Clinical trials on medicinal products for human use under the new EU Clinical Trials Regulation No. 536/2014 (“CTR”)

Part 1.
Introduction to new regulatory framework of the CTR, its applicability and transitional periods

On January 31, 2022, the new Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (Clinical Trials Regulation - "CTR") entered into full force. The CTR replaces the former Good Clinical Practice Directive 2001/20/EC ("GCP Directive") and, through its unrestricted applicability in all Member States of the European Union ("EU"), leads to a harmonisation of the application procedure, authorisation and supervision of clinical trials in the EU.

1. Essential Considerations and Objective

The European Commission first announced its intention to evaluate the impact and functioning of the GCP Directive in practice in December 2008, setting in motion a new legislative process for the progressive harmonisation of clinical trial regulations in the EU only four years after its implementation in the Member States on May 1, 2004. According to the Commission, the experience with the GCP Directive had shown that the harmonised approach to regulating clinical trials had only been partly achieved: The different application of the requirements established by the GCP Directive for the authorisation of clinical trials in the Member States led not only on the sponsors' side to increased administrative costs and considerable delays in the start of especially multinational clinical trials, but also from the Member States' perspective to an inefficient use of resources due to unnecessary multiple assessment of the same information.
With the CTR, the Commission has therefore set itself the goal of facilitating the conduct of larger clinical trials in several EU Member States and strengthening Europe as a research base. The exchange of information between all stakeholders involved in the authorisation process is to be improved and collective decision-making in clinical trials simplified. Other essential objectives are to increase transparency and ensure higher safety standards for all participants in clinical trials in the EU.

2. Overview of the Main Characteristics of the CTR

• New authorisation procedure: In case of multinational clinical trials, a Member State will henceforth take over the coordination of the authorisation procedure as reporting Member State (“rMS”). With regard to general aspects of the clinical trial, this Member State will also have the responsibility of reviewing the trial in a manner that is binding for all participating Member States in which the clinical trial is also to be conducted ("Member States concerned" – “MSc”). A deviation ("opt-out") of the Member States concerned from this assessment is only permitted in strict, exceptional cases. The scope of the review by the Member States concerned, on the other hand, mainly comprises national aspects such as the safety of the trial subjects, the qualification of the trial team and the suitability of the trial sites.
• Involvement of Ethics Committees in the authorisation procedure: In addition, the new authorisation procedure entails a shift away from the two-pillar system of parallel and independent assessments by the competent national authority and a local Ethics Committee. The sponsor will receive the authorisation of the clinical trial (or its refusal) only in the form of a single decision; the obligation to separately apply for and obtain the favourable opinion of the competent Ethics Committee will no longer be required. The extent to which local ethics committees are henceforth involved in the authorisation procedure is at the discretion of the Member States.
• Clinical Trials Information System (CTIS): From now on, sponsors have to submit their applications for the authorisation of intended clinical trials via a central online portal, which acts as a communication platform between the applicant and the individual actors in the Member States involved in the authorisation decision. The submission of applications via the CTIS is mandatory for both mononational and multinational clinical trials.
• New definitions: With an extensive catalogue of (partly new) terminology, the CTR contributes to a uniform EU-wide understanding of the terms used in the context of clinical trials. The clinical trial itself is now to be understood (alongside the non-interventional study) under the generic term of “clinical study”. The definition of a low-interventional clinical trial is new as well. In addition, although not specifically defined and subject to a deviating Member State regulation, the CTR allows for the implementation of so-called cluster-randomised clinical trials, with less stringent requirements for obtaining informed consent.
• New regulatory responsibilities introduced: The CTR introduces the possibility of clinical trials being conducted by several sponsors and thus the concept of co-sponsoring. The primary requirement is, above all, a clear allocation of tasks and division of all sponsors’ responsibilities in a written contract. According to the Commission's considerations, this new provision is intended to simplify the procedure for all informal networks of researchers and research institutions through shared responsibilities. However, the opportunity of co-sponsoring is not limited to these so-called investigator-initiated trials, but can also mean more flexibility in cooperation for smaller pharmaceutical companies as well as research cooperations between the pharmaceutical industry and academic institutions.
• Substantive legal requirements for the protection of trial subjects: The provisions on the protection of trial subjects are extensively framed: The CTR devotes no less than two detailed articles to the requirements for informed consent as an indispensable condition for participation in a clinical trial and lays down detailed provisions on the content, scope and execution and the obtainment of informed consent. In addition to general protective provisions applicable to all trial subjects, the CTR also provides detailed requirements for the inclusion of minors, adults who are not capable of giving consent, patients in emergencies, pregnant and breastfeeding women. The possibility of including adult subjects who are incapable of giving consent in so-called group beneficial research projects was – after heated discussions in the legislative process – ultimately left to the Member States for stricter regulation.
• Extension of retention periods: In addition to standardising concrete requirements for archiving the master file on the clinical trial, the CTR obliges investigators and sponsors to archive the contents of their master file for at least 25 years after the end of the clinical trial - an innovation that should henceforth be specified accordingly in clinical trial agreements. However, the retention of the patient files of the trial subjects is (still) governed by the law of the respective Member State.

3. Transitional Periods

The CTR provides for a transition period of three years for clinical trials, as follows:

• Within the first year from the date of application of the CTR, sponsors are granted a right of choice: From January 31, 2022 to January 30, 2023, sponsors can still apply for approval according to the old, solely national procedure under the former regulatory framework of the GCP Directive (and respective national laws implementing the GCP Directive) or according to the new requirements of the CTR via the CTIS.
• As of January 31, 2023, all applications for new clinical trials in the EU have to be submitted via CTIS in accordance with the new CTR requirements.
• As of January 31, 2025 (and thus, after expiry of the transition period of three years), all clinical trials that were still initiated under the former legal framework of the GCP Directive will have to be transferred to the new CTR procedure. Although this does not necessarily mean that a (new) authorisation of the ongoing clinical trial according to CTR provisions is required, all study documents must be entered into the CTIS. It remains to be seen whether there will be separate transitional rules drawn up by the Commission in this regard.

This means that initiating a clinical trial according to the former regulatory framework of the GCP Directive may only be reasonably considered if the duration of the trial is rather short and there is thus a well-founded expectation that the clinical trial will be completed by January 30, 2025. For sponsors who have not yet familiarised themselves with the new requirements of the CTR, in particular the new authorisation procedure and the functioning of the CTIS, there is now an urgent need for action. After all, the CTR does not provide for an extension of the three-year term.