Since 2004, clinical trials in the EU have been controlled by the European Union Clinical Trials Directive (EU-CTD). The directive was an attempt to standardize rules and enhance patient protections in clinical trials; however, its real-life implementation created some unintended challenges.
Since it is a directive, the CTD does not carry the same mandatory weight as a regulation. Each EU member state has had to implement its legal requirements through national legislation, causing sponsors to face a fragmented assessment process for multinational clinical trial applications, as well as a complicated data submission framework. Additionally, the public has had limited access to clinical trial applications and results in the EU.
A new regulation known as the Clinical Trials Regulation (EU-CTR) is designed to simplify and harmonize clinical trials in Europe. It began to replace the CTD on January 31, 2022. The CTR is intended to overcome the directive’s shortcomings—it aims to increase public transparency around clinical trials, as well as create a more favorable research environment by reducing administrative requisites and streamlining workflows. As a regulation, the CTR is mandatory for all EU member states.
The three-year transition period started on January 31, 2022:
- Before January 31, 2023: Sponsors may submit clinical trials under the legal framework of EU-CTD or EU-CTR.
- After January 31, 2023: All clinical trial applications are subject to the CTR and will need to use CTIS (discussed below) to start a new clinical trial. Trials approved under EU-CTD before this date can continue to be regulated by the CTD for no more than 2 years.
- After January 31, 2025: All clinical trials must be regulated under the CTR.
The Clinical Trials Regulation harmonizes the processes for assessment and supervision of clinical trials throughout the EU. The evaluation, authorization, and supervision of clinical trials are the responsibilities of EU member states and European Economic Area (EEA) countries.
The CTR enables sponsors to submit an online application via a platform called the Clinical Trials Information System (CTIS) for approval to run a clinical trial in multiple European countries, thus making it more efficient to carry out multinational trials. This centralized, single electronic submission provides a more efficient process for EU member states to evaluate and authorize such applications together. Sponsors can upload and submit all data, including initial clinical trial application and documentation, to the platform.
CTIS will also help increase public transparency, as sponsors are required to make all data and documents publicly available (with a few exceptions). The new transparency rules aim to increase information sharing among studies—and to promote greater public awareness and understanding of clinical trials. For that reason, summaries of trial results, including a layperson summary, must be submitted via the CTIS.
Some other benefits of the CTR include:
- Enabling sponsors to apply for clinical trial authorization in up to 30 European countries with a single online application
- Facilitating the expansion of trials to other EEA countries
- Allowing national regulators to collectively process clinical trial applications in more than one country, request further information, authorize or refuse a trial, and oversee an authorized trial
- Speeding up the timeline for which sponsors must respond to application queries or requests for information
- Improving patient protections for vulnerable subjects with changes made to informed consent
The CTR intends to overcome the limitations of the CTD to increase the EU’s competitiveness in the drug development market. It will hopefully result in a more efficient clinical trial submission and assessment process, given its implementation of a single dossier and single electronic submission for all member states, harmonized authorization, and flexible risk-based rules.
However, with the 2023 deadline fast approaching for the mandatory use of the CTR, authorities are still trying to repair some of the issues in the new system. This does not come as much of a surprise, given the complexity and scope of the regulation and the variety of users of the CTIS. According to the European Medicines Agency (EMA), who is at the heart of the trouble, they are working hard to resolve any detected issues prior to the looming deadline.
So far, the majority of clinical trials submitted in the CTIS have been approved without issues, but some users have experienced “technical difficulties that have been challenging.” A major problem has been the fact that member states are diverging and requiring additional documents not required by the CTR. Another difficulty is that the portal does not flag or send any information to sponsors when new information is received, so sponsors must check frequently for updates. Others have had issues with the fact that the system does not flag any missing information, so sponsors must often check the application.
However, these small issues will not impact the transition period—the EU will not grant any extension for compliance with CTIS by January 31, 2023. The EMA is working to remedy any technical glitches before the effective date.
Despite the impending deadline for the mandatory switch to CTIS, only a small percentage of trials are registered in the system—in September, it was estimated that only about 10% of trial were registered in CTIS. Beyond the technical challenges that may arise come January with the increase in CTIS usage, sponsors should also be aware of stricter transparency and reporting obligations, new safety and patient protection provisions, updated definitions, and shorter deadlines that come with the CTR.