Application for authorisation of substantial modifications

Overview of guidelines and forms to be used in connection with substantial modifications to clinical investigations of medical devices.

Applying for modifications to clinical investigation

The sponsor must submit an application by email to the Danish Medicines Agency and the ethics committee, describing the modification together with a rationale, along with the updated documents, see Appendix XV of the regulation such as investigation plan, investigator’s brochure, participant information, or the like.

In case of clinical investigations authorised by the Danish Medicines Agency before 26 May 2021, the modification must be applied for to the Danish Medicines Agency, and the Regional Research Ethics committee having initially assessed the research project. Application form for modifications to clinical investigations authorised before 26 May 2021.

In case of clinical investigations authorised by the Danish Medicines Agency after 26 May 2021, the modification must be applied for to the Danish Medicines Agency and the Medical Research Ethics Committees. Application form for modifications to clinical investigations authorised after 26 May 2021.

Applying for substantial modifications in general

If a sponsor intends to introduce modifications to a clinical investigation that are likely to have a substantial impact on the safety, health or rights of the subjects or on the robustness or reliability of the clinical data generated by the investigation, the Danish Medicines Agency must authorise the modifications before these may be implemented.

The Danish Medicines Agency has 38 days to assess an application for a modification, and the research ethics committee must have completed its assessment of the modification before the Danish Medicines Agency can decide in the matter. The sponsor must submit updated versions of the relevant documentation and make the changes to the documentation clearly identifiable.

Read more about substantial modifications in the MDCG guidance MDCG 2021-6 Rev. 1: Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation.

The application must include information about whether the investigation is ongoing, the number of subjects that has been included as well as considerations about how the modifications may affect the safety of the subjects or the reliability of data being generated.

It is important to submit the documents as new, updated documents and as documents clearly highlighting the changes, for example in tracked changes.

If the sponsor or investigator should otherwise become aware of circumstances that might expose the subjects to a safety risk, the sponsor and investigator must immediately take the necessary measures to protect the subjects. The sponsor must immediately notify the Danish Medicines Agency of these circumstances and the measures that have been taken.

If the sponsor updates previously submitted investigational documents, and it concerns minor, non-substantial modifications, the new documents may be continuously submitted to the Danish Medicines Agency for information.