Transition trials: CTD to CTR

• Authorised under CTD with an EudraCT number;
• At least one active site in the Netherlands (mononational CT) or in the EU/EEA (multinational CT) after 30 January 2025;
• No ongoing assessment of a substantial modification/amendment in any Member State Concerned (MSC) under CTD.

An active site in the context of transition trials means that the last visit of the last subject (LVLS), or other trial-specific interventions with the trial participant as specified in the protocol, will take place after 30 January 2025. If a clinical trial is temporarily on hold but is expected to be restarted and ongoing after 30 January 2025, this is also considered to be a clinical trial with an active site(s).

• The sponsor should transition the clinical trial in time.
• An expedited administrative procedure is foreseen up to 16 October 2024. This procedure may take up to 22 days if there is no validation RFI (request for information), or up to 37 days for files containing validation RFI’s.
• Basically, there is no re-assessment of a clinical trial in transition. In exceptional cases there may be an RFI in the assessment phase, in which case the expedited procedure is cancelled and default CTR timelines are applicable (maximum 106 days).
• During transition, the clinical trial may continue under CTD.

• European Commission:
  • Guidance on the transition of clinical trials (Eudralex volume 10)
• CTCG:
  • Best practice guide for sponsors on the transition of multinational clinical trials and a template cover letter. Both can be found under: key document list, section Transitional Trials.

The transition clinical trial application should be submitted in the new Clinical Trials Information System (CTIS). To access CTIS, users need an EMA account. To submit a clinical trial application, the user needs to have acquired the correct system roles and permissions. Most of the clinical trials submitted to CTIS have a sponsor admin role. The person fulfilling the sponsor admin role is responsible for assigning roles to users of a clinical trial.

For academic clinical trials if the University Medical Centre (UMC) is the sponsor, please contact the representative for clinical trials at the UMC. Contact details can be found on the Questions and answers CTR – The Netherlands webpage.

A CTIS sponsor handbook and CTIS training modules can be found on the CTIS website. The transition of clinical trials is discussed in module 23.

The sponsor should submit an initial application relying on the existing CTD file that has been assessed and authorised. In case of multiple versions of a document, only the latest authorised version should be submitted.

The following minimum set of data/documents is required:

• All mandatory application data fields in CTIS including the Dutch translations for the following items: the full study title and public study title (found in CTIS under Part I, Trial Identifiers) and for the Medical condition, Main/Secondary Objectives, Inclusion/Exclusion criteria, Primary/Secondary Endpoints (found in CTIS under Part I, Trial Information);
• Statement on GDPR compliance (new, template available, required for CTIS users);
• Cover Letter. The cover letter should follow the format of the CTCG template cover letter for transition trials (see annex to CTCG best practice guide for sponsor on transition trials, under References);
• Protocol (one consolidated or harmonised version);
• Investigator’s Brochure (one consolidated or harmonised version);
• Investigational Medicinal Product Dossier (IMPD) (one consolidated or harmonised version);
• GMP relevant documents;
• Documents related to auxiliary medicinal products (non-IMPs under CTD);
• Subject information sheet and informed consent form.

Please note, no proof of payment document is required for initial transitional trials.

For all other documents (part I and part II), the sponsor may submit a placeholder document with the text “This aspect was assessed by National Competent Authority (NCA) and/or ethics committee who has given a positive opinion on the clinical trial under the CTD and is therefore covered by the conclusion of the assessment under the CTD’’. For more details, please refer to the European Commission guidance on the transition of clinical trials and the CTCG best practice guide for sponsors (under References).

Under the CTR, the sponsor  is obliged to electronically report SUSARs to the clinical trial module of Eudravigilance. This is also required for non-commercial sponsors. This obligation starts from the moment that the study is authorised in at least one Member State. 

SUSAR reporting requires access to the Eudravigilance database. We recommend sponsors to organise this centrally within their organisation. Check timely if there is an existing process within your organisation, if not please start the process to request access timely. For more information, refer to (Serious) adverse events and SUSARs | Investigators | The Central Committee on Research Involving Human Subjects.
 

Clinical trials submitted to CTIS will be made public taking into account the revised rules on the protection of personal data and commercially confidential information. For transition trials, the protocol (all CT categories) and subject information sheet (only category 2 and 3 clinical trials) will be made public under the revised rules. For these documents, the sponsor may submit a redacted version in the slot “for publication” and an unredacted version in the slot “not for publication”. 

For further information: Transparency rules: general information on english.ccmo.nl and chapter 2.4 ‘Transparency aspects of transition trials’ of the ‘EMA guidance document’.

For transition trials combining a medicinal product with a medical device under Medical Device Regulation 2017/745 (MDR) or In Vitro Diagnostics Regulation 2017/746 (IVDR) the following applies:

• State in the cover letter that the submitted clinical trial combines a medicinal product with a medical device and declare that the relevant provisions of the national legislation and/or MDR or IVDR regulation (only applicable for studies submitted after 26 May 2021 or 26 May 2022, respectively) will be followed. For more information please consult the CCMO website: MDR investigations, IVDR performance studies.
• ToetsingOnline and its registration number remain applicable to the MDR or IVDR part of the clinical trial.

• EMA:
  • CTIS sponsor handbook
  • CTIS: how to get started and how to transition a trial
• European Commission:
  • Guidance on the transition of clinical trials (Eudralex volume 10)
  • CTR quick guide
• CTCG:
  • Best practice guide for sponsors on the transition of multinational clinical trials and a template cover letter. Both can be found under: key document list, section Transitional Trials.
• ACT EU:
  • Q&A on protection of Commercially Confidential Information and Personal Data while using CTIS
  • Training for non-commercial sponsors: Transitioning trials to CTIS. A Youtube training video d.d. 9 februari 2024.

• The clinical trial should be conducted in accordance with the rules of CTR, even if not all documentation (e.g. protocol) is updated to be in compliance with CTR. This includes the safety reporting and all mandatory notifications.
• The start date of the clinical trial (i.e. the starting date under CTD) per Member States concerned (MSC) should be registered in CTIS.

With the submission of the next substantial modification (SM), the clinical trial application in CTIS should be completed in compliance with CTR. If this SM concerns only Part I or only Part II, then only that Part should be completed. The CTCG best practice guide for sponsors, including templates for the SM cover letter and SM description, should be followed (see “First SM: document requirements after transition” under Key document list).

• For procedures within the clinical trial that have already ended, no documents need to be completed. For example, if recruitment of trial participants has ended, the recruitment material does not have to be submitted with the next substantial modification (SM) to complete part II of the dossier.
• The site suitability statement does not need to be retro-actively created. The site suitability statement (in Dutch “Onderzoeksverklaring” or “VGO”) authorised under CTD continues to be valid.
• Labels authorised under CTD do not need to be re-labelled pro-actively. After the transition, the sponsor may update the labels for batches that require (re)labelling.

If the sponsor is planning to start the transitioned clinical trial in a new MS, the clinical trial should also be authorised in this new MS. This may be accomplished through an additional MS procedure in CTIS. Before starting this procedure, the sponsor should first submit an SM part I on the transitioned clinical trial to complete the application and to allow the RMS to draft an assessment report part I for this new MS to be added. This SM is not needed for any subsequent addition of a new MSC.

• CCMO:
  • Clinical trials with medicinal products (CTR)
• CTCG:
  • Best practice guide for sponsors, including templates for the SM cover letter and SM substantial modification description. The documents can be found under: key document list, section Transitional Trials, First SM: document requirements after transition.