How to maintain EU-CTR compliance for studies after slim transition

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

With the period to transition trials to the Clinical Trials Information System (CTIS) in its final weeks, focus now turns to actions related to ongoing compliance with the EU Clinical Trial Regulation 536/2014 (EU-CTR). Trials that benefited from a slim transition may have outstanding requirements, and companies should carefully prioritize the information to be submitted to the Member States (MSs). 

Here, we outline three key considerations for sponsors with a trial transitioned with a slim dossier:

1. First Substantial Modification (SM) after transition: Fulfill the requirements 

Objective: One of the high-priority requirements is to have all dossiers aligned with EU-CTR before the first SM submission. All documents and requirements for Part I and Part II must be aligned with the EU-CTR when the first SM Part I or SM Part II or SM Part I + Part II is submitted.

Timing and requirements: 

• There is no specific deadline to submit the SM after transition. 
• For studies that are close to completion or long-term follow-up studies (with little interaction with participants and no need for modification): There is no requirement to submit a SM for the purposes of having a fully EU-CTR-compliant dossier.
• It is mandatory for the SM to align the documentation with the EU-CTR before any Additional Member State (AMS) is considered in the clinical trial.
• In cases where the submission of a single request for authorization of a multi-trial substantial modification application (restricted to IB, IMPD and GMP documents) is intended, the SM Part I of the application dossier should be updated to align with the CTR. 

Dossier content for first SM after slim transition: Clear information about new, updated or already authorized documents must be provided. In Part I and Part II, the information to be provided must complete the full list of documents as per EU-CTR annex I, for example:

• All the documents related to Part II of the dossier must be submitted, except for the site suitability statement (which does not need to be retrospectively created and would only be needed for sites added after the transition). 
• There is also no need to upload a new document template for the trials’ procedures that have been already completed (e.g., if recruitment of trial participants has ended).
• Regarding the labelling of IMP and AxMP, there is no requirement to proactively relabel released IMPs. Old labels can still be used for IMP batches manufactured after transition, if the new label is not yet approved in an SM Part I application. 

2. Act proactively to ensure EU-CTR dossier compliance 

We recommend proactive actions to ensure EU-CTR compliance when the first substantial modification is planned, including: 

• Plan the relabeling of all medication (IMPs and AxMPs) ahead. New (EU-CTR compliant) labelling should be released right after the SM approval.
• Since the transparency rules apply once transition is authorized, include the redaction of all the new documents in your planning. It should be done before making them publicly available.
• The clinical trial application should be completed with the correct information in cases where:

1. a medicinal product (MP) did not fall under the AxMP but into the IMP category (during the transition), or 
2. an IMP is classified as AxMP under the EU-CTR 

3. Submit the right information at the right time

• In general, different SMs can’t be under assessment at the same time, but there are few exceptions: 

1. SM part II standalone update 
2. SM submitted in different countries
3. Additional Member State Concerned (AMSC) with SM Part II review only, running in parallel with other member states

Those exceptions should be assessed to allow the implementation of the updates needed. It might be also strategically justified to combine Part I and Part II modifications, even if the changes are not related, as it could save time and effort compared to sequential submissions. 
Careful planning on any possible IB annual amendment and safety reference information updates, as well as IMP-related changes (medication changes, manufacturing changes as well as QP release, importer, distributor updates) is recommended.

Last, but not least – when multiple changes are included in one SM, the decision will apply to the entire package of changes. If one part of the SM is rejected or requires further clarification; it could delay the approval of all other updates included in that SM. Additionally, any unapproved change (included in the SM that is not authorized), must be documented in the next SM. 

Next steps 

To ensure a smooth continuation of the lifecycle of your trial, and regulatory compliance within the first SM after transition, companies should carefully review and plan for the requirements.  

If your organization is facing challenges in determining timelines to update your dossier – or – you’re concerned about meeting the requirements for the first SM after slim transition, please sign up for the webinar on January 30th, 2025, led by Parexel regulatory experts. You will have the opportunity to engage directly in the live Q&A session. 

Register for the webinar now

With proven experience of managing SMs after slim transition, having submitted more than 30 already, we’re here to support you in navigating regulatory complexities and progressing confidently. If you’re not able to join the webinar, we are always available for conversation. 

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References:

1. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, EUR-Lex. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32014R0536
2. Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, Dec 2023. https://health.ec.europa.eu/document/download/10c83e6b-2587-420d-9204-d49c2f75f476_en?filename=transition_ct_dir-reg_guidance_en.pdf
3. Best practices guide. https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-Working_Groups/CTCG/2023_11_CTCG_Best_Practice_Guide_for_sponsors.pdf
4. EudraLex – Volume 10 – Clinical trials guidelines, European Commission. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-10_en
5. Clinical Trials Regulation, Q&A, Substantial Modifications, Q 3.4, Version 6.7. EMA. Dec 2023.
6. Clinical Trials Regulation, Q&A, Version 6.9., EMA. July 2024, Substantial modifications, Q 3.5 https://health.ec.europa.eu/document/download/bd165522-8acf-433a-9ab1-d7dceae58112_en?filename=regulation5362014_qa_en_0.pdf
7. CTCG Best Practice Guide to sponsors – first substantial modification application Part I and/or Part II after CTR transition vs. 2.0 adopted by CTCG April 15 2024 https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-Working_Groups/CTCG/2024_CTCG-Best-Practice-Guide-to-sponsors-first-substantial-modification-application-PartI-and-or-Part-II-after-CTR-transition-vs.-2.0.pdf 
8. Annex I Cover Letter Template for first SM after transition vs. 2.0 adopted by CTCG June 19 2024.CTCG Best Practice Guide to sponsors – first SM application Part I and/or Part II after CTR transition: Annex I Cover letter template First SM after _vs 2.0
9. Annex II Substantial Modification Description Template - first SM after transition vs. 2.0 adopted by CTCG June 19 2024 CTCG Best Practice Guide to sponsors – first substantial modification application Part I and/or Part II after CTR transition: Annex II Substantial modification template First SM after transition_vs 2.0  
10. Annex III First SM Part II after transition vs. 1.0, adopted by CTCG April 15 2024: Annex III First SM Part II after transition_vs._1.0
     

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