Substantial modifications
Substantial Modifications (SM) must be submitted in CTIS portal as SM. When submitting, you must decide whether the changes concern Part I, Part II or Part I+II.
The European Commission has published a guide on which changes are classified as substantial. The EU Commission's question/answer document is found under the header "Set of documents applicable to clinical trials authorised under Regulation EU No 536/2014" in the updated EudraLex Volume 10 for the Regulation.
For trials authorised under the Regulation, SM can only be submitted if there are no other cases pending in CTIS.
For Multinational trials, the trial must be authorised by all Member States concerned and there must be no pending cases regarding Additional Member State. For Part II changes there will be a little flexibility.
For more details, please see EU Commission's question and answer section 3. The EU Commission's question/answer document is found under the header "Set of documents applicable to clinical trials authorised under Regulation EU No 536/2014" in the updated EudraLex Volume 10 for the Regulation.
Formats required for the Cover letter
According to Annex 2 of the Regulation, a Cover letter for a SM must contain following:
a) in the subject line, the EU trial number with the title of the clinical trial and the substantial modification code number that allows unique identification of the substantial modification and shall be used consistently throughout the application dossier.
b) identification of the applicant
c) identification of the SM (sponsor's substantial modification code number and date), whereby the modification may refer to several changes in the protocol or scientific supporting documents
d) a highlighted indication of any special issues relating to the modification and an indication as to where the relevant information or text is located in the original application dossier
e) identification of any information not contained in the variation application form that may affect the risk to subjects; and
f) where applicable, a list of all clinical trials that have substantial amendments with the EU trial numbers and the respective substantial amendment code numbers.
Billing information can be mentioned in the cover letter or uploaded as a separate document in the "Proof of payment" section.
The modification shall be presented and described as follows:
a) an extract from the documents to be amended showing previous and new wording in track changes, as well as an extract showing only the new wording, and an explanation of the changes and
b) notwithstanding point (a), if the changes are so widespread or far-reaching that they justify an entirely new version of the document, a new version of the entire document should be provided (in such cases, an additional table lists the amendments to the documents, whereby identical changes can be grouped).
The new version of the document shall be identified by the date and an updated version number.
Documents uploaded to CTIS must not contain date and version number in the file name.
Instead, please refer to “Instruction Naming Documents”.
Instructions for submission
Read more about how to submit a SM in the GCP unit's guideline.
Read more about how to submit First Substantial Modifications after transition to the Regulation (for trials previously approved under the Directive) in the "Transition (from Directive to Regulation)" section.