Submission of a substantial modification

The definition of a SM implies that a SM request can only be considered after the decision on the clinical trial has been taken. This means that no SM request can be assessed while any assessment is still ongoing (be it an assessment of an initial application, a request to add a MSc or a request for another substantial modification). Therefore, the substantial modification can be assessed only after the decision on the previously submitted application is issued. If there is no ongoing assessment in any of the MSc and the clinical trial has been authorised, the sponsor can submit a SM without any constraints.

When submitting a SM through CTIS it has to be indicated whether the modification(s) affect(s) part I, part II or part I/II of the clinical trial. The list of required documentation and information is set out in Annex II of the CTR. A template cover letter for the application of a SM is available (under development).

Part I or Part I + II substantial modification

A part I or part I+II SM can be submitted if all of the following criteria apply:

  • the decision of all MSc which received the initial whole or staggered application (resp. article 5 and 11) has been communicated and at least one of them authorised the trial. This means that in multinational trials, the last Member State (for staggered applications this is the last MS that received a part II) communicating its decision determines when a part I or part I+II SM can be submitted;
  • there is no ongoing application for an additional MSc (Article 14);
  • there is no other ongoing SM assessment in any of the MSCs.

Important notice: The functionalities related to the implementation of Article 11 provisions are under development and expected to be available at the time of the first release after the go-live of CTIS. Thereafter, the first condition is changed so that that at least one MSc with a full application (article 5) has already communicated its decision to authorise the initial application. See also Question 3.6 of Q&A CTR.

Part II substantial modification

A part II SM can be submitted in a MSc if all of the following criteria apply:

  • this MSc has fully authorised the trial (regardless of whether it was through a full or a staggered application);
  • there is no other ongoing SM assessment (Part I, I+II or II) in this MSc.

Part II SM assessments can run in parallel in different MSc. A part II SM can be submitted if there is an ongoing assessment in a different MSc for an additional MSc.

Multiple substantial modifications

In case the sponsor realises that a SM may be needed while an assessment is still ongoing, the following actions can be undertaken, depending on the urgency:

  • wait for the ongoing assessment to end before submitting the SM.
  • withdraw the ongoing application and introduce the SM.

Substantial modification in multiple trials

Parallel submission of the same SM of a document used in multiple clinical trials is accepted (and encouraged, see Annex II A.1. of the CTR). CTIS allows one single SM application covering multiple (authorized) trials. The cover letter must contain a list of all clinical trials to which the application for SM relates.

See for more details on substantial modifications Question 3 of the Q&A document.