Brief Introduction to the CT Regulation

Several years after enactment of the Clinical Trials Regulation (Regulation EU/536/2014, “CT Regulation”) governing clinical trials with medicinal products in the EU, the CT Regulation eventually became applicable on 31 January 2022. The CT Regulation aims to create a harmonized regulatory environment favourable for conducting clinical trials in the European Union and will soon fully replace the Clinical Trials Directive (Directive 2001/20/EC, “CT Directive”) and the implementing laws in the member states (together “Former Legal Framework”). All clinical trial applications will have to be submitted to the European Medicines Agency (“EMA”) using the Clinical Trials Information System (“CTIS”).

Clinical Trials requiring transition to the CT Regulation

Already since 31 January 2023 all applications for new clinical trials must be submitted under the legal framework of the Clinical Trials Regulation (Regulation EU/536/2014, CT Regulation). By 31 January 2025 all clinical trials that have been authorized under the former CT Directive and have at least one active clinical trial site on 31 January 2025 will have to be transitioned to the CT Regulation. In this context a site is considered “active”, if the last visit of the last patient in the EU/EEA has not yet occurred or if the trial subject in the EU/EEA still has to undergo trial specific interventions according to the Protocol. During the transitioning process, an ongoing clinical trial does not have to be halted.

The transitional period cannot be extended. I.e. clinical trials that could not be transitioned, but are still ongoing following 30 January 2025 will have to be authorized as “new clinical trial” under the CT Regulation. In absence of such authorization these trials are non-compliant with the CT Regulation and may be subject to corrective measures by the member states pursuant to Article 77 of the CT Regulation, i.e. they may be subject to an hold order by competent authorities.

Clinical trials that are currently halted e.g. for safety reasons can be transitioned to the CT Regulation if the sponsor expects the continuation of the trial beyond 30 January 2025. The general rules for the transition to the CT Regulation also apply for these trials. After the transition the sponsor should update the status of the trial as “halted” in the CTIS.

Implementation of changes prior to the transition

The clinical trial should generally be in line with the principles of the CT Regulation and follow the requirements for transitioning from the CT Directive to the CT Regulation as stated in the Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation published by the European Commission currently March 2024, version 3) and relating guidance published by the Clinical Trial Coordination Group (under “Key Documents list”.)

The general assumption for clinical trials already approved by the member states under the Former Legal Framework is that these multinational trials and the pertaining documents are already harmonized. However, this may not be the case as specifics can apply in some member states. All documents subject to the assessment report under Part I have to be harmonized prior to the transition, i.e. generally including the Investigator’s Brochure (“IB”) and the Investigational Medicinal Product Dossier (“IMPD”). Where a change qualifies as substantial amendment of the clinical trial, the sponsor needs to seek prior authorization of the substantial amendment under the CT Directive first declaring its intention to transition the trial to the CT Regulation. Only after such harmonization the sponsor can apply for the transition to the CT Regulation.

With regards to the protocol of a multinational clinical trial the sponsor has to check, if the trial procedures in the respective countries can be fully harmonized und can be transferred into a “harmonised protocol”. In most cases, as noted above, substantial amendments approved by the member states under the Former Legal Framework will be required prior to the transition to the Clinical Trials Regulation. If the trial procedures cannot be harmonized, a “consolidated protocol” is possible, if the clinical trial has the same EudraCT number across all countries, the same trial title, the protocol version number and the same primary objective, primary endpoint and definition of end of trial. The main inclusion and exclusion criteria should be the same. The consolidated protocol itself or an annex thereto should outline the non-substantial specifics of the trial in the member states, but can only contain what was previously approved by the member states. The consolidated protocol itself will not be approved by the member states prior to transition and will only be provided in the CTIS. In addition to a consolidated protocol, the sponsor can also prepare consolidated documents of the IP or IMPD, if complete harmonization is not possible across all relevant member states.

Please note that transitioning a clinical trial to the CT Regulation is not possible while a substantial amendment authorization procedure is still pending in a member state. This also applies when there is the urgent need for an amendment e.g. to ensure patient safety. In such case, the sponsor should reach out to the reporting member state (under the CT Regulation) (a) which may be able to speed up the transition allowing the sponsor to file for a substantial modification in a timely manner, or (b) which may advice the sponsor to withdraw the transition for the moment and apply for the necessary substantial amendment under the former legal framework. Once the substantial amendment has been approved, the sponsor can then re-submit the transition of the application under the CT Regulation.

General Aspects of the transition process

Firstly, if not yet done, the sponsor will have to obtain access to the CTIS by registering (please refer to our article on the CTIS.) Prior to commencing the transition, the sponsor needs to register the clinical trial in the CTIS.

Since the transitioning trial and any substantial amendments have already been authorized by the member states under the national law implementing the CT Directive, the trial is not required to undergo a complete assessment. Documents that have already been assessed and approved under the Former Legal Framework, will not be re-assessed. For that purpose, the sponsor is expected to submit a “transitioning application” in the CTIS to those member states in which the trial has at least one active site after 30 January 2025. The CTIS provides for the possibility to mark a clinical trial application as “transitional trial”. It is not possible for sponsors to respectively mark the clinical trial application at a later stage in the process.

Generally, the latest authorized versions of the following documents will have to be submitted as a minimum dossier together with a cover letter:

• Protocol
• Investigator’s brochure (IB)
• GMP relevant documents
• Investigational Medicinal Product Dossier
• Documents relating to non-investigational medicinal products (if any)
• Subjects’ information sheets and consent forms

In the cover letter, the sponsor is required to declare that protocol, IB and IMPD do not include any substantial changes compared to the documents approved by the member states under the Former Legal Framework, and that all other Part I and Part II documents are identical to the documents previously authorised. In this cover letter, the sponsor is also meant to indicate whether the IB, IMPD and the protocol are fully harmonised or if consolidated documents are provided. A template cover letter by the Clinical Trials Coordination Group can be found here under “Key Documents list”.

In case, sponsor wants to include additional countries in the conduct of clinical trials, this can only be done after the transition to the CT Regulation. However, sponsors should outline this intention in the cover letter of the transitioning application.

Please note that in general all documents submitted to the CTIS are meant for public disclosure. Regarding the minimum dossier, the sponsor can generally submit to EMA redacted versions of the protocol, subject information sheet(s) and informed consent form(s) in addition to the unredacted documents that have already been approved by the member states (specifics apply for Phase I clinical trials). Following the transition to the CT Regulation, the clinical trial will by fully subject to the transparency rules applicable to the CTIS. I.e. in general, if the sponsor does not request EMA a deferral for certain documents, the sponsor is allowed to prepare an additional document version for publication in which redactions can be made for data privacy reasons and to protect commercially confidential information. If the sponsor does not submit such redacted document version for publication, the submitted information will be publicly disclosed in the CTIS.

Duration of transition

An expedited transition procedure of 22 days for the minimum dossier was agreed upon that is restricted to documents that have already been approved under the CT Directive (in case there is no request for information). The expedited transition procedure consists of the following steps:

• 10 days validation phase
• 7 days assessment phase
• 5 days for decision.

The procedure can take longer if there are requests for information by the member states. Also, such expedited review can switch to the normal review procedure with a the review time line of 106 days, in case a complete application is required. In addition, the winter clock stop from 22 December 2024 to 6 January 2025 needs to the taken into account.

Sponsors are advised to prepare their clinical trials still authorized under the Former Legal Framework early for the transition and submit the transitioning application as soon as possible.

After the transition to the CT Regulation

Following the transition, the clinical trial will be subject to the CT Regulation, the Commission Delegated Regulation (EU) 2017/1569 on good manufacturing practice for investigational medicinal products for human use and arrangements for inspections and the Implementing Regulation (EU) 2017/556 on good clinical practice inspection procedures. This in particular includes the submission of notifications via CTIS (operated by EMA), safety reporting, archiving and transparency requirements, requests for substantial amendments and submission of results and the clinical study report.

After the transitioning application was granted, the sponsor should notify the start of the clinical trial in the CTIS by stating the date of the initial authorization under the Former Legal Framework (and not under the CT Regulation). In addition, the sponsor should update trial documents to the CT Regulation by way of a substantial amendment Part I procedure and/or bay way of a substantial amendment Part II procedure (except for the site suitability statement, which cannot be changed retrospectively).

Regarding the labelling of the investigational medicinal product (“IMP”), there is no need to relabel already released IMP. Old labels can still be used after the transition as long as the new label is not yet approved in a substantial amendment Part I procedure.

For additional information on the transitioning of clinical trial to the Clinical Trials Regulation please refer to Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation published by the European Commission currently March 2024, version 3), relating guidance published by the Clinical Trial Coordination Group (under “Key Documents list”) and relating guidance on the CTIS.

Interested in more details on the transition process? Read our article “Transition soon to the EU Clinical Trials Regulation”.

Authored by Dr. Tina Welter-Birk, Dr. Joerg Schickert, Arne Thiermann, and Hein van den Bos.