1. Introduction

The European Commission has published an updated Questions and Answers document concerning the Clinical Trials Regulation (EU) 536/2014. The document provides clarification regarding the implementation of the rules governing clinical trials within the Regulation. The draft document has been submitted for discussion to the Expert Group on Clinical Trials.

2. Clinical Trials Regulation

The Clinical Trials Regulation is intended to replace the Clinical Trials Directive 2001/20/EC. Unlike the Clinical Trials Regulation, the Clinical Trials Directive is accompanied by national implementing laws of individual EU Member States. The new Regulation is intended to harmonise the assessment and supervision processes for clinical trials throughout the European Union (EU), through a Clinical Trials Information System (CTIS). Although the Regulation was adopted and entered into force in 2014 it has not yet entered into application. This is because entry into application depends on confirmation of full functionality of the CTIS through an independent audit. In October 2019, the European Medicines Agency’s Management Board endorsed a six-monthly monitoring report on the development of the CTIS. The CTIS will not, however, be functional until at least 2020 because of current technical difficulties with the development of the IT systems.

3. Clarification of responses

In the document, the European Commission provides updated responses to frequently-asked questions related to the Clinical Trials Regulation. The responses provided relate to the following topics:

  • The scope of the Clinical Trials Regulation

The first section of the document provides responses regarding the new characteristics of the Regulation and its scope of application. In addition to these responses, Annex II of the document provides a decision tree to establish whether a trial is to be considered as a “clinical trial”.

  • The application procedure for a clinical trial

This section includes responses concerning the submission of both whole applications (Part I and Part II) and limited applications (Part I or Part II) for authorisation of clinical trials. Part I provides information related to the clinical trial, product subject and the trial protocol. Part II consists of data specific to the EU Member States where the trial will be conducted. The section also provides responses concerning the management of requests for information (RFI) to trial sponsors by EU Member States. RFIs should be formulated with clear and concise instructions to the sponsor and focus only on critical issues. Due to time limitations it is expected that only one RFI will be feasible during the assessment period.

  • Substantial and non-substantial modifications

This section provides clarification on how “substantial modification” of a clinical trial is understood under the Regulation. This includes responses on what is considered to be a substantial modification. The section also provides clarification concerning the role of the trial sponsor regarding these modifications. Annex I to the document also provides examples of substantial and non-substantial modifications that may lead to changes in the clinical trial.

  • Withdrawals

This section provides responses to questions concerning withdrawal of applications for authorisation of a clinical trial by the sponsor.

  • Parties involved

This section provides clarification concerning the role of trial sponsors, legal representatives and investigators in the conduct of a clinical trial. The section also includes responses concerning shared responsibilities.

  • Submission of results of clinical trials

According to the Regulation, a summary of the results of the clinical trial must be submitted to the EU database within one year from the end of the clinical trial. This section includes responses concerning this summary of results, including which endpoints must be summarised.

  • Safety reporting

This section includes clarification concerning the definition of both adverse events and adverse reactions and their application in the context of clinical trials. The section also includes responses regarding Reference Safety Information (RSI), its content and purpose. The section also includes responses regarding the reporting of adverse events and reactions to EU Member States. Responses regarding Safety Annual Reporting and safety issues concerning auxiliary medicinal products are also provided. Finally, this section provides responses concerning safety reporting during the transition period during the Regulation implementation.

  • Authorisation of manufacturing and importation of investigational medicinal products

This section provides clarification concerning clinical trials involving investigational medicinal products.

  • Substantial requirements for conducting clinical trials

This section provides clarification concerning, among other things, the documentation of the “informed consent” under the Regulation.

  • The course of clinical trials

This section provides responses concerning the definition of start, end, temporary halt and early termination of a clinical trial.

  • Arrangements for the transitional period

This section includes clarification regarding the switch from the Clinical Trials Directive to the Clinical Trials Regulation. The section also provides clarification regarding transparency requirements under the Regulation.