How to Classify Changes to Ongoing Clinical Trials

The European Commission (EC) has published an updated Version 3 of the draft Questions & Answers (Q&As) relating to the Clinical Trials Regulation (EU) No 536/2014 (CTR). The Q&As have been discussed progressively since December 2014 and the final draft (Version 1) was published in April 2018. The Q&As enter into force with application of the CTR which depends on the notice of the full functionality of the EU Portal / database (CTIS). The EMA is still planning with January 2022 as the date for the first application of the CTR. Therefore, the agency published already training material on their webpage in order to support organizations in preparing to comply with the requirements of the CTR.

How can changes to ongoing clinical trials be classified?

The following new Q&A regarding the classification of changes has been introduced:

• 3.3. How the different changes to ongoing clinical trials are classified in the Clinical Trials Regulation?, together with 
• Annex III Classification of changes to ongoing clinical trials (contains specific examples, including changes to the IMPD, amendments to the trial protocol, like, for example, replacement of physical visits with “remote” visits etc.)

The Q&A document clarifies the following items in detail:

• A substantial modification (SM) of trial data (e.g. the addition of a clinical trial site or the change of a principal investigator) is defined in the CTR as "any change to any aspect of the clinical trial which is made after notification of a decision (on the substantial modification) 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 change (e.g. update of the sponsor’s or CRO´s contact details) relevant to the trial oversight is a new concept under the CTR, which aims to update certain, specified information in the CTIS without the need for an SM application (i.e. the change does not have a substantial impact on patient safety and rights and / or data integrity). However, the combination of several non-substantial changes can cumulate into one change that needs to be submitted as an SM.
  
• A non-substantial modification (NSM, i.e. changes outside the scope of substantial modifications and irrelevant to the supervision of the trial) should not be notified as such. Correction of typos and other administrative changes are always expected to be updated as NSMs. NSMs will have to be recorded in the Trial Master File (TMF) and made available on request for inspection purposes as appropriate. They need to be listed and identified as NSMs in the cover letter of an SM application. 

According to the Commission, there will be no functionality in the CTIS to support submission of changes to trial data / documents other than via an SM or as a non-substantial change. Moreover, the CTIS will not be able to differentiate between the different types of content changes. For example: A new version of the investigator’s brochure (IB) can be uploaded as an SM (e.g. with changes impacting benefit / risk in the trial) or as a non-substantial change (e.g. annual update with no significant changes on participants safety and / or benefit / risk in the trial). According to the Q&A document, it is up to the sponsor to define the correct path, depending on the nature of the changes.

Other updates compared to the superseded Version

• 3.13 Can a substantial modification of aspects covered by Parts I and II of the assessment report be partially authorized (e.g. only the Part II)? (new)
• 5.8. What should be included in the protocol synopsis described in Annex I, D.24? (new)
• 7.26 What is the minimum information to be provided in the SUSAR reports? (new)
• 7.28 What adverse event reporting should be performed in low intervention trials? (revised)

More information can be found in the draft CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS VERSION 3.