Clinical Trials Regulation - Version 6.1 of the Q&As

In April, the European Commission (EC) published an updated Version 6 of the Questions & Answers (Q&As) relating to the EU Clinical Trials Regulation (CTR). The Q&As entered into force together with the application of the CTR on 31 January 2022. However, certain Q&As are still being discussed and updated versions of the document will be published progressively. The document has now been revised again. In the current Version 6.1 - in addition to the previous changes - the requirements for the "Protocol synopsis" for Belgium and Norway have been adapted in Annex II: Language requirements for part I documents.

New Q&As in Version 6

Compared to the previous Version 5 the following new Q&As have been introduced:

1.22 What are the legal warranties for the validity of decisions by tacit approval? 

The process for decision on a clinical trial in a given Member State (MS) is described in the CTR and an explicit conclusion on the (harmonized) part I is required. A decision can only be taken when the reporting MS (RMS) has submitted the assessment report part I with a positive conclusion (or positive conclusion with conditions). However, an explicit confirmation of the part I conclusion by a MS concerned (that is not the reporting MS) or a part II conclusion is not a requirement for a MS decision to be positive. A tacit approval is a legally binding decision at MS level and the sponsor can start the clinical trial when the application is authorized by tacit approval in any MS concerned.

1.23 Appeal and implementation of change of decision due to an appeal

Changing of a decision from refusal to authorization in an appeal procedure under the CTR is expected to be exceptional and limited to cases when a Member State Concerned (MSC) refuses an application with a positive part I conclusion. Justified reasons for this are when part II aspects are not complied with or where the ethics committees have issued a negative opinion in accordance with national law. MS shall provide a procedure for such cases (e.g. requesting the sponsor to modify the trial via a substantial modification (SM)). With the SM the sponsor can modify the trial docs as applicable.

6.5 What is the recommended strategy for the publication of trial documents with proprietary information?

The CTR states that trial related documents in the Clinical Trials Information System (CTIS) shall be publicly accessible apart from justifiable exemptions (e.g. personal or proprietary data protection). Importantly, the trial protocol of trials with the potential to address public health emergencies needs to be published after the decision on the application. Sponsors are encouraged to submit trial documents with relevant redactions. However, it needs to be emphasized that the redacted documents have to remain meaningful to the public (including potential trial participants and health care professionals). This approach would enable the earliest publication of trial documents and at the same time keep sponsors confidence in using EU for clinical trials, especially for early development where sensitivities are highest.

Revised Q&As in Version 6

The following Q&As have been revised:

1.4. What document / data shall be submitted with an application? (Q&A introduced with Version 5)
1.5  How to proceed in case of discrepancies between the CTR and ICH Good clinical practice guidance? (Q&A introduced with Version 5)
5.8. What should be included in the protocol synopsis described in Annex I, D.24? (Q&A introduced with Version 4.1)

11.10 What are the consequences of switching the regulatory framework applicable to a clinical trial?

From the Directive (CTD) transitioned clinical trial will be governed by the CTR from the moment of its (tacit) authorization under the Regulation. From this time point onwards, all requirements of the CTR will apply (e.g. obligations of notification, safety reporting rules, archiving requirements as well as the procedural rules of the CTR for requesting SM, addition of a MS). Some specific fields (e.g. the start of the clinical trial) will need to be filled in with the correct date, i.e. the date of start of the trial under the Directive. As for GMP requirements, with the exception of labelling (see Annex 6 of the CTR), the Commission Delegated Regulation on GMP for IMPs will become applicable once the trial is approved under the CTR. However, for trials authorized under the CTD, EU GMP Annex 13 remains applicable.

In addition, Annex I (decision tree to establish whether a study is a clinical trial) has been updated.

More information can be found in the CLINICAL TRIALS REGULATION (EU) NO 536/2014 - QUESTIONS & ANSWERS VERSION 6.1 in EudraLex - Volume 10 - Clinical trials guidelines.

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