The goal of the EU Clinical Trials Regulation (Regulation (EU) No. 536/2014) is to maintain and develop an innovative clinical trial framework in the EU for the benefit of all involved parties.

The EU Clinical Trials Regulation (CTR) is an integral part of the Accelerating Clinical Trials in the EU (ACT EU) strategy paper priority actions. The objectives of the CTR include harmonizing the management of clinical trials across the EU and providing transparency, data robustness, and strong protection for trial participants. The regulation represents an important change for the industry from a process and operational standpoint – promising to deliver a unique, simplified, and harmonized clinical trial application (CTA) approval and management process.

A new public database of clinical trials

Since January 31, 2023, the Clinical Trial Information System (CTIS) – a centralized European portal and database established for the submission, monitoring, and evaluation of clinical trials – is mandatory for all new interventional clinical trials at any phase of a product’s development.

The next important step is January 31, 2025, when all ongoing clinical trials already approved under the previous regulation (EU Clinical Trials Directive [CTD]; Directive 2001/20/EC) with an active site in the European Economic Area (EEA) will be either (1) automatically terminated through the repeal of the CTD, or (2) transitioned into CTIS, according to EU CTR obligations. For trials added to CTIS, trial information will become publicly available at that point.

The Part I assessment, conducted through CTIS electronic submission, is performed via a coordinated procedure across the EEA. This evaluation of the dossier allows differences in the EU to be minimized, although full harmonization of the review process across all involved ethics committees has yet to be achieved. A fully harmonized assessment process would ensure consistency of acceptability across the EU beyond the Part I assessment.

Review of the changes implied by the new CTR show that the process harmonization and the Part II country-specific templates have permitted accelerated reviews.

The EU CTR presents numerous challenges for clinical trial sponsors, vendors (e.g. clinical research organizations [CROs]), regulators, and ethics committees, such as:

  • High initial administrative burden
  • Response times for requests for information (RFIs)
  • The need to accommodate the translation and redaction of information, which may require adaptation of internal processes

The number of documents needed for a submission has also increased significantly under the EU CTR (nearly two-fold) due to stricter transparency rules.

Lessons learned from early adopters

The EU CTR is still in an early phase of adoption, but there are already learnings that could help inform and support users to comply with and efficiently apply new requirements:

  • Prepare for country mandatory guidelines and other registration requirements
  • Identify countries which could slow down the progress to define submission strategy
  • Consider countries that can drive faster recruitment times
  • Consider at least six months to transition a trial from the EU CTD to the EU
    CTR to allow for adding new EEA countries
  • Handpick initial countries to drive the best reporting Member State (RMS) selection to maximize Part I assessment positive outcome, then add challenging member states after initial trial approval
  • Be proactive with RMS communication to ensure conclusion of the application and avoid non-aligned outcomes between the Part I and Part II
  • Consider which member states concerned have accelerated timelines
  • Be aware of the maximum turnaround (12 calendar days) for Sponsors to
    respond to RFIs
  • Monitor CTIS often for RFIs to ensure requests are seen as soon as

Transition or face termination

Trials authorized under the EU CTD and with at least one active site in the EEA on January 30, 2025, must be transitioned into CTIS by January 31, 2025, if:

  • The last visit of the last participant in the EU or other interventions are due on after January 30, 2025;
  • A new EEA member state is to be added

Otherwise, they will be automatically terminated as part of the complete repeal of the EU CTD. If an end-of-trial notification is issued in the member states with trial sites, the trial does not have to be transitioned – even if the global part of the trial is not completed.

In the event of a transition to CTIS, there can be no pending or ongoing review in any of the EEA member states at the time of transition (i.e., no substantial amendments).

Clinical trials that are stopped temporarily for any reason will need to be transitioned when they restart. Please note Sponsors need to flag the “on hold” status in CTIS.

For Sponsors putting together a transition strategy, consider the following:

  • Align your processes with EU CTR requirements
  • Plan your transition activities in coordination with upcoming activities (e.g. investigator’s brochure [IB] or chemical, manufacturing, and control [CMC] documents, addition of a new countries)
  • Maintain your harmonized key documents (e.g. protocol, IB or investigational medicinal product [IMP] dossier)
  • Consider your redaction and translation needs and timelines
  • Prepare for possible impact on IMP labels
  • Allocate time and resources to CTIS set-up
  • Adhere to public disclosure rules once transitioned to the EU CTR

To date, a significant number of clinical trials are transitioning to the CTIS. The approval timeline is between 22 (expedited approval) and 106 calendar days. The time for RFIs needs to be added to these timelines (i.e. 60-80 calendar days).

The integration of regulatory new submission requirements in conjunction with a dynamic clinical trial conduct presents numerous challenges, so it will be important for CTIS functionality to continually evolve to meet the needs of clinical research environment.

The focus now is to ensure that all applicable trials are transitioned to the CTIS under the EU CTR within the January 31, 2025.

We can help you prepare for the transition of your trial and check your plan for adherence to the EU CTR. Contact us for more information.