Clinical Trials Regulation Questions & Answers Version 2.2

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

The European Commission (EC) recently published an updated Version 2.2 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 finalized in April 2018. The Q&As enter into force on application of the CTR which depends on the notice of the full functionality of the CTIS.

Changes compared to the superseded Version 2.0 are:

•  Inclusion of new Q&As 2.7, 2.8 and 3.3;
•  Updates to Q&As 1.6, 2.2 and 6.2. 
  

New Q&As 2.7, 2.8 and 3.3

• 2.7 How will a request for information (RFI) during the initial assessment of a clinical trial (CT) application, the assessment of an application for substantial modification and/ or the assessment of application for subsequent addition of a Member State (MS) concerned be managed?
  The CTR foresees strict timelines for the assessment of initial CT applications as well as for the assessment of applications for substantial modifications and the subsequent addition of a MS concerned. Sponsors shall submit additional information within the period set by the MS which shall not exceed 12 days from the receipt of the request of the reporting MS. Where the sponsor does not provide the additional information within the period set, the application shall be deemed to have lapsed. The RFI should focus only on critical issues that need to be addressed by the sponsor as to allow authorization and to avoid rejection of the application. "In order to shorten the assessment and approval timelines and to avoid unnecessary rejections due to time-constraints, the submission of complete and high-quality applications is of particular importance."
  
  
• 2.8 Will the assessment report on part I and II be made public at the time of decision?
  The CTR aims to increase transparency and availability of information on CTs through the EU CTIS. Information in the CTIS shall be publicly available unless one or more exceptions, when confidentiality is justified, apply. A specific document was developed to give more insight in the application of the disclosure rules. In any case, MSs concerned will gain a view-only access to the conclusion and assessment report on part II from the other MSs concerned as soon as they submit their conclusions for part II to the sponsor even before a decision is notified by these MSs.
  
  
• 3.3. What are the sponsor’s responsibilities regarding changes to a CT which are not substantial modifications (SM), but are relevant for the supervision of the trial?
  Information on any changes to a CT, which are not SMs but are, nevertheless, relevant for the supervision of the CTs by the MSs concerned, shall be permanently updated in the CTIS by the sponsor. In case of doubt about whether a change is a substantial modification or not, the sponsor shall seek the opinion of the MSs concerned. Sponsors can always provide non-substantial changes as part of an application for a substantial modification (part I only, part II only or part I & part II) whenever the scope of the non-substantial changes matches with the scope of the application under evaluation. However, sponsors are encouraged not to submit non-substantial changes during the RFI phase of any ongoing assessment, unless they are required as part of the RFI response.

Revised Q&As 1.6, 2.2 and 6.2

• 1.6 Is the definition of 'medicinal product' relevant for the scope of the CTR?
  Yes, when assessing whether a study is a CT as defined in the CTR, the first question is always whether the object of the study is a medicinal product.
  
  
• 2.2 In cases of applications limited to Part I how should a sponsor proceed to submit an application for Part II?
  Only during the subsequent 2 years, a sponsor may submit an application for aspects covered by Part II of the assessment report. The list of the documentation and information required is set out in Annex I of the CTR. However, if at this stage the sponsor becomes aware of the need for a substantial modification of Part I, different scenarios are possible.
  
  
• 6.2 Which endpoints need to be summarized in the lay summary of results of a CT?
  According to Annex V of the CTR the overall results should cover the main objectives of the CT and should reflect at a minimum the primary endpoints (see also the recommendations in "Summaries of Clinical Trial Results for Laypersons"). In the case that the trial is prematurely ended or early terminated due to lack of subjects or lack of data to analyze, the layperson results summary should exclude primary endpoint data points and include a statement indicating that sound statistical analysis of the information was not possible.

More information can be found in the draft CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS VERSION 2.2.