Transitioning On-going Trials to the CTR: Considerations for the First Substantial Modification

Following the introduction of the EU Clinical Trials Regulation (CTR) on 31^st January 2022, which replaced the previous EU Clinical Trials Directive (CTD), a transition period was implemented. This transition period allowed clinical trial sponsors time to comply with the new legislation. Any initial clinical trial application submitted from 31^st January 2023 onwards was required to be completed under the CTR. For trials which were already approved under the CTD the deadline for transition to the CTR was set at 31^st January 2025. Transition to the CTR was necessary only for those trials which were expected to have at least one active site in the European Union (EU) on 30^th January 2025.

In order for an on-going trial to transition to the CTR, an initial application was required to be submitted via the Clinical Trials Information System (CTIS). Compared to submission requirements for new trials, a simplified dossier was required for a transition submission. This consisted only of documentation that had already been assessed and authorised under the CTD. The minimum set of required documents is outlined in the Guidance for Transition of clinical trials from the CTD to the CTR.

Following approval of the transition application, clinical trial sponsors are expected to update trial documentation in line with the CTR. This update is required at the time of submission of the first Substantial Modification (SM). Sponsors leveraging the benefits of submitting a minimum dossier for the transition has resulted in complexities being pushed onto the first SM submission, increasing the burden of work at this stage. This article outlines the key considerations for clinical trial sponsors when submitting the first SM after the transition.

Consideration 1: Content of the Substantial Modification Dossier

At the time of submission of the first SM following transition, the clinical trial sponsor is required to complete all elements in the part of the dossier impacted by the SM; all Part I elements must be completed at the time of the first Part I SM, all Part II elements at the first Part II SM (for that particular MSC), and both Part I and Part II elements if the first SM is a Part I/II modification. The clinical trial sponsor must ensure that for the part(s) of the dossier impacted by the modification:

• All documentation is in line with the requirements of the CTR
• Any documentation not submitted at the time of transition is aligned with the CTR requirements and included at this stage.

There are a number of efficiencies that can be employed regarding the CTR-alignment of documentation:

Additional information can be found in the following documents:

• Guidance for the Transition of clinical trials from the CTD to the CTR
• CTCG best practice guides:
  • Updating the Part I dossier after CTR transition
    • Includes an overview of the revisions expected for Part I documentation to be considered aligned with the CTR
  • Updating the Part II dossier after CTR transition

Consideration 2: First Substantial Modification is a Part I SM applicable to Multiple Trials

As outlined above, if the first SM is a Part I SM, all elements of the Part I dossier must be completed. This is applicable regardless of which Part I document is subject to substantial modification. The only exception to this is where the first Part I SM submitted after transition is a single request for authorisation of IMP documentation which is applicable for multiple clinical trials with the same sponsor and IMP. In this case, the Part I documentation for a particular transitioned trial should be aligned with the CTR at the next Part I SM.

Consideration 3: Potential for Requests for Information (RFIs)

It is important for clinical trial sponsors to consider the impact of the substantial modification procedure. There is the potential for requests for information (RFI) to be issued as part of the review process. For instance, DLRC has had experience of RFIs being issued for documentation which had already been approved previously, and for documentation which had not been subject to substantial modification. Sponsors should keep in mind the possibility of this situation occurring.

In general, the approach taken with regards to modifications under the CTR is to bundle revisions together where possible. However, it may be prudent for sponsors to consider submitting a smaller SM for the first SM following transition. This is to increase the likelihood of a smooth pathway to full alignment with the CTR. If the assessing member state perceives any element of the SM to be unacceptable, the whole SM in that member state may be rejected. This would mean that the updated documents would have to be resubmitted with the next SM.

Consideration 4: Revised Transparency Requirements

The implementation of the revised transparency rules for publication of information included in CTIS was completed on 18^th June 2024. This was following the release of the updated version of CTIS. The most significant change was the removal of the deferral mechanism for the publication of certain information and documentation. This has been implemented alongside a reduction in the number of study document types in scope of publication.

The requirement to complete all elements of the impacted part(s) of the dossier at the first SM includes the provision of redacted documents. Redacted versions of those documents which are in scope of publication as per the revised transparency rules are required. Any document in scope of publication for which a redacted version was not already submitted as part of the minimum transition dossier, the redacted document must be provided at this stage.

Consideration 5: Planned Inclusion of an Additional Member State Concerned

Clinical trial sponsors can include an additional member state concerned (MSC) in the trial following the transition. Part I of the dossier must first be brought in line with the CTR before submitting the additional MSC application. This will mean careful planning of the timelines for the submission of the two applications.

Consideration 6: Country-specific Idiosyncrasies

Denmark – Part II Dossier

The Danish Medicines Agency released guidance on the Transition of clinical trials from Directive to Regulation. This states that for Part II dossiers it’s not necessary to align all documents with the CTR at the first Part II SM. It’s only necessary to submit the documentation which is the subject of the SM. All other documents can be left as submitted during the transition application.

Consideration 7: Trials with no Substantial Modification Expected

For most trials, alignment of documentation with the CTR at the first SM slots easily into trial maintenance activities. However, there is an open question around the management of the process for those trials where no SM is expected. This is the case for trials which are in the long-term follow up stage or are close to end of trial. For these trials it is likely that no substantial revision of documentation will be required. There is currently no guidance on the management of the process for these trials. There is also no established timeframe after transition within which all trial documentation must be fully aligned with the CTR. Sponsors of these trial types are encouraged to monitor official guidance.

Summary

The deadline for transition to the CTR is almost upon us. Many clinical trial sponsors will now be switching their focus from the transition application to the full alignment of their documentation at the first substantial modification. Whilst the precise requirements for each trial will differ depending on the study attributes, the considerations described here will form the basis of the initial planning for many trials.

DLRC has extensive experience in successfully supporting companies to conduct clinical trials. To find out how DLRC can support you, contact our team via hello@dlrcgroup.com or use the links below.