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Transition of clinical trials to the Clinical Trials Regulation

The CTR and its Impact

The Clinical Trials Regulation (CTR)[i] came into force on January 31, 2022. CTR marked a significant shift in how the EU authorizes clinical trials for medicinal products for human use.

CTR introduced the Clinical Trial Information System (CTIS), a centralized system for submission of clinical trials in the EU. This system simplifies processes, making them more efficient and transparent.

A notable feature of the CTR is its single-application approach. Previously, sponsors needed separate approvals from each member state’s authority and ethics committee. Now, they can apply once for authorization in up to 30 countries. This change significantly eases the burden on sponsors.

[i] 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.

Transitioning from CTD to CTR

As of January 31, 2023, CTIS has become the single-entry point for new clinical trial applications in the EU/EEA. Trials authorized under the older Clinical Trial Directive (CTD)[i] using EudraCT[ii] must be transitioned to the CTIS platform under the CTR by January 30, 2025. Until then, sponsors can still submit significant amendments and end-of-trial notifications under the CTD.

[i] Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001, repealed by the CTR.

[ii] EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) is the database for all interventional clinical trials on medicinal products submitted to the National Competent Authorities (NCAs) of the European Union (EU)/European Economic Area (EEA) from 1 May 2004 until 30 January 2023 under Directive 2001/20/EC, as well as for all trials conducted outside of the EEA that are part of a Paediatric Investigation Plan (PIP) and/or are conducted under Article 45 or 46 of Regulation (EC) No 1901/2006.

Transition Timeline

Transitioning a trial from the CTD to the CTR can require up to 60 days. If the submitted documentation differs from what was approved under the CTD, sponsors might face delays. This extension could add up to 46 days, split into 15 days for validation and 31 days for assessment. Thus, sponsors expecting to continue trials in the EU/EEA beyond January 30, 2025, should start the transition process at their earliest convenience. This proactive approach ensures trial continuity after the deadline.

Guidelines for Transition

Trials in the EU/EEA ending before the transition period’s close don’t need to undergo transition. Only trials authorized under the CTD with at least one active site[i]in the EU on January 30, 2025, need to be transitioned.

When submitting transition applications, sponsors should refer to two key guidance documents:

1. Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation[ii];
2. CTCG Best Practice Guide for sponsors of multinational clinical trials with different Part I document versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014[iii].

[i] In the context of transition trials, an active site means that the last visit of the last subject, or other trial-specific interventions with the subject specified in the protocol will take place after 30 January 2025.

[ii] Latest version 3.0 approved on 13.11.2023 is available at https://health.ec.europa.eu/system/files/2023-07/transition_ct_dir-reg_guidance_en.pdf

[iii] Latest version approved on 21.12.2023, available at https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-Working_Groups/CTCG/2023_09_CTCG_Best_Practice_Guide_for_sponsors.pdf

The Transition Process

Transitioning from CTD to CTR involves submitting a “transitioning application” through CTIS. This administrative process streamlines the transition by requiring a reduced dossier. This dossier includes key elements of Part I and II of the clinical trial and a sponsor’s declaration of harmonized or consolidated European status.

For mono-national trials, transition happens via a new CTIS application mirroring the currently approved dossier by the Member State under the CTD.

Multinational clinical trials under the CTD should transition as a single multi-country application under the CTR. This requires either a harmonized or, at least, a consolidated protocol.

If clinical trials in different Member States under the same EudraCT number lack sufficient harmonization[i], sponsors must harmonize them through substantial amendments under the CTD. For trials where full protocol harmonization is unfeasible due to varying national requirements, sponsors should prepare a consolidated protocol[ii]. This protocol must align with each concerned Member State’s authorization. However, it doesn’t require unanimous pre-transition approval if no substantial modifications are made in this process.

[i] For this purpose, a harmonized protocol, IB and/or IMPD means that the respective document(s) is identical and includes the same trial procedures in all countries approved across all EU Member States under the CTD.

[ii] A consolidated protocol means that there are substantial differences in the respective document(s) in different Member States, but the document itself is identical. The consolidated protocol does not need prior approval under CTD before the transition.

Final Steps and Urgency

Once approved, ongoing trials will fall under the CTR’s regulation. Given the fast-approaching deadline, sponsors should prioritize registering their clinical trials under CTIS. Timely registration is crucial for ensuring uninterrupted trial continuity post-January 30, 2025.