EU Clinical Trials Regulation: Overview and Implications for the Industry

The new Clinical Trials Regulation (EU Nº 536/2014) will enter into application on 31 January 2022 harmonizing assessment and supervision processes for clinical trials through a Clinical Trials Information System (CTIS). This regulation will imply major changes that will impact on the way clinical trials are conducted in the EU.

Background

Between 2007 and 2011, the number of Clinical Trials (CTs) in the EU decreased by 25%, costs of conducting CTs got higher and average start-up time for clinical trials increased by 90% to 152 days.

In the light of this situation, the European Commission proposed a new Regulation in 2012 with the aim to create an environment favorable to conducting clinical trials in the EU with the highest standards of safety. This regulation was finally published in 2014 and on July 31^st 2021 it was confirmed that it will be start applying on January 31^st 2022.

Transition Period

Once the CTR is applicable, a three-year transition period applies:

• From Jan 31^st 2022 to Jan 31^st 2023, sponsors may apply for a new trial authorization under old (Directive) or new (Regulation) system at their own choice. Member States (ECs + CAs) must all be ready to use CTIS from day 1 (and still run the old process as well)
• From Jan 31^st 2023 to Jan 31^st 2025 any new clinical trial application must be submitted and managed via CTIS. Clinical trials authorized under the old directive may continue, or may already switch to the CTIS at sponsor choice
• By Jan 31^st 2025, all trials authorized under the old directive must end or have been transferred to CTIS by the sponsor.

Regulation Overview

• Streamlined submission and review process via EU Portal and Database including a tacit approval system. Part A (general) + Part B (country specific).
• Shorter timelines
  • 10 days for validation (25 if queries)
  • 45 days for assessment (76 if queries)
  • Short response timelines (max 10 days for validation, max 12 days during assessment)
• Coordinated assessment with one Reporting Member State (RMS) proposed by the sponsor and involvement of all Member States Concerned (MSc)
• More transparency on the conduct and results of clinical trials to allow adequate public scrutiny. Free open access to general public. No registration or log-in required.
• Single decision per Member State (= National Competent Authority + Ethics Committee)
• Overall, a smoother process with a higher standard for CTs in the EU

Implications for the Industry

• In the beginning it is likely to expect issues due to new system for all stakeholders
• Trials not completed by 31 Jan 2025 need to be shifted into CTIS. New full submission latest by end Sep 2024 with aligned documentation across countries
• Time for trial preparation will extend
• Trial Start-Up timelines will become shorter:
  • The need to make the overall contract negotiation timelines shorter (as sponsors may expect trials to start immediately after getting approvals)
  • Provision of response readiness due to very short response timelines to Request for Information (RFIs) is crucial
• Need of accurate documentation and well thought out trials
• Cooperation with partners and CROs in the EU will become more complex in terms of the submission due to various administration settings in CTIS for responsibilities
• New types of documents required (i.e., lay language synopsis, lay language summary of results, new harmonized CV template)
• Document templates need to be newly created or amended (i.e., protocol, IB, lay language synopsis)
• SOPs/WPs need to be amended (i.e., serious breach, regulatory submissions, pharmacovigilance)
• Focus on submission and document quality
• Rapid response processes to be established
• Standard regulatory submission budget needs revision

Outlook & Summary 

• CTs can be submitted according to the CTR from 01 Feb 2022 via CTIS but can be submitted also under CTD until 31 Jan 2023 (consider an end date before 2025)
• Ongoing trials under CTD need to be submitted in time for a full assessment before the end of the transitional period 31 Jan 2025 (submission twice!)
• Many guidance documents are yet to be published by EMA (i.e., transparency guidance)
• Some processes yet to be established by EMA (i.e., safety reporting)