Implementation of the European Clinical Trial Regulation (EU-CTR)

First, let’s explain the difference between a European “Regulation” and a “Directive”. A”Directive” is a legislative act that sets out a goal for all EU countries that must be achieved. However, it is up to the individual countries to translate this into their own laws to achieve these goals.In other words, the “directions” are given by the EU but the member states have the authority to decide the implementation strategy and legal framework. A “Regulation” on the other hand is a binding legislative act which must be followed by all member states without being translated into the national legislations.

The implementation of the EU-CTR is part of the centralisation and harmonisation of drug development and new drug applications. On 31 January 2022, the new EU-CTR (EU Clinical Trial Regulation 536/2014) became effective replacing the EU-CTD, which was effective since 2004 aiming to coordinate the regulation of clinical trials in EU countries. Some of the major changes are listed below but this is not a conclusive list:

• Clinical Trial Applications (CTA) are from now on submitted through a central electronic portal: the Clinical Trials Information System (CTIS). This enables Sponsors to submit an application for one or several EU countries simultaneously and receive approval for all countries included in the submission, provided that all member states agree during the coordinated procedure. This should reduce the lead times as the evaluation is done more efficiently through a coordinated assessment which is led by one reporting member state.
• The CTIS: since the go-live date on 31 January 2023, all new CTA’s must be submitted through this portal which offers a lot of advantages:
  • Sponsors can apply for clinical trial authorization in up to 30 EU countries at once
  • National authorities can collaboratively process and evaluate the application and bundle their remarks and questions through the reporting member state. While previously, the same questions were repeatedly asked by the different national authorities.
  • A similar centralized approach is applicable to the Ethics Committee approval for which the MedEthicsEU-group can be consultuted. This is a group of representatives of Medical Research Ethics Committees (MRECs) from the concerned member states, streamlining the ethics committee approval process. Through this portal, extensions to other European Economic Area (EEA) countries can be requested
  • The portal enhances public transparency and accessibility of clinical trial data, as it is obligatory to publish trial data and results
• Introduction of “low intervention clinical trial”. There are three main conditions which differentiate a low intervention clinical trial from other clinical trials:
  • The Investigational Medicinal Product (IMP) is authorized in the concerned member states (excluding placebos)
  • The IMP is used in accordance with the Marketing Authorisation, or its use is evidence-based and supported by sufficient published scientific evidence.
  • The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice (for example:  no invasive sampling like a biopsy)
• Simplified safety reporting: according to the EU-CTD, safety submissions to each concerned national authority and ethics committee were required. The EU-CTR simplifies this process by requiring safety reporting through the EudraVigilance portal, streamlining the submission process.

Based on the above you can understand that the change from the EU-CTD to the EU-CTR is a significant step forward but also has a substantial impact on ongoing clinical trials and clinical trials being initiated. Therefore, a three-phased transition period was initiated.

• 31 January 2022 to 31 January 2023: sponsors could submit clinical trials under the legal framework of either the EU-CTD or EU-CTR.
• Starting 31 January 2023: all clinical trial applications are subject to EU-CTR. However, trials approved under EU-CTD before 31 January 2023 could continue to be regulated under EU-CTD until 31 January 2025.
• 31 January 2025 onward: all clinical trials must be regulated under EU-CTR.

This means that 31 January 2025 is an important date with the final completion of the transition from the EU-CTD to the EU-CTR. Making it obligatory for all new CTA to be done under the EU-CTR and all currently ongoing clinical trials must be transitioned to the EU-CTR in case they were previously approved under the EU-CTD.

The harmonization introduced by the EU-CTR aims to create uniformity across all EU member states, reducing administrative burdens while ensuring high-quality standards are upheld. However, it requires significant investments from sponsors and organizations in terms of training personnel and updating internal processes to align with the new regulations. Sponsors must carefully manage the transition process to ensure compliance. This includes revising existing agreements, such as Clinical Trial Agreements (CTAs), to reflect the requirements and legal framework of the EU-CTR.

The role of ethics committees has also evolved under the EU-CTR. Their functions are now streamlined and integrated within the CTIS framework, enabling efficient collaboration across member states. Furthermore, the introduction of the CTIS serves not only as a platform for initial applications but also contributes to the transparency of clinical trial data as a centralized system for managing ongoing communications, monitoring trial progress, and implementing updates throughout the lifecycle of a clinical trial.

References:

EU: https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en

EMA : Clinical Trials Regulation | European Medicines Agency (EMA)

https://european-union.europa.eu/institutions-law-budget/law/types-legislation_en

Understanding the new EU Clinical Trial Regulation: seven things sponsors should know

Clinical Trials Regulation (Regulation (EU) No 536/2014)