All modifications to an approved clinical trial that are likely to have a substantial impact on the safety, health or rights of the participants or on the robustness or reliability of the clinical data generated by the study (substantial modifications) must be approved by the ethics committee prior to their implementation. This obligation does not extend to measures that have to be taken immediately to protect the participants.52
The sponsor shall submit the application documents specified in Article 10 paragraph 1 that are affected by the modification. The changes must be clearly marked. At the same time, the sponsor shall submit information on the reasons for and the nature of the modification.53
The ethics committee shall issue its decision on substantial modifications within 30 days. Article 12 applies mutatis mutandis.
Where a further clinical trial site is to be added and that site lies outside the competence of the ethics committee that approved the clinical trial, the procedure set out in Article 13 applies mutatis mutandis.
Other modifications must be notified to the ethics committee with the annual safety report as specified in Article 35.
For clinical trials in sub-category A2, the sponsor shall also notify the contracting states in which the clinical trial is being conducted or is due to be conducted of the nature of and reasons for the modifications; it shall attach the documents as specified in Annex 1 which are affected by the modification.