The January 31, 2025, deadline for active clinical trials to transition to the European Union Clinical Trial Regulation as per the EU Clinical Trial Directive 2001/20/EC, which was in place for more than 20 years, is fast approaching. Clinical trial sponsors who wish to continue their trials in EU member states beyond January 2025 needed to complete their submissions for regulatory review by October 16, 2024. This would ensure their approval for transition by the deadline, helping them avoid non-compliance, significant delays and additional costs.
 
In January 2022, EU lawmakers established the EU CTR to provide trial sponsors a single application submission process for trials in EU member states while advocating for stronger patient engagement. However, as with any change, especially a significant overhaul like the CTR, effective transitions require time, guidance and dedicated resources. Lawmakers provided sponsors and Clinical Research Organizations eight years (2014-2022) to familiarize themselves with the CTR and take steps to update submission strategies and processes accordingly. The regulation also included a three-year period for ongoing trials to transition to the new requirements.
 
Now, nearly three years since CTR initiation, it’s crucial to look back at the transition process to identify what has enabled trial sponsors to gain authorization to continue critical clinical research under the CTR in 2025 and beyond. This will be beneficial to apply to future regulatory requirements, as CTR is not the only change sponsors will face. 
 
A historical glance
Prior to CTR implementation, sponsors had many questions to navigate. What does an application for successful transition look like? How will trials be affected? What trial information will be made public? 
 
Adding to uncertainty, when CTR was initiated in 2022, most stakeholders were focused on new trial start-ups because they would be most significantly impacted. Trial transition was often a secondary priority. Also, for the first 18 months of the transition period, sponsors had many unanswered questions about the process and application requirements. 
 
These issues and an already complex clinical landscape initially led to many stakeholders taking a cautious approach to trial transitions under CTR. 
 
Simplifying CTR transition: EMA doing its part 
From January 31, 2022, to January 30, 2023, it was possible to submit clinical trials under either the EU CT Directive or the EU CTR. 80% of trials during that “optional” period were uploaded to the old directive’s EudraCT database, indicating sponsors had a significant preference for the CTD and processes they had used for decades. 
 
However, the European Medicines Agency estimated up to 4,000 ongoing trials would ultimately need to transition to EU CTR because they were expected to continue beyond January 30, 2025. In July 2023, the EMA released new guidance to simplify the transition and clarify directions, including:

• Not requiring document templates to be updated for CTR submission and not reassessing documents already assessed under the CTD. 
• Guidance on the definition of “active sites” required to transition.  

In late 2023, the EMA revised rules regarding publicly available trial documentation, reducing requirements for publishing information on the EU Public Portal. Effective June 2024, this revision encouraged sponsors to transition trials, especially with removal of the deferral mechanism. This allowed sponsors to delay publication of specific data and documents for up to seven years after trial completion to protect commercially confidential information, which was a key concern for drug developers. Instead, the revised rules removed many documents from publication entirely. 
 
In parallel, the EMA and the Clinical Trials Coordination Group, which includes experts and the Heads of Medicines Agencies, helped stakeholders stay informed on the evolving process by: 

• Sharing a detailed guide summarizing updated documentation requirements and guidance for personal data and company information when submitting to the CTR’s Clinical Trial Information System portal. 
• Hosting online webinars, “walk-in clinics,” and “bitesize talk sessions” to answer questions.

Though there have been technical and other challenges with the CTIS and with the EU member states’ varying approaches to the assessment of transition applications, overall, the EMA’s efforts to simplify the process while offering ongoing details has helped sponsors familiarize with the CTR. 
 
These updates have led to a dramatic increase in transition applications submitted in mid-to-late 2024. Of these, 62% were submitted from June through October 2024, which may be related to the June 2024 transparency rules revision, in addition to the approaching deadline. 

 
 
Open communication with EMA and sponsor guidance 
Because CTR requirements were new for all stakeholders, there were many nuances to consider when transitioning trials (e.g., ongoing revisions, potential transparency liabilities, CTIS technical insights, etc.). 

For one, with ongoing revisions to EMA guidance, it was critical that all application submission strategies were supported by specific expertise gained from constantly monitoring the regulation. From the start, experts in ongoing discussions with EMA, and as needed, country-specific regulators, helped ensure sponsors, CRO team members, study teams, etc. were aware and able to stay nimble to alter action plans when guidance was revised and/or risks were identified. For example, in some trials, transition timelines were difficult to identify because the process would prevent documentation submission regarding changes to principal investigators. This is where CRO team experts helped oversee document submissions in a coordinated manner. 

Throughout the transition, questions for the EMA were ongoing. Topics included the potential for publishing documents authorized prior to transition to EU CTR and expectation for retrospective information about the start of the trial or of recruitment, which must be posted under EU CTR but not required previously. These scenarios made it important to maintain dialogue with the EMA and member state regulatory agencies to integrate their nuanced guidance into individual trial submission activities. One key example was CROs familiarizing themselves with the EMA Service Desk,which offered to help resolve technical issues in CTIS. Through this resource, in addition to providing live support, the EMA made available a list of known issues and steps for resolution. 

Sharing insights and offering ongoing guidance 
With many sponsors focused on new trial submissions, it was critical for CRO partners to provide guidance to also prioritize transition strategies for active trials for the upcoming deadline. Experienced study start-up managers, regulatory experts, local country-specific start-up specialists, operational leads, etc., worked hand-in-hand to consolidate, coordinate and disseminate ongoing EMA guidance to sponsors and fellow team members to ensure all changes were accounted for and applied to submissions.  

However, it was not as straightforward as simply relaying EMA updates. It required ongoing communications within CRO teams and to sponsors, providing recommendations to keep transition strategies on track and ensuring relevant stakeholders were on the same page, including: 

• Conducting regular training sessions and materials regarding transition needs, EMA updates, etc., for relevant CRO team members. 
• Hosting open forums for CRO team members to discuss transition strategy pain points per trial, lessons learned and best practices to apply in other trials. 
• Ensuring a clear understanding among CRO team members and sponsors regarding roles, responsibilities and timeframes for action items. 
• Creating template documents for trial submission packages. 
• Communicating regularly with sponsors regarding transition needs per trial, accommodating plans for other submissions required for routine trial management and addressing their potentially unrealistic expectations and risks to trial programs if the upcoming deadline was not met. 

In its May 2024 guidance, the EU Commission emphasized that trials not successfully transitioned prior to the deadline would be in breach of the regulation, and “sponsors could be subject to corrective measures and penalties by member states” and “subject to civil and criminal liability.” Though what actions authorities may take was not clear, the risk of serious consequences was likely a significant motivational factor behind the noticeable increase in recent submissions. 
 
What’s next? 
Though the trial transitions deadline is approaching, CROs assisting sponsors have to continue accounting for if and how the regulation will evolve and the impact on individual trials and clinical programs. 
 
Will the CTIS portal be further fine-tuned? What else will the EMA and member states provide to equip sponsors and CROs for future trials? Will the EMA apply insights from the EU CTR transition to other regulatory changes? Questions will continue to come. Sponsors and CROs should strive to stay informed, be ready to adapt swiftly and apply best practices and lessons learned to successfully meet other regulatory requirements and changes.