With just one year left of the legal transition period, it’s vital that companies strategically plan the transition of their ongoing EU clinical trials from the “old” regulatory framework of the Clinical Trials Directive i to the Clinical Trials Regulation ii and into the Clinical Trial Information System (CTIS).
On 30 January 2025, the three-year transitional period from the directive will end, and ongoing trials that have not completed the transition will lose their legal basis. To prevent that from happening, companies must build in adequate time for the transition, since 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 iii. Only with proper strategic planning can companies perform their transitions to the CTR (Regulation (EU) No 536/2014) within the remaining time and continue their clinical trials in the EU.
There are several key steps and considerations that should be incorporated into strategic planning for transitioning to the CTR and CTIS.
First steps to transition
There are two crucial first steps to be taken before a sponsor can transition trials to the CTR: harmonization (or consolidation, where possible) of the core dossier and the administrative set-up of CTIS.
- Generating a harmonized dossier across the member states iv
Under CTR there will be only one core dossier (Part I) applicable to all EU member states (MS). This means that 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.
If document changes are necessary to achieve this, as a rule of thumb, the general study design, population and scientific evaluation need to be harmonized by means of substantial amendments in all MS concerned, while smaller, unavoidable differences can be accounted for by 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 (e.g. patient information, insurance documentation), which do not need to be harmonized or consolidated. Sponsors only need to make sure that they still reflect the clinical trial adequately, after Part I documents have been adapted, where applicable.
Depending on whether they want to perform an expedited or a full transition, companies can choose to submit a minimal set of documents or provide additional documentation that has been approved under the CTD. At this point, it is not required that the document content comply with the regulation. Full CTR compliance only needs to be established with the first substantial modification submitted after the transition.
- Administrative CTIS strategy and setup v
Sponsors have two options with the administrative setup of their CTIS submission: either appoint a high-level administrator with the highest level of administrative responsibility for all studies of the organization and use the “organization-centric approach” or adopt the “trial-centric approach” in which any person can create a study in CTIS and automatically becomes its administrator.
High-level administrators can manage all users within their affiliated organization and define the roles assigned to other users. Only persons that have been assigned a respective role by a high-level administrator can perform the initial setup step for new clinical trials of this company in CTIS.
This approach requires a more complex setup than the trial- centric one vi. First, the sponsor organization must be registered in the Organisation Management Services (OMS) database and the proposed high-level administrator needs an EMA account. Then, that person must place a request to be assigned this role via the EMA Account Management System and attach a Letter of Affiliation to their organization vii. The organization-centric approach is the recommended administrative model for companies that are planning to perform multiple studies in the EU and are able to designate at least one person – ideally two or three – as high-level administrator.
The trial-centric approach is recommended for smaller companies and academia since it is less complicated, requires fewer resources and expertise at the sponsor company and it can more easily be handed over to a service provider. Of course, this doesn’t absolve sponsors from their GCP-mandated sponsor oversight responsibility, which becomes more challenging when more activities are outsourced to different service providers. Therefore, it’s still recommended that sponsors achieve a minimum CTIS proficiency in order to be able to verify the activities in CTIS (e.g. by means of a viewer role) and to make timely decisions when needed.
The administrative setup and the dossier harmonization steps can, and should, be handled simultaneously as they are not dependent on each other.
Managing information in databases in addition to CTIS viii
Transitioning sponsors as well as all participating organizations — including investigational sites, central laboratories and other service providers — will need to register in the OMS database. This has to be done because those organizations will be connected to the trial via CTIS, which is a prerequisite for a valid dossier.
Pharmaceutical companies will also need to ensure details of their products used in clinical trials are up to date in the extended EudraVigilance medicinal product dictionary (XEVMPD) database. This is an important step that should not be left until the last minute. While neither of these activities are complex, they can be time-consuming, especially for organizations new to those tasks. So, it is important for sponsors to incorporate those items in their timetable for the transition.
Prepare for delays
In order to do the transition, all regulatory processes under the CTD need to have been completed. This means, for example, that clinical trials in which a substantial amendment is under evaluation cannot transition until the decision is received.
For trials taking place in many countries, it can be a struggle to find a window where there are no regulatory processes ongoing, since there will be regular IB updates and annual safety reports, and potentially line listings, interim analysis reports, progress reports / annual renewals as well as amendments ongoing in several countries at different times and with different review timelines.
Additionally, some countries currently require more time to review, which can delay approvals and, as a consequence, further hold up the transition. These delays arise because many health authorities and ethics committees are also facing challenges with the new system and personnel resources. For example, we are working with one client who faced a more than six-month delay to one of their trials awaiting initial approval from an ethics committee in one member state. In this period of change, it’s important to recognize that standard processes can take far longer than anticipated and to start planning early.
About the author:
Xandra Neuberger is Associate Director Regulatory Affairs and international service lead for clinical trial applications at PharmaLex, leveraging her extensive experience with clinical trial applications and life cycle management to support the industry. She also handles project and team coordination in her role. Xandra is a registered pharmacist in Germany and has also practiced pharmacy in the UK.
Notes
i Directive 2001/20/EC, https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-directive-200120ec_en
ii Regulation EU No 536/2014, https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en
iii Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, European Commission, Dec 2023 https://health.ec.europa.eu/system/files/2023-12/transition_ct_dir-reg_guidance_en.pdf
iv 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, Nov 2023. https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-Working_Groups/CTCG/2023_11_CTCG_Best_Practice_Guide_for_sponsors.pdf
v FAQs: Management of roles and permissions, EMA, Oct 2022. https://www.ema.europa.eu/en/documents/other/faqs-management-roles-and-permissions-ctis-training-programme-module-07_en.pdf
vi Getting started with CTIS: Sponsor quickguide, EMA. https://www.ema.europa.eu/en/documents/other/getting-started-ctis-sponsor-quick-guide_en.pdf
vii Step-by-step guide: Management of roles and permissions, EMA, Oct 2022. https://www.ema.europa.eu/en/documents/other/step-step-guide-high-level-ctis-administrator-management-roles-and-permissions-ctis-training-programme-module-07_en.pdf
viii Clinical Trials Information System (CTIS) – Sponsor Handbook, EMA, Nov 2023. https://www.ema.europa.eu/en/documents/other/clinical-trial-information-system-ctis-sponsor-handbook_en.pdf
