Deciphering the New Regulatory Landscape for Clinical Trials Across Europe

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The Clinical Trials Regulation (EU) No 536/2014 (CTR), introduced by the European Union (EU), became mandatory as of 31 January 2023, and it represents a significant overhaul of the regulatory framework for conducting clinical trials within the EU and European Economic Area (EEA), i.e., 27 EU countries plus Iceland, Norway, and Liechtenstein. The regulation aims to streamline the clinical trial process, enhance patient safety, and promote transparency. Deciphering the requirements laid out in this regulation is crucial for researchers, sponsors, and all stakeholders involved in clinical trials. In this short article, I will explore the key requirements of the CTR and how to navigate the new regulatory landscape effectively.

•    Scope and Application
The first step in deciphering the CTR is understanding its scope and application. The regulation applies to all clinical trials conducted with medicinal products for human use, including investigational drugs, biologics, and ATMPs. It covers interventional trials only; it does not apply to non-interventional trials or trials with a medical device.

•    Single Application and Portal
One of the fundamental changes introduced by the CTR is the establishment of a single application and authorization procedure for clinical trials. Sponsors now need to submit a single application for all EU member states through the Clinical Trials Information System (CTIS). This replaces the previous system of submitting separate applications to each member state involved in the trial.

•    Harmonized and Faster Approval Timelines 
With a centralized submission and authorization system, the approval timelines for multi-country clinical trials are expected to be the same for every submitted country and significantly reduced. This expedites the setup of trials, allowing quicker access to potentially life-saving treatments for patients.

•    Simplified Reporting and Safety Monitoring
The regulation mandates the use of a simplified reporting process for safety issues related to the clinical trial. The sponsor must report serious adverse reactions and events promptly to the EU safety database (EudraVigilance). Additionally, the reporting requirements for the annual safety reports have been harmonized to reduce administrative burden and improve efficiency.

•    Database for Clinical Trials and Public Access
Transparency is a key focus of the CTR. All clinical trials conducted in the EU must be registered in the EU Clinical Trials database. Moreover, sponsors are required to publish a summary of the results of their clinical trials in a publicly accessible database, regardless of the trial's outcome. This move towards greater transparency aims to improve accountability and ensure that valuable trial data is made available for scientific and public scrutiny.

•    Enhanced Patient Safety 
The regulation places a strong emphasis on patient safety. Stricter requirements for informed consent ensure that participants' rights and well-being are protected throughout the trial.

•    Collaboration and Cooperation
The CTR fosters collaboration and cooperation among EU member states to streamline the clinical trial process. The coordination of assessments by member states is facilitated through a streamlined procedure, which aims to reduce duplication of efforts and expedite trial approvals.

•    Simplification for Low-Intervention Clinical Trials
For low-intervention clinical trials, the regulation offers a simplified approach, taking into account their lower risk profile. These trials benefit from reduced administrative requirements, accelerating their setup and execution.

While the CTR offers several advantages and improvements to the regulatory landscape for clinical trials in Europe, it also presents some challenges that stakeholders need to address. Here are some of the key challenges of the new regulation:

•    Implementation Complexity
The new regulation represents a significant change from the previous system, and its successful implementation requires adaptation from all stakeholders involved in clinical trials. Raising awareness and providing education and training opportunities for all involved parties are critical to support successful compliance with the new requirements. Linical recognized the importance of staying compliant with these requirements, and thus, our EU Regulatory team has become structured and extensively trained for submissions under the new CTR and through the CTIS. This enabled us to move smoothly through the first submissions under the new CTR.

•    Data Privacy and Transparency Concerns
While the new regulation promotes transparency by requiring the publication of summary results, there could be concerns regarding the privacy data in the publicly accessible EU Clinical Trials database. Applicants are now supposed to upload two versions of documents: redacted and unredacted to consider aspects of privacy or confidential information which requires more effort in preparing core submission documents.

•    Transition of Ongoing Studies to CTIS
If your clinical trial has an end date projected after 31 January 2025, a transition to CTIS is required. If a clinical trial does not comply with the CTR (e.g., protocol versions are not aligned across countries), the sponsor is expected to submit a substantial amendment first and request the approval for the aligned documents. Only after the substantial amendment is approved, a transition to CTIS can proceed for the sponsor.

In conclusion, the Clinical Trials Regulation (EU) No 536/2014 represents a significant step forward in harmonizing and enhancing the regulation of clinical trials within the EU. While the CTR aims to improve the clinical trial landscape in the EU, it also presents challenges that need careful consideration and collaborative efforts from all stakeholders. By deciphering the requirements of this regulation, applicants can navigate the new regulatory landscape effectively. The first critical step is to stay informed about the latest regulatory developments. The landscape for clinical trials is continually evolving, and regulations may be subject to updates and changes. Refer to official sources such as the European Medicines Agency (EMA), and national regulatory authorities within EU member states. Regularly check their websites for guidance, announcements, and updates on clinical trial regulations.

Jowita Wojciechowska 
Director Regulatory Affairs – Linical Western Region Compliance Department

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