Version 5 of the Q&As regarding the Clinical Trials Regulation

Recommendation

4-6 June 2024
Munich, Germany

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The European Commission (EC) published an updated Version 5 of the Questions & Answers (Q&As) relating to the Clinical Trials Regulation (EU) No 536/2014 (CTR). The Q&As entered into force together with the application of the CTR on 31 January 2022. However, certain Q&As and a section (Annex III) are still being discussed and are therefore not yet included. Updated versions of the document will be published progressively.

New Q&As

Compared to the previous version 4.1 the following new Q&As have been introduced:

• 1.4 "What document / data shall be submitted with an application" (e.g. for a clinical trial (CT) application, substantial modification and / or subsequent addition of a Member State)
  
  
• 1.5 "How to proceed in case of discrepancies between the CTR and ICH GCP" (the CTR takes precedence over conflicting rules in guidelines, and that is applicable for ICH as well as other guidelines).  
  
  
• 9. “INFORMED CONSENT” AND OTHER SUBSTANTIAL REQUIREMENTS FOR CONDUCTING CLINICAL TRIALS
  - 9.5  Could the provisions on “deferred informed consent” be used when there is not sufficient time to obtain informed consent, even though the objective of the trial is not to study a medical emergency situation?
  No. The medical condition studied must be directly related to the emergency situation. There must always be a medically justified need to perform the first intervention within a short time frame in relation to the emergency situation.
  - 9.6  Is a trial with a mixed subject population, where some subjects consent prior to inclusion and others after the first trial-specific intervention, still an emergency trial?
  Yes, if the protocol provides for inclusion of any subjects without prior informed consent in a medical emergency. If prior informed consent is possible to obtain from some subjects (or their legal representatives) but not from others, the protocol should clearly explain the reasons and justification for this mixed population.
  - 9.7  Is the use of placebo allowed in a CT in an emergency situation?
  In emergency situations, where comparison is performed between one or several treatment arms receiving active treatment vs. a control arm, no subject should receive inferior treatment compared to normal clinical practice. Thus, placebo-treatment should be restricted to situations where it is added to such standard of care.
  - 9.8 What is meant by a subject’s prior objection to participate in an emergency situation trial?
  If objections to trial participation can be identified among personal belongings of the subject or are known to the investigator responsible for subject inclusion, e.g. found to be clearly stated in the medical record, national registries, such concerns should be respected.
  - 9.9  When should informed consent be sought in an emergency situation trial?
  Informed consent must be sought without undue delay and these efforts must be duly documented in the medical record of the subject, e.g. clearly mentioned in the source documents and describing efforts to reach a legal representative.
  - 9.10  Are secondary objectives and corresponding endpoints acceptable even if they are without any expected direct clinically relevant benefit for the subject but instead could provide a group benefit for patients?
  The main objective of an emergency situation trial should always meet the legal requirement for a scientific basis for the potential to have a direct clinically relevant benefit for the subject. This would make it possible to gather pharmacokinetic and biomarker data, as long as such secondary or exploratory endpoints do not pose more than minimal risk and burden for subjects.
  
  
• 11. ARRANGEMENTS FOR THE TRANSITIONAL PERIOD
  - 11.3 Should all trials be transitioned by 31/1/2025?
  Transitioning to the CTR is only required for CTD (Directive 2001/20) trials which will have at least one site active in the EU on 30/01/2025. Trials authorized under the CTD that have the end of trial notified in all Member States (MS), will not need to be transitioned, even in the case where the global end of trial has not been reached yet.
  - 11.12 When is a sponsor expected to update trial documents and labels?
  The sponsor should bring documentation in line with the CTR requirements at the time of revision of a given document. For labelling, the sponsor should update the label for those batches that are (re)labeled after the authorization under the CTR. There is no need to pro-actively relabel released IMPs. 
  - 11.17  What is the final deadline for submission of a clinical trial according to the CTD rules?
  A CT can be started in accordance with the CTD when the request for authorization of that trial to the NCA and Ethics Committee is submitted before 31/1/2023. The authorization itself can be after that date. However, it is already possible to submit trial applications through the CTR. Sponsors should note that in order to remain open in the Union, each CTD trial, including those submitted before but authorized after 31/1/2023, will need to be transitioned to the CTR before 31/1/2025.
  - 11.18  Can Member States be added to a trial ongoing under the CTD after 31/1/2023?
  Submission of CT Applications under the CTD is not possible after 31/1/2023. Thus, there is no possibility to add other MS through a national CTA submission under the CTD following this date. Sponsors can add a new MS to an ongoing CTD trial after 31/1/2023 by transitioning the trial to the CTR first and after a successful transition, adding an additional MS in accordance with the CTR.
  
  
• Annex III: acceptability of Part II templates in the Member States (still under development)

In addition, several Q&As have been revised including the introduction section and annex I (decision tree to establish whether a study is a “clinical trial”).

More information can be found in the CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS VERSION 5 in EudraLex - Volume 10 - Clinical trials guidelines.