschland.de Dr. Heike Wollersen wollersen@pharmadeutschland.de   Medizinprodukte Meldung von Risiken aus Medizinprodukten „außerhalb der Dienstzeit“ Auf der Webseite des Bundesinstituts für Arzneimittel und Medizinprodukte (BfArM) wurde am 30. Juli 2025 die aktualisierte Übersicht der Adressen zur Meldung von Risiken im Zusammenhang mit Medizinprodukten „außerhalb der Dienstzeit“ veröffentlicht. Themen Medizinprodukte Rechtliches MDR und IVDR Dokumente Normen 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 19/25 https://links.pharmadeutschland.de/c/109675338/cd51ed011-t09oes mailto:anton@pharmadeutschland.de mailto:wollersen@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675339/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675339/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675339/cd51ed011-t09oes Die Übersicht, datiert vom 29. Juli 2025, dient dazu, Meldungen zu Risiken aus Medizinprodukten entgegenzunehmen, wenn die für das Medizinproduktewesen zuständigen Landesbehörden außerhalb der regulären Dienstzeiten nicht erreichbar sind. Kontakt Marie Anton anton@pharmadeutschland.de Dr. Heike Wollersen wollersen@pharmadeutschland.de   Nachhaltigkeit EU-Kommission: Vorschlag für Nachhaltigkeitsberichterstattung von KMU Am 30. Juli 2025 hat die EU-Kommission einen Vorschlag für eine vereinfachte Nachhaltigkeitsberichterstattung von kleinen und mittleren Unternehmen (KMU) veröffentlicht Am 26. Februar hat die EU-Kommission im Rahmen des Omnibus-1- Pakets einen Vorschlag zur Überarbeitung der CSRD- Nachhaltigkeitsberichterstattung veröffentlicht. Hiermit soll die Berichtspflicht auf Unternehmen mit min. 1.000 Mitarbeitenden begrenzt werden. Der Gesetzgebungsvorschlag wird im Rahmen der Trilogverhandlungen final ausgearbeitet. Für Unternehmen mit bis zu 1000 Mitarbeitenden regte die EU- Kommission einen VSME-Standard für die freiwillige Berichterstattung an, auf dessen Grundlage  ein delegierter Rechtsakt erlassen werden soll. Dieser soll nach der Verabschiedung des Omnibus-I als „Obergrenze“ 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 20/25 https://links.pharmadeutschland.de/c/109675340/cd51ed011-t09oes mailto:anton@pharmadeutschland.de mailto:wollersen@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675341/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675341/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675341/cd51ed011-t09oes fungieren. Große Unternehmen mit min. 1.000 Mitarbeitenden dürften von KMU keine Daten abfragen, die über den VSME-Standard hinausgehen. Gleichzeit bekommen KMU eine Hilfestellung um die eigene Nachhaltigkeitsleitung zu verbessern.  Der Bericht kann dabei helfen, leichter nachhaltige Finanzierungen zu erhalten und somit die Wettbewerbsfähigkeit zu optimieren. Wird der delegierte Rechtsakt verabschiedet, könnten noch inhaltliche Anpassungen an dem vorgeschlagenen VSME-Standard vorgenommen werden.  Sie finden die Empfehlungen der EU-Kommission (Annex 1 & Annex 2) im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. Kontakt Dr. Dennis Stern stern@pharmadeutschland.de   Recht BGH bestätigt unzulässige Werbung mit Vorher-Nachher-Bildern für Nasen- oder Kinnkorrektur durch Unterspritzung mit Hyaluron Themen Nachhaltigkeit CSRD & Berichterstattung Dokumente EU-Kommission: öffentliche Konsultation zu den Anforderungen der CSRD 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 21/25 https://links.pharmadeutschland.de/c/109675342/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675343/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675343/cd51ed011-t09oes mailto:stern@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675344/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675344/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675344/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675344/cd51ed011-t09oes In seinem heutigen Urteil (31. Juli 2025, Az.: I ZR 70/24) hat der Bundesgerichtshof (BGH) das Urteil des Oberlandesgerichts (OLG) Hamm vom 29. August 2024 (Az.: I-4 UKl 2/24) bestätigt, welches die Werbung von verschiedenen ästhetische Gesichtsbehandlungen durch Vorher-Nachher-Bilder untersagt hatte.  Die Verbraucherzentrale NRW hatte ein Unternehmen, welches in seiner Praxis ästhetische Behandlungen des Gesichts, wie z.B. medizinisch nicht indizierte Lippenformungen, Nasenkorrekturen, Kinnaufbau etc, durch Unterspritzung mit Medizinprodukten wie Fillern auf Hyaluronsäurebasis oder Sculptra sowie mit dem Muskelrelaxans Botox anbietet, auf Unterlassung verklagt. Hintergrund war, dass diese Behandlungen sowohl auf der eigenen Webseite als auch auf dem Instagram-Account mit sogenannten Vorher-Nachher-Bildern beworben wurden.  Die Klägerin sah in dieser Art der Werbung einen Verstoß gegen § 11 Abs. 1 S. 3 Nr. 1 HWG. Nach dieser Vorschrift darf außerhalb der Fachkreise für die in § 1 Abs. 1 Nr. 2 lit. c genannten operativen plastisch-chirurgischen Eingriffe nicht mit der Wirkung einer solchen Behandlung durch vergleichende Darstellung des Körperzustands oder des Aussehens vor und nach dem Eingriff geworben werden. Das Werbeverbot mit vergleichenden Darstellungen erfasst hierbei alle operativen plastisch-chirurgischen Eingriffe, sofern sich nicht aus der jeweiligen Werbung selbst ergibt, dass der Eingriff auf einer medizinischen Notwendigkeit beruht. Dieser Ansicht ist das OLG Hamm gefolgt und hierin heute auch vom BGH bestätigt worden.  Das Oberlandesgericht habe zu Recht angenommen, dass es sich bei der von der Beklagten beworbenen Behandlung, bei der mittels eines Instruments - hier: einer Kanüle - in den menschlichen Körper eingegriffen und seine Form oder Gestalt - hier: durch Einbringung einer Substanz (Hyaluron oder Hyaluronidase) zur Korrektur von Nase oder Kinn - verändert werde, um einen operativen plastisch-chirurgischen Eingriff im Sinne des § 1 Abs. 1 Nr. 2 Buchst. c HWG handelt. Für die Wirkung eines solchen Eingriffs darf nach § 11 Abs. 1 Satz 3 Nr. 1 HWG nicht durch vergleichende Darstellung des Körperzustandes oder des Aussehens vor und nach dem Eingriff geworben werden. Dieses weite Begriffsverständnis des operativen plastisch-chirurgischen Eingriffs sei mit dem Wortlaut der Vorschrift vereinbar und entspreche sowohl dem Willen des Gesetzgebers als auch dem Schutzzweck dieser Vorschriften, unsachliche Einflüsse durch potentiell suggestive und irreführende Werbung für medizinisch 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 22/25 nicht notwendige Eingriffe zurückzudrängen, die Entscheidungsfreiheit betroffener Personen zu schützen und zu vermeiden, dass sich diese Personen unnötigen Risiken aussetzen, die ihre Gesundheit gefährden können, heißt es in der Pressemitteilung. Zudem komme es nicht darauf an, ob die Risiken dieser Behandlung mit den Risiken von Ohrlochstechen, Piercen und Tätowieren vergleichbar seien. Denn diese Maßnahmen stellten keine operativen plastisch-chirurgischen Eingriffe im Sinne des § 1 Abs. 1 Nr. 2 Buchst. c HWG, sondern lediglich ästhetische Veränderungen der Hautoberfläche dar, die nicht in den Anwendungsbereich des § 11 Abs. 1 Satz 3 Nr. 1 HWG fallen. Kontakt Vera Strecker strecker@pharmadeutschland.de Andrea Schmitz schmitz@pharmadeutschland.de Lena Müllen, MHMM muellen@pharmadeutschland.de   Recht Grundstoffüberwachung: Unterstellung von 2 weiteren Stoffen unter die gesetzliche Grundstoffüberwachung Im Amtsblatt der Europäischen Union ist die Delegierte Verordnung (EU) 2025/1475 zur Änderung der Verordnung (EG) Nr. 273/2004 und der Verordnung (EG) Nr.111/2005 betreffend der Aufnahme bestimmter Drogenausgangsstoffe veröffentlicht worden. 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 23/25 https://links.pharmadeutschland.de/c/109675345/cd51ed011-t09oes mailto:strecker@pharmadeutschland.de mailto:schmitz@pharmadeutschland.de mailto:muellen@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675346/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675346/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675346/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675346/cd51ed011-t09oes Am 25. Juli 2025 wurde im Amtsblatt der Europäischen Union die Delegierte Verordnung (EU) 2025/1475 zur Änderung der Verordnung (EG) Nr. 273/2004 und der Verordnung (EG) Nr.111/2005veröffentlicht. Die Änderungen betreffen die Aufnahme bestimmter Drogenausgangsstoffe in die Liste der erfassten Stoffe. Sie gilt in allen Mitgliedstaaten der Europäischen Union unmittelbar. Mit der neuen Delegierten Verordnung werden die Stoffe in die Kategorie 1 des Anhangs der genannten Verordnungen neu aufgenommen. Damit unterliegen sie mit Inkrafttreten der Delegierten Verordnung am 14. August 2025 der Erlaubnis sowie der Ein- und Ausfuhrgenehmigungspflicht nach den oben genannten Verordnungen. Unternehmen, die mit diesen Stoffen umgehen, müssen entsprechende Genehmigungen bei den zuständigen Behörden beantragen. Diese Verordnung tritt am zwanzigsten Tag nach ihrer Veröffentlichung (25. Juli 2025) im Amtsblatt der Europäischen Union in Kraft. Diese Verordnung ist in allen ihren Teilen verbindlich und gilt unmittelbar in jedem Mitgliedstaat. Das EU-Amtsblatt finden Sie im Mitgliederbereich unter dem Pfad bzw. unterhalb dieses Artikels auf der Webseite. 4-Piperidon l-Boc-4-piperidon Themen Recht Betäubungsmittel Dokumente Delegierte Verordnung und Durchführungsverordnung zum Grundstoffverkehr  31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 24/25 https://links.pharmadeutschland.de/c/109675347/cd51ed011-t09oes Online Version  Newsletter abmelden Nehmen Sie Kontakt mit uns auf Haben Sie Fragen oder brauchen Hilfe? Wir helfen Ihnen gerne weiter.   Kontakt Dieser Newsletter ist für Pharma Deutschland Presse lizensiert und darf nicht weitergeleitet werden. Pharma Deutschland e.V. Geschäftsstelle Bonn Ubierstraße 71-73 53173 Bonn   Geschäftsstelle Berlin Friedrichstraße 134 10117 Berlin   Geschäftsstelle Brüssel Rue Marie de Bourgogne 58 1000 Brüssel info@pharmadeutschland.de www.pharmadeutschland.de Impressum Folgen Sie uns X Instagram Linkedin Youtube 31.07.25, 16:04 Pharma Deutschland aktuell 146/2025 https://links.pharmadeutschland.de/m/16398129/526382-367df3fe33e5d3f3cc0afbcbc73eeba94d8b44cc0736f1a6fbcdfdca067a0e1ac04fe25c4… 25/25 https://links.pharmadeutschland.de/m/16398129/526382-6e93a780f610ae724bf0f39190102cb2ba315a7deedbc6394c193dd171545f3d9c5ab4a5a7920dc8724934b710d776a5 https://links.pharmadeutschland.de/rmftlp.php?cid=526382&mid=16398129&h=526382-cd51ed011-t09oes mailto:kontakt@pharmadeutschland.de mailto:aktuell@pharmadeutschland.de https://links.pharmadeutschland.de/c/109675348/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675349/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675350/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675350/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675350/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675351/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675351/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675351/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675352/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675352/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675352/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675353/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675353/cd51ed011-t09oes https://links.pharmadeutschland.de/c/109675353/cd51ed011-t09oes