EMA issues more updates to prepare for clinical trials transition

Offices throughout the EU—including those of the EMA—have slowed operations for the summer holiday, but that didn’t keep the EMA from publishing a stack of updated documents. AgencyIQ summarizes the noteworthy changes in the updates to several documents designed to help sponsors and other entities involved with clinical trials to transition to the Clinical Trials Information System (CTIS) on January 30, 2025.

Background/Context

For the last several decades, sponsors in the EU have maintained the ability to submit dossiers (i.e., applications) on biopharmaceutical products to regulators for review and marketing authorization throughout the region via three routes. First, sponsors can opt to pursue marketing authorization in an EU member state by submitting their dossier to that state’s health authority (i.e., the “national competent authority,” or NCA). Then, once a product has been approved by an NCA, the sponsor can use a laddered approached to expand its approval to other EU countries using the mutual-recognition procedure. Alternatively, sponsors can submit their dossier to several NCAs at once, enabling their product to be reviewed and approved in parallel by multiple EU member states through what is known as the decentralized procedure. However, the third and most commonly used approach— required for certain, innovative products—is the centralized procedure, a streamlined process whereby sponsors can submit a single application for consideration by all NCAs collectively via the EMA. Following this unified review process, the European Commission’s (EC) final decision to approve a product immediately takes effect throughout the EU and European Economic Area (EEA).
While the centralized procedure has offered sponsors a simplified process for application preparation, submission and review, the same could not be said for submitting investigational applications earlier in clinical development for the conduct of clinical trials—that is, until recently. In April 2014, the European Parliament and the Council of the European Union passed a new law (Regulation (EU) No 536/2014), known as the Clinical Trials Regulation (CTR), to address this issue. In turn, the regulation called for the repeal of the EU’s longstanding directive on clinical trial conduct, Directive 2001/20/EC. However, the implementation of both actions was delayed for several years due to practical challenges in transitioning from one framework to the other. Mainly, the regulation called for the use of a secure online platform that sponsors and regulators could use to access and update investigational applications simultaneously in real time—a tool (to be titled the Clinical Trials Information System) that did not yet exist.
At the start of 2022, the Clinical Trials Information System (CTIS) finally went live, thrusting the on-hold legislation into action and starting the clock on the three-year CTIS transitional period. At the time the new system was unveiled, sponsors were able to start submitting clinical trial applications via the centralized system and were required to submit all new applications using CTIS one year later. However, the transitional period was put in place so that sponsors with trials already underway wouldn’t have to discontinue ongoing trials or place them on hold because of the change. Likewise, this three-year delay in mandating the use of CTIS gave the EC time to bring its existing rules in line with the CTR, sponsors to test out the system, and the EMA to update all of its relevant guidelines and guidances. [See AgencyIQ’s analyses of CTIS readiness, the launch of CTR becoming mandatory for all new trials, and when CTIS went live.]
Per the CTR, all clinical trials are to be moved over to the CTIS by January 30, 2025. At that time, any clinical trials not transitioned over will be considered noncompliant and in breach of regulations. To keep things organized during the transition, the EC has kept guidelines relevant to the previous process in one section of the Eudralex Volume 10 website and new documents for CTR implementation in another. To keep policymakers and external stakeholders informed on the status of CTR implementation, the EC, EMA and the Heads of Medicines Agencies (HMA) launched the Accelerating Clinical Trials in the European Union (ACT EU) initiative when CTIS went live. Since then, the initiative has facilitated the publication of monthly reports on clinical trials conducted in the EU and EEA countries in addition to several pilot programs.

What resources are available to shepherd sponsors through the transition?

To ease the transition process, the CTR called for each EU member state to designate a “national contact point” to participate in a Clinical Trials Coordination and Advisory Group (CTAG). The aim of this advisory group was to “support the exchange of information between the Member States and the Commission on the experience acquired with regard to the implementation of this Regulation,” maintain and update the EU portal and databases according, and develop criteria for evaluating the ability of member states to adequately assess clinical trial applications.
What other stakeholders are involved and who publishes which resources? Along with the resources developed by the CTAG under the EC, the EMA and HMA have developed other resources to aid in the CTR transition. In particular, the HMA’s Clinical Trials Coordination Group (CTCG) has been working to establish best practices for member states evaluating clinical trial applications. In contrast, the EMA has taken the lead on creating most of the operational and technical resources to assist users in working within the CTIS platform itself (e.g., creating an account, submitting and updating applications)
Among the various documents maintained by the CTAG are three introductory-level references to assist sponsors in interpreting the CTR and its implications. The first of these documents is a general guidance on the transition of clinical trials from the previous regulation to the CTR, last updated in May 2024. Second, the CTAG maintains a “Quick Guide” on the rules and procedures of CTR, which intended to serve as a supplement to the actual text of the new regulation; this guide was lasted updated in March 2024. Third, the group maintains an extensive Q&A document that answers common questions on CTR implementation spanning a wide range of topics (e.g., which member states have access to an application, how to submit patient-facing documents, how to modify an application, how to summarize clinical trial results, what constitutes the “temporary halt” versus the suspension). Of note, this document was updated in early July 2024.
Rinse and repeat: After the CTR went into effect, the EC, EMA, and HMA have worked to revise existing guidances, guidelines and training resources to conform with the new regulation. However, as sponsors and regulators have gained experience with the CTIS over the past 2.5 years and the website has been continually updated and improved, many documents that were initially revised have become outdated. Therefore, documents have been frequently revised and replaced, often in batches at a time.

What’s new?

This week, the EMA updated several resources for sponsors on the rollout of the CTR and ongoing updates to the CTIS. Even though the EMA was closed for the Feast of the Assumption earlier this week, the holiday did not stop the agency from releasing a batch of updates on CTIS training materials the day before (August 14, 2024). While AgencyIQ has historically flagged these changes in our EMA Today newsletter, it’s still the summer holiday season in Europe, which means that many standard operations, including the EMA’s biweekly updates regarding the CTIS, have been slowed or halted until the second week of September.
With this in mind, we’ve compiled the recent updates published by the EMA along with a quick summary of which modules are impacted and the magnitude of the changes made.

EMA documents updated on August 14, 2024	Purpose of document (as described by EMA)	Type of change
Guide to CTIS Training Catalogue	Serves as “a full catalogue of available training modules, organised by clinical trial lifecycle stage.”	Minimal: A broken link has been fixed.
Clinical Trial Information System (CTIS) – Sponsor handbook	“A compilation of key guidance, technical information, recommendations, and references for getting ready for the use of CTIS.”	Minimal: Between the last version and the August update, very few changes have been made. That said, sponsors who haven’t been tracking the updates closely may want to review them, as 20-40 changes have been made in the past year.
Quick guide: Transition of trials from EudraCT to CTIS – CTIS Training Programme – Module 23	– Remember what a Transitional trial is – Understand how to submit a Transitional trial – Understand how to submit notifications and clinical trial results for a Transitional trial – Understand the roles and permissions involved	Minor: A handful of changes for clarification have been made to the January 2023 version.
FAQs: Transition of trials from EudraCT to CTIS – CTIS Training Programme – Module 23	– Answers to general questions regarding Transitional trials. – Answers to questions regarding how to create and submit Transitional trials. – Answers to questions regarding how to submit notifications and clinical trial results. – Answers to questions regarding how to complete the evaluation of a Transitional trial. – Answers to questions regarding the roles and permissions involved in the Transitional trial processes.	Moderate: Three new questions have been added since January 2023, and four have been updated.
FAQs: Supervise a Clinical Trial: Ad Hoc Assessment – CTIS Training Programme – Module 17	Note: The target audience for Module 17 resources is member states (MS) exclusively (not sponsors). All three resources share these purposes: – Remember what an ad hoc assessment is and when an MS can create one – Understand how to create, cancel, save and share an ad hoc assessment – Understand how to raise a Request for Information, consult with other MSs, and how to complete an ad hoc assessment – Understand how to search, view, download, and update an ad hoc assessment – Understand the roles and permission involved in the ad hoc assessment process	Minor: Two “minor changes in questions” in the August update. Unclear whether the answers are significantly impacted.
Instructor’s guide: Supervise a Clinical Trial: Ad Hoc Assessment – CTIS Training Programme – Module 17		Minimal: Appears to include a slight change in timing of the first activity.
Step-by-step guide: Supervise a Clinical Trial: Ad Hoc Assessment – CTIS Training Programme – Module 17		Minimal: A track-changes table has been added.
FAQs: How to create, submit and withdraw a Clinical Trial Application – CTIS Training Programme – Module 10	– The different types of clinical trial applications and non-substantial modifications – Process for creating, submitting and canceling an initial clinical trial application – Process for withdrawing an initial clinical trial application – Key differences in creating, submitting or withdrawing an initial clinical trial application and other types of applications – Evaluation process for a clinical trial application Understand the roles and permissions involved	Major: In the past few months, a handful of questions have been updated, added and removed. Since January 2023, there have been several batches of 10+ changes.
FAQs: How to manage a CT – CTIS Training Programme – Module 05	– Responsibilities of sponsors, from the submission of a clinical trial application to the submission of the summary of results – Use of notifications – Processes for ad hoc assessments and corrective measures – How to address requests for information (RFIs) – How to prepare and submit clinical trial results	Moderate: One question has been added since January 2023, and three have been updated.

What’s next?

As the EMA has frequently reminded sponsors, the CTIS transitional period is ending soon. Within the next six months, it is likely that more updates to existing materials will be issued as the EMA, EC, and HMA gear up for mandatory compliance with new regulations.

To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Jason Wermers ( jwermers@agencyiq.com).