The transition from the Clinical Trials Directive (CTD) to the Clinical Trials Regulation (CTR) caused quite a stir for pharmaceutical companies, biotech’s, clinical research organisations, and those of us in regulatory affairs.
The CTR came into effect in January 2022; however, a 3-year transition period ended in January 2025, during which all ongoing clinical trial applications (CTAs) had to be transitioned to the CTR.1
This blog examines how the transition from the Clinical Trials Directive to the Clinical Trials Regulation has reshaped clinical trial submissions in the EU, and what three years of Clinical Trials Information System (CTIS) data reveal about the impact on sponsors, regulators, and clinical trial activity.
What did the transition from the CTD to CTR entail?
- Between January 2022 and January 2023, sponsors could choose to submit new CTAs under the old CTD or under the new CTR (via CTIS).* 1
- From January 2023, sponsors were required to submit new CTAs, via CTIS, under the CTR.1
- From January 2025, any ongoing clinical trials that had CTAs approved under the CTD, had to be transitioned to the CTR and use CTIS for any filings.1
*New CTAs could include initial CTAs submitted under the CTR; authorised trials under the CTD transitioning to the CTR, or resubmitted initial CTAs which were previously withdrawn, lapsed or not authorised under the CTD.
Under the CTD, CTAs and substantial amendments were submitted separately to the individual ethics committees (ECs) and national competent authorities (NCAs) in each country, following any local formats and submission avenues. Each EC and NCA conducted its own independent review and could raise concerns about different aspects of the clinical trial. For those of us who worked on CTAs, submissions under the CTD were labour-intensive and required a lot of coordination. This was further amplified in the case of sponsors with multinational trials and multiple sites per country, as they would need to manage a considerable amount of submissions to national ethics committees and competent authorities.
It seems quite a fractured process in hindsight, but this was what everyone working on clinical trials was used to.
Fast forward to January 2022, the Clinical Trial Regulation and Clinical Trials Information System (CTIS).
What did the CTR and CTIS change about submitting CTAs?
A lot.
Among other things, the CTR was implemented to harmonise CTA dossiers into a single dossier consisting of two parts, and to use a single point of entry for all submissions related to clinical trials in Europe.2
Part 1 of the CTA dossier includes information common to all member states concerned with the trial. This relates to scientific and regulatory documentation, for example, the protocol, investigator’s brochure (IB) and the investigational medicinal product dossier (IMPD).3
Part 2 of the CTA dossier includes information specific to each member state concerned in the clinical trial, as it relates to specific trial sites in each country. This includes, for example, informed consent forms, participant information documents, suitability of trial investigators and trial facilities and insurance/financial arrangements.4
In essence, Part 1 of the CTA dossier is reviewed in a coordinated assessment by all member states a trial is run in, overseen by a reporting member state. Part 2 of the dossier is assessed nationally by each member state where a trial is being run. Sponsors can also submit full CTAs (part 1 and part 2) or part 1 and part 2 separately.3-4
What are the guiding principles of the Clinical Trial Regulation?
The CTR aimed to streamline and harmonise the clinical trials process in Europe. The idea was that a single CTA dossier is submitted to all countries through a single portal (CTIS).2
Coordinated assessment by member states also aimed to harmonise review timelines and hold individual member states to a clear maximum timeline to review CTA dossiers. Whereas previously, each national authority that received a CTA had its own timelines, information and formatting requirements. Some national authorities had submission portals, while others allowed clinical trial documents to be submitted via email.
For pharmaceutical and biotech companies, the CTR also came with increased transparency requirements regarding clinical trial data and documents that should be made publicly available.2
What does the landscape of clinical trials look like 3 years on from the CTR transition?
The European Medicines Agency (EMA) published a report based on data retrieved from CTIS, providing details on clinical trial applications in the EU/EEA during the 3-year transitional period (from 31 January 2022 to 30 January 2025).1
Highlights
During the transition period (2022-2025):1
- 10,608 CTAs were submitted through CTIS
- 8,521 trials were authorised
- 5,008 trials migrated from EudraCT to CTIS
- An average of 200 initial CTAs were submitted each month (2023-2025)
To break down the demographics of the 10,608 CTAs submitted during the transition period, 42% were multinational, and 49.8% came from commercial sponsors.1 Additionally, 2024 saw the largest number of CTA submissions, and throughout the 3-year transition period, the majority of CTA submissions involved one concerned member state.1
During the transition period, 8,521 initial CTAs were authorised.1 The majority of trials that were not authorised were mono-national and conducted by non-commercial sponsors (57.1%).1 This trend was similar in the number of CTA withdrawals. Of the 571 initial CTAs withdrawn, 48.3 % were from non-commercial sponsors conducting mono-national trials.1
Summary
The transition from the Clinical Trials Directive to the Clinical Trials Regulation, which came into effect in January 2022 and concluded with a mandatory transition deadline in January 2025, fundamentally reshaped how clinical trial applications are submitted and reviewed in the EU.
Replacing fragmented national submissions under the CTD, the CTR introduced a single, harmonised CTA dossier submitted via the Clinical Trials Information System, with coordinated assessment of common scientific elements (Part 1) and national review of country-specific elements (Part 2). According to EMA data covering the 3-year transition period, 10,608 CTAs were submitted through CTIS, 8,521 trials were authorised, and 5,008 trials were migrated from EudraCT, with 2024 seeing the highest submission volume. The data show a predominance of mono-national trials and highlight differences in outcomes between commercial and non-commercial sponsors, offering early insights into how the CTR has changed EU clinical trial activity.
