MDCG 2021-28 – Substantial modification of clinical investigation under Medical Device Regulation
As per MDR 2017/745 Art. 75 Substantial modifications to clinical investigations, and Art. 78.12, Sponsors of clinical investigations are requested to submit any substantial modification to the ongoing clinical investigation via EUDAMED (electronic system referred to in Article 73 of the MDR).
EUDAMED was deemed to be functionally in June 2022, instead of 26 May 2021, but this is still delayed.
The MDCG created guidance MDCG 2021-28 to support Sponsor’s and Competent Authorities in the submission processes for substantial modification notifications, also known as substantial amendments, in ongoing clinical investigation in the absence of the European EUDAMED.
MDCG 2021-28 Clinical investigation Content:
Per Art. 75 and Art. 78.12 MDR 2017/745, substantial modifications are such that would have “a substantial impact on the safety, health or rights of the subjects or the robustness or reliability of the clinical data generated by the investigation”.
The Sponsor shall notify the Member States concerned within one week, of the modifications, and submit the updated version of the relevant documentation referred to in Chapter II of Annex XV, and the changes shall be clearly identifiable.
documents to be submitted
time until implementation
Art. 78 (12)
MS / CMS via Electronic System per Article 73
all modified Documents as per Annex XV Chapter II
38 days (+7days, if consulting with experts, Art. 75 (4))
Art. 75 (3) The sponsor may implement the modifications the earliest 38 days after the notification referred to in that paragraph, if the Member State(s) has not sent a notification of refusal to the Sponsor (75 (3) a), and no negative opinion of the ethics committee in that Member State was received (75 (3) b). In case the Member State(s) concerned consulted with experts, the period might be extended for additional 7 days (75 (4).
The Guidance provides a template for ‘Substantial modification of clinical investigation under MDR’ is also provided, and also highlights the MDCG 2021-8 on submission documents for clinical investigations and 2021-20 on the CIV-ID, see more information below in “Other helpful MDCG Guidance”.
Annex 1: Clinical investigation – Substantial modification of clinical investigation under Medical Device Regulation.
This form provided by the MDCG may be helpful for the Competent Authorities and sponsors, though it is always requested to check with the relevant NCA if they require their own official application forms to be used.
The notification form incorporates fields the following information:
Identification of the clinical investigation
- The CIV-ID number
- Information if the clinical investigation is currently on hold or suspended
- Overview of the current recruitment status in the clinical investigation (Worldwide, Europe, concerned Member State)
- a short rationale of the substantial modification
- if the substantial modification has an impact on subjects, or clinical data
The form can be signed digitally (PDF signature).
Annex 5 of MDCG 2021-8 shall be used.
Annex 5: Clinical investigation supporting documents – Appendix of documents to attach.
The use of the checklist is not mandatory. However, to be in line with already performed submissions and tracking of submissions and their contents, it is recommended to be used, except the relevant NCA requests their official forms shall be used, or they request additional documents. See more information below in “Other helpful MDCG Guidance”.
Other helpful MDCG Guidance
- MDCG 2020-10-1 Guidance on safety reporting in clinical investigations, and MDCG 2020-10-2 Clinical Investigation Summary Safety Report Form v1.0.
- MDCG 2021-6 Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation.
- MDCG 2021-08 Clinical investigation application/notification documents, see also our blog: Summary of the MDCG Guidance Document MDCG 2021-8.
- MDCG 2021-20 Instructions for generating CIV-ID for MDR Clinical Investigations, see also our blog: Summary of the MDCG Guidance Document MDCG 2021-20.
- The MDCG 2021-1 Rev.1 Guidance on harmonised administrative practices and alternative technical solutions until EUDAMED is fully functional (respectively referrals to: Art. 70, Art. 73, Art. 74, Art. 75, Art. 76, Art. 77, Art. 78, Art. 80), see also our blog: Summary of the MDCG Guidance Document MDCG 2021-20.
- MDCG 2019-9 Rev.1 Summary of safety and clinical performance A guide for manufacturers and notified bodies.
Helpful guidance is provided for the Classification of Devices and Combination Products Medical Device and Medicinal Product:
- MDCG 2022-5 Guidance on borderline between medical devices and medicinal products under Regulation (EU) 2017/745 on medical devices
- MDCG 2021-24 Guidance on classification of medical devices.
- Exchange of information between medical device competent authorities on borderline and classification cases Helsinki Procedure 2021
In addition, helpful guidance is provided for “actors” registration under MDR:
- MDCG 2020-15: MDCG Position Paper on the use of the EUDAMED actor registration module and of the Single Registration Number (SRN) in the Member States.
- MDCG 2021-13 rev.1: Questions and answers on obligations and related rules for the registration in EUDAMED of actors other than manufacturers, authorised representatives, and importers subject to the obligations of Article 31 MDR and Article 28 IVDR.
Thank you for your time. If you found this interesting, please check-out for our next blog on the MDCG Document summaries: MDCG 20210-10/1 Guidance on safety reporting in clinical investigations and MDCG 2020-10/2 Appendix: Clinical investigation summary safety report form.