The new European Union (EU) legislation regulating clinical trials, known as the Clinical Trials Regulation 536/2014 (CTR), repealed the previous legislation, the Clinical Trials Directive 2001/20/EC (CTD), and national implementing legislation in EU Member States. Although the CTR had entered into force on 16 June 2014, it become applicable only on 31 January 2022, when the EU clinical trials portal and database, named Clinical Trials Information System (CTIS), was fully functional.

The new Regulation harmonises the processes for assessment and supervision of clinical trials throughout the EU. It enables sponsors to submit 1 online application via a single platform (CTIS) for approval to run a clinical trial in several European countries, making the conduct of such multinational trials more efficient.

The launch of CTIS on 31 January 2022 started the clock for a 3-year transition period from the CTD to the CTR. Since 31 January 2023, it has been mandatory for sponsors to submit all initial clinical trial applications via CTIS. In less than a year, from 31 January 2025 onwards, sponsors will need to fully comply with their obligations under the CTR and its Delegated Acts. Therefore, all ongoing clinical trials authorised under the CTD which will have at least 1 active site in the EU on 30 January 2025 must be transitioned to CTIS by this date.

Currently, there is still a huge number of clinical trials to be transitioned to the CTR/CTIS. Sponsors are encouraged to consider the time necessary for completion of the authorisation procedure and are strongly advised to submit the transitioning application early enough before 30 January 2025. To facilitate the transition for multinational applications, the Clinical Trials Coordination Group (CTCG) agreed on an expedited evaluation procedure that will be open until 16 October 2024, based on the validation of minimum application dossiers restricted to documents already authorised under the CTD. The timeline for the expedited transition procedure is estimated to be maximum 22 days (10 days for validation, 7 days for assessment, and 5 days for decision) assuming no Request for Further Information (RFI) is needed.

Only trials without any ongoing assessment of documents in any of the EU/EEA countries are eligible for the transition: clinical trials for which a request for a substantial amendment is under assessment are not eligible for the transition until the amendment procedure is completed. Sponsors should carefully plan for any potential amendment need in relation to their transitioning application submission and evaluation timelines.

In terms of documentation requirements for the transition application, Sponsors will require a new cover letter, a General Data Protection Regulation (GDPR) statement, and an application form completed in CTIS. For Part I, the latest authorised versions of the following documents need to be provided as a minimum in the transitioning application:

• harmonised or consolidated protocol;
• investigator’s brochure (latest harmonised version);
• an Investigational Medicinal Product Dossier (IMPD; latest harmonised version);
• any Good Manufacturing Practice (GMP) relevant documents;
• documents related to non-investigational medicinal products (i.e. auxiliary medicinal products under the CTR, if applicable).

A harmonised document means that the respective document is identical and includes the same trial procedures in all countries approved across all EU Member States under the CTD. A consolidated document means that there are substantial differences in the respective document in different Member States, but the document itself is identical, i.e. Member State-specific issues are outlined within the document text or in an appendix to the respective document. The consolidated protocol, IB and/or IMPD do not need prior approval under CTD before the transition.

For Part II, the latest authorised versions of the subjects’ information sheet(s) and the informed consent form(s) are required as a minimum. Redacted versions of the documents are expected when necessary in compliance with transparency requirements.

It is allowed to submit other documentation in addition to what is mentioned above, if these documents were authorised under the CTD. No other documents should be submitted, otherwise the expedited transition procedure will no longer be applicable and the standard assessment timelines of up to 3 months will apply. The application dossier should be updated later in line with CTR requirements at the first Substantial Modification under CTR.

After the transition to the CTR, clinical trials will have to comply with its obligations, such as: obligations of notification via CTIS, safety reporting rules, archiving requirement, transparency requirements, rules for requesting substantial modification and addition of a Member State and rules for submitting the summary of results and the clinical study report.

If you still need to transition your clinical trial, our Rho CTIS experts can help you. Don’t wait any longer and contact us.

References:
EC Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, v2, 21-Dec-2023
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, v3, 13-Nov-2023

Rasa Vencpoliene, Senior Regulatory Affairs Manager, earned her Masters in Pharmacy from Kaunas University of Medicine. She has over 18 years of industry experience across Phase 2 through 4 studies including more than 8 years of Regulatory Affairs Manager experience in the CRO environment. She has a strong educational knowledge in pharmacy and medicine, and is experienced in all aspects of ICH/GCPs, quality assurance, PV, and regulatory requirements. Her main areas of regulatory experience include European Regulatory and Ethics submissions, oversight of regulatory requirements in countries of operations, and regulatory consulting. Ms. Vencpoliene is a CTIS expert in the company, leading and overseeing CTR/CTIS submissions for various Sponsors. She is also involved in EMA procedures, such as Orphan Drug Designation, Scientific Advice and PIP applications.