As of February 2024, we are less than one year out from 31 January 2025, a date that marks the end of the three-year transition period granted to sponsors with ongoing clinical trials since the Clinical Trial Regulation (CTR) No 536/2014 became applicable in the European Union (EU) in January 2022. This regulation, which was specifically designed to enhance transparency, safety, and efficiency in clinical trials, has instituted several notable changes in the structure and operational procedures of EU clinical trials. Continue reading as we revisit CTR No 536/2014 once again to explore the impact of its implementation on the evolving clinical trial landscape in this region.

The Clinical Trial Regulation (CTR) No 536/2014

The CTR is a pharmaceutical legislation that came into application on 31 January 2022, replacing the Clinical Trials Directive (EC) No. 2001/20/EC from 2004. The purpose of introducing the CTR was to harmonize the processes for assessment and supervision of EU clinical trials. In addition to enabling better efficiency in the regulatory process for new trials, the CTR’s purpose was also to facilitate the conduct of larger clinical trials in multiple EU Member States/European Economic Area (EEA) countries by improving information-sharing and collective decision-making.

By this time next year, all ongoing clinical trials in the EU are required to be transitioned to the Clinical Trials Information System (CTIS). All new clinical trial applications must also be submitted to the CTIS beginning as of January 2023, allowing sponsors to apply for clinical trial authorization in up to 30 European countries with only a single application. To learn more about how sponsors and contract research organizations (CROs) can set themselves up for success with EU clinical trial regulations under the CTR and become ready for 2025, visit our previous article here.

Impact on the Structure of EU Clinical Trials

The CTR was primarily introduced to simplify processes with EU clinical trial regulations, improve harmonization, and increase efficiency for sponsors conducting multi-state clinical trials across multiple EU countries. With the transition from the EudraCT online platform to the CTIS, as well as the transition from the previous directive, the EU established a single application procedure for multi-state trials. The purpose was to significantly reduce the need for duplicated work and improve consistency in application assessments; as such, sponsors are no longer required to obtain separate clinical trial authorizations from national competent authorities and ethics committees from each participating EU Member State.

In theory, this streamlined approach to regulatory approvals enables sponsors, local EU CROs, and global CROs running clinical trials in the EU to better navigate this typically complex research landscape. Under the 2004-era directive prior to the CTR’s introduction, there was a lack of harmonization that resulted in inconsistencies in the conduct and reporting of clinical trials, limiting the ability for sponsors and EU CROs to share research results. With the introduction of CTR No 536/2014, these barriers have been relatively diminished, contributing to a more integrated and collaborative clinical trial landscape in the EU.

Changes in Operational Procedures

In addition to the structural impact the CTR has had on EU clinical trials regulations, it also prominently features the CTIS, a feature that promoted additional changes in operational procedures for sponsors, EU CROs, and global CROs. The CTIS was implemented to act as a unified EU portal and database for the submission and maintenance of clinical trial applications and data. Central to the CTR, the CTIS was intended to improve transparency and facilitate greater public access to information on EU clinical trials.

According to the European Medicines Agency, this system is also expected to facilitate the expansion of trials to other EEA countries because it allows national regulators to collaboratively process clinical trial applications in more than one country. The CTIS now acts as a central repository of clinical trial data and serves as a valuable resource for researchers, enabling them to learn from previous trials and build on existing knowledge. At minimum, the regulation mandates that the following data be reported in the system prior to the clinical trial starting:

• The main characteristics of a clinical trial.
• The conclusion on Part I of the assessment report for the authorization of a clinical trial.
• The decision on the authorization of a clinical trial.
• The substantial modification of a clinical trial.
• The end date of the trial, with reasons for which trials are ended prematurely where applicable.
• The summary of results and a summary in lay language within 12 months of the trial end date.

The stipulation that requires the reporting of summary results within one year of the end of the trial has particularly functioned to ensure the timely dissemination of findings for EU clinical trials. This requirement has also fostered greater accountability among researchers, as they are now obligated to share their results, regardless of the outcome of the trials. These CTIS data mandates are aligned with the CTR’s objective of public disclosure, which aims to foster innovation within the EU to develop novel products and research novel applications of existing products.

Real-World Uptake of the CTR and CTIS: Trends and Challenges

According to a report from May 2023, many sponsors and CROs are still struggling to adapt to these new systems, despite some time passing since the launch of the CTR and CTIS. Although the CTIS was expected to significantly speed up the application process and reduce administrative work, many sponsors were hesitant to adopt it initially. The situation has somewhat improved since then, but many sponsors are believed to be holding back, hoping to complete their studies before the 2025 deadline, thus avoiding having to complete the CTIS registration. According to the EMA’s key performance indicator report, the real-world uptake of CTIS has increased since its launch, with the number of clinical trial applications submitted jumping from only nine in February 2022 to 185 in April 2023.

However, regulators still face considerable challenges delaying the complete implementation and adoption of the CTIS and the EU CTR. First are the technical limitations posed by the CTIS portal itself. Following their initial submission, sponsors must abide by a 30-day waiting period before any new EU countries can be added to the application. This hinders last-minute changes to clinical trial planning, requiring companies to plan further ahead.

Second, CTIS requires data to be entered manually because it does not have any application programming interface (API) capabilities; as is the case with manual data entry, there is a greater risk of human error when clinical trial data is entered. Finally, the CTR presents challenges associated with the organizational restructuring it requires from sponsors. Because of how the structure and operational procedures of EU clinical trials are evolving as a result of the Regulation, it places pressure on organizations to reorganize how they operate. Larger pharmaceutical companies or global CROs may especially face greater difficulty adjusting to the new system given their size.

Conclusion

The implementation of the CTR has significantly transformed the landscape of clinical trials in the EU. It has led to structural and operational changes that are gradually working to make the conduct of clinical trials in the region more efficient, transparent, and trustworthy. Although the Regulation is not without its challenges, trends indicate the EU clinical trials industry will continue to increase its adoption of the new legislation, as well as the CTIS platform. However, there may be additional work required as we move closer to 2025 to ensure all stakeholders are better prepared to fully utilize this new system and receive its intended benefits.

About TFS HealthScience CRO

TFS HealthScience is a mid-size, global CRO that supports biotechnology and pharmaceutical companies throughout their entire clinical development journey. Our mission is to build solution-driven teams who are dedicated to creating a healthier future. As a trusted CRO partner to clients around the world, TFS remains committed to supporting our EU customers through this changing landscape of clinical trials in the region.

Visit our website to learn more about the solutions TFS can offer for your next clinical trial, or connect with a TFS representative today!