Planning strategies for transitioning to the Clinical Trials Regulation

There is a pressing need for companies to transition their EU clinical trials that are ongoing under the “old” regulatory framework of the Clinical Trials Directive¹ to the Clinical Trials Regulation.² The risk for those that don’t meet the 30^th January 2025 deadline for transition is that they will lose their legal basis.

Starting in January 2022, a three-year transition period was foreseen. Now, with less than one year to go, companies need to develop strategic plans for transitioning to Regulation (EU) No 536/2014, the CTR, and transferring the dossier into the Clinical Trial Information System (CTIS), which will be the single entry point for the submission and assessment of clinical trial applications³ and the system in which almost all clinical trial-related regulatory processes are managed.

However, the review of the transition application takes up to 106 days and achieving compliance with all requirements prerequisite to applying for transition may take even longer.⁴ Strategic planning is, therefore, essential to carry out the transition in the remaining time in order for sponsors to continue their clinical trials in the EU.

Creating a harmonised dossier

Strategic planning should begin with generating a harmonised dossier across the EU member states (MS) involved in a study and implementing an administrative strategy for CTIS. Since these activities are not dependent on each other, they can - and should - be handled simultaneously.

Under the CTR, only one core dossier, referred to as Part I, will be applicable to all MS. Before a study can be transitioned, the sponsor must ensure that all Part I documents, which include the protocol, Investigator’s Brochure (IB), and Investigational Medicinal Product Dossier (IMPD), are the same for all participating MS.⁵

A guidepost with any document adaptations prior to transition, if necessary, is to handle changes to the general study design, population, and scientific evaluation by means of substantial amendments. This is called “harmonisation”. Smaller differences that don’t impact on other MS can be accounted for by way of document “consolidation”, which means including MS-specific passages in the documents without prior regulatory approval.

Part II of the dossier in CTIS only contains MS-specific documents, such as patient information, which do not need to be harmonised or consolidated. The main priority is to ensure they still reflect the clinical trial adequately, after any adaptation of Part I documents.

Companies can choose to either perform an expedited transition, submitting a minimal set of documents, or a full transition, providing additional documentation that has been approved under the CTD. Full CTR compliance only needs to be established with the first substantial modification submitted after the transition.

CTIS – Administrative strategy and set-up

Sponsors can choose between two management models for their trials in CTIS - the organisation-centric and the trial-centric approach. With the organisation-centric approach, a sponsor-associated high-level administrator will have highest administrative responsibility for all clinical trials from the organisation, as well as for defining the roles assigned to other CTIS users. This approach requires a more complex setup than the trial-centric one and is recommended for companies that are planning to perform multiple studies in the EU. The organisation first needs to register in the Organisation Management Services (OMS) database and ensure the proposed administrator has an EMA account. That person must then request to be assigned the high-level administrator role via the EMA Account Management System and attach a Letter of Affiliation to their organisation.⁶

Smaller companies or academia should consider adopting the trial-centric approach, which is less complex and resource-intensive, because it doesn’t require a high-level administrator, and can therefore more easily be handed over to a service provider. However, sponsors remain fully responsible for GCP-mandated oversight and should therefore have at least minimal CTIS proficiency in order to verify and make decisions about activities in the database.

As an essential part of creating a valid dossier, any organisation involved in the trial needs to be connected via CTIS to their OMS entry. This means that the sponsor, investigational sites, central laboratories, and other service providers will need to register in the OMS database.

Sponsors will also need to ensure in advance that details of their products used in clinicals trial are up to date in the extended EudraVigilance medicinal product dictionary (XEVMPD) database. While OMS registration and checking data in the XEVMPD are not complex activities, they can be time-consuming, especially for organisations new to those tasks. So, sponsors should build these into a timetable for the transition.

Building in time for delays

Before transitioning to the CTR, all regulatory processes under the CTD must be completed. So, clinical trials in which, for example, a substantial amendment is under evaluation cannot transition until the decision is received.

Complications and delays frequently arise when a trial is ongoing in several countries, which makes it difficult to find a time when there are no regulatory processes ongoing.

Furthermore, it’s important to recognise that many health authorities and ethics committees are also facing challenges with the new system and personnel resources. Therefore, in some member states currently reviews are taking longer than usual, which delays approvals, further impeding the transition. Given these constraints, it’s important to start planning early.

Gearing up for a CTR-compliant dossier

Once a trial needs a substantial amendment, now referred to as a substantial modification, the dossier will need to be updated to be in line with the CTR. This will require significant preparation. Careful consideration is needed if and when a dossier has to be updated to CTR requirements where no substantial modification is planned for reasons originating from the study. This will also be dependent on guidance from the EMA, which is yet to be published.

When preparing for the first substantial modification, sponsors should ensure they know whether both Part I and Part II are affected. An important consideration is that when making the first substantial modification, the entire part, not just the affected documents, will need to be updated to comply with CTR standards.

Staying informed

Since the CTR, and consequently adapted MS law, became applicable on 31^st January 2022 there has been a constant flow of new guidance documents, information material, and events, as well as frequent updates to the published information. Given that this information is shared through different channels – the European Commission (EC), European Medicines Agency (EMA), Heads of Medicines Agencies (HMA), and the individual MS – it can be difficult to keep track of all regulatory intelligence.^7,8,9

Given the criticality of being in compliance with the CTR, it is highly advisable to have an internal or external expert or team of experts charged with following these developments. This will ensure all recommendations are known and understood and will help with good strategic planning.

The contents of this article are solely the opinion of the author and do not represent the opinions of PharmaLex GmbH or its parent Cencora. PharmaLex and Cencora strongly encourage readers to review available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.