Types of modifications

In compliance with the CTR, a change to a trial data-field or document in CTIS is either:

  • a substantial modification (art 2.2.13);
  • a change relevant to the supervision of the trial (art 81.9) which is a new concept under CTR;
  • a non-substantial modification (changes outside the scope of substantial modifications and changes irrelevant to the supervision of the trial).

For a non-exhaustive list of substantial modifications, non-substantial modifications and non-substantial modifications relevant to the supervision of the clinical trial please consult Annex III of the Q&A CTR.

See also Questions 3.2-3.4 of the Q&A CTR.

A new concept under CTR is theĀ  subsequent addition of a MSc (art 14). See for this type of modification the section Addition of a Member State.

Substantial or non-substantial?

During the trial, the sponsor may modify the clinical trial. It is up to the sponsor to decide whether a modification is to be regarded as substantial or not, based on the definitions given in the CTR.

A substantial modification (SM) is defined as "any change to any aspect of the clinical trial which is made after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 of the CTR and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial".

A non-substantial modification is a modification without substantial impact on the safety or rights of the subjects and/or the reliability and robustness of the data, and the information is not necessary for oversight. This modification should not be reported as such. The non-substantial changes should be implemented during the next substantial modification. Non-substantial modifications need to be listed and identified as such in the cover letter of the SM application. However, the changes do not have to be described in detail.

In case the SM application is rejected and the documents with non-substantial modifications are reverted, these changes should be resubmitted with the next SM application. In the meantime, the non-substantial modifications will have to be recorded in the Trial Master File and made available on request for inspection purposes as appropriate.

Non-substantial modifications that should be notified

Information on any changes to the clinical trials which are not substantial modifications but are relevant for the supervision of the clinical trials by the MSc shall be permanently updated in CTIS by the sponsor, in line with Article 81(9) of the CTR.