Version 4.1 of the Q&As regarding the Clinical Trials Regulation

The European Commission (EC) published an updated Version 4.1 of the draft Questions & Answers (Q&As) relating to the Clinical Trials Regulation (EU) No 536/2014 (CTR). The Q&As will enter into force together with the application of the CTR on 31 January 2022. However, certain sections of the Q&A document are still not yet complete and updated versions of the Q&A will be published progressively.  

New Q&As

Compared to the previous version 4 the following new Q&As have been introduced:

  • 5.8 What should be included in the protocol synopsis according to Annex I (dossier for the initial trial applicationof the CTR?

    Sponsors should include the following information in the protocol synopsis to be submitted with the clinical trial application:
    – EU trial number and trial title,
    – Background and hypothesis of the trial,
    – Main & secondary objectives of the trial,
    – Primary & secondary endpoints,
    – Trial design & trial population,
    – Interventions,
    – Ethical considerations & benefit-risk analysis.

    The protocol synopsis can be part of the protocol or a separate document. In the latter case, it should always be submitted to the CTIS together with the protocol.
  • 7.39 How should the sponsor report the anticipated date of Annual Safety Report (ASR) submission?

    It is recommended to clarify within the cover letter of the initial trial application the anticipated date of ASR submission based on the “Development International Birth Date” (DIBD) or in case of clinical development following a marketing approval based on the “PSUR International Birth Date” (IBD). In any case, including cases when a single ASR is submitted for more than one IMP, the sponsor should indicate in the cover letter the intended submission date for the first ASR following trial authorization.

Revised Q&As

The following Q&As have been revised or updated:

  • 8.4 What documentation is required in the application for the authorization of a clinical trial relating to GMP?

    The documentation required to show GMP compliance of Investigational Medicinal Products (IMPs) and Auxiliary Medicinal Products (AxMPs) is outlined in Chapter IX (manufacturing and import of IMPs and AxMPs) and Annex 1 (dossier for the initial trial application), section F, of the CTR:
    – For IMPs authorized in the EU (even if not manufactured in the EU) no documentation is required.
    – For IMPs that are not authorized in the EU and do not have a marketing authorization from a third country that is party to ICH, and are not manufactured in the EU, an authorization and a QP declaration of GMP equivalence is required. In the latter case, if a Mutual Recognition Agreement (MRA) covering also clinical trials is in place with the particular country, the latter declaration is not required if the MRA provides for GMP equivalence.
    – In all other cases, an authorization according to article 61 (authorization of manufacturing and import) of the CTR is required.

    Information regarding the GMP compliance of the API is not required by the CTR.

In addition, changes to “Annex II: Language requirements for part I documents” have been made.

More information can be found in the draft CLINICAL TRIALS REGULATION (EU) NO 536/2014 – QUESTIONS & ANSWERS VERSION 4.1 in EudraLex – Volume 10 – Clinical trials guidelines.