The EU Clinical Trials Regulation (EU CTR) became live on January 31, 2022. The first-year transition period ends on January 30, 2023, so from January 31, 2023, onward, EU CTR is mandatory for any initial submission of interventional clinical trials with investigational medicinal products conducted in one or more EU/European Economic Area (EEA) Member States (MS) .Ongoing trials authorized under the EU Clinical Trial Directive (EU CTD) may continue under that framework for now, but if they’re still in progress by January 30, 2025, they will have to transition to EU CTR at that point.
Sponsors and clinical trial applicants need to consider several EU CTR impacts on an organization’s infrastructure (e.g., quality management systems, outsourcing strategy and vendor management, regulatory intelligence gathering, and training) as well as study management/operational conduct activities (e.g., regulatory, clinical, and transparency) for starting or ongoing trials (whether they’re transitioned or not). Here are five key points for you to consider to assess your readiness for EU CTR.
1. Go Through an EU Clinical Trials Regulation Readiness Exercise
EU CTR impacts will vary based on organizational infrastructure, portfolio status and size, activities insourced or outsourced, etc. Consider an EU CTR readiness exercise using a change management approach to define the extent and magnitude of the possible changes. We recommend using a stepwise approach to holistically address the different EU CTR components affecting your quality management system (e.g., SOPs, work instructions, templates) and clinical trial systems. The approach should involve:
- An EU CTR impact assessment/gap analysis/change implementation roadmap
- Functional representatives from key departments (e.g., clinical development, regulatory affairs, clinical operations, medical affairs, medical writing, clinical trial disclosure, supplies, legal, etc.)
- Deploying additional technical solutions or updating staff training
Smaller organizations at the beginning of their clinical development may see small changes, but you may see much more significant changes if you have a more established portfolio of products and studies. You can adapt the timing of this exercise and, while it is already underway or completed for larger organizations, smaller ones may still align this to match new trials in the coming months. You should also continue this exercise after initial implementation as you may expect further changes and evolutions after you go live with EU CTR, which may lead to additional change management actions—most likely on a smaller scale.
2. Consider Your Outsourcing Strategy and Vendor Management
While the fundamentals of a study start-up remain the same with site identification, essential document collection, submissions and approvals by authorities and ethics committees, and site contract negotiations, the way to execute submissions via Clinical Trial Information System (CTIS) in particular introduces new tasks in the potential activities to be performed internally or delegated to other vendors. For example:
- CTIS management and oversight – who manages the CTA compilation for the core scientific dossier (Part I) and country dossiers (Part II).
- CTIS user management – allocate viewer/preparer/submitter roles for initial submissions, modifications, notifications, and Annual Safety Reports.
- Transparency oversight (with eventual document redaction) – ensure that all information submitted is aligned with EU CTR requirements in terms of protected personal data (PPD) and that no commercially confidential information (CCI) is accidentally breached upon trial approval and the start of publication of trial information.
Once you have agreement on the responsibilities between internal functions and eventual evolution in the split of insourced vs. outsourced activities, vendor management teams should cascade those responsibilities in the vendor selection and contractual agreements that cover those activities.
3. Study Operations
With the introduction of a revised Clinical Trial Application (CTA) assessment process and CTIS to support all submission-related activities, consider new activities and ways to manage and maintain EU CTAs until the end of the trial and the results/clinical study report publication. This will involve planning impact submission, executing trial activities, and training the corresponding teams (regulatory and clinical in particular) in charge of those activities. It’s important to study operations to navigate this new environment and ensure that you comply with all new requirements and obligations throughout the clinical trial lifecycle and adequately document them in the trial master file.
The unique entry point for CTAs introduces a greater dependency between individual country submissions as Part II dossiers (country level) need to be submitted along with Part I (Core Scientific Dossier) if a timely activation through the different EU countries is expected. This also needs to be accounted for in the compilation of Part I and Part II applications, as well as in the timing and oversight of the corresponding clinical operations and start-up activities (e.g., essential documents collection and site contract agreement negotiations) with eventual “cut off” dates to limit delays. Staggered submission of Parts II or later by an additional MS is, of course, possible and may need to be considered in certain instances but with an impact on country and site activation timelines.
Different rules also need to be considered in the maintenance phase including:
- Stricter rules for submitting modifications (only one Part I modification assessment at a time)
- New types of notifications (third-country inspection reports)
- Specific timelines to match for notification of certain events, whether planned (e.g., the start of trial or start of recruitment) or unplanned (e.g., unexpected event, temporary halt, or serious breach)
- Shorter turnaround time for answers to requests for information (RFIs) issued by authorities or ethics committees (i.e., up to 12 days for assessment RFIs)
4. Consider Clinical Trial Disclosure/Transparency
EU CTR introduces greater transparency principles, leading to more information becoming public over time. Most information other than quality-related (investigational medicinal product dossier) or financial (investigational site contracts) uploaded in CTIS may end up being published at certain times as defined in the appendix on disclosure rules published by the European Medicines Agency (EMA) or after a deferral period set up at the time of the initial CTA submission by the clinical trial applicant.
The increased transparency mandates that sponsors pay specific attention to managing CCI and PPD in their files, which may even document templates or authoring guidance for medical writing teams. New documents, such as layperson summary results, should also be provided to trial participants after the trial is completed. Full clinical study reports will also be published when a marketing authorization procedure under EMA or an individual MS is completed.
Transparency requirements may affect documents and structured data included in the online application forms, which means that redaction procedures need to cover all information to be uploaded. These procedures should also be thoroughly communicated and understood by all teams involved in the trial management and oversight.
5. Evaluate Transitioning Trials to EU Clinical Trials Regulation
The regulation includes transition considerations for ongoing trials, leaving the possibility for sponsors to continue managing their trials under the current regulatory framework until January 30, 2025. After that date, all trials falling under the scope of EU CTR, which includes interventional clinical trials for medicines conducted in one or more EU/EEA countries, should be completed or transitioned (decision received) under EU CTR. In practical terms, this transition is a submission of the trial in CTIS to officially formalize its transfer upon approval under the new framework (including a potential impact on study documents, including redaction). All EU CTR obligations will apply on that date, including transparency and reporting/publication.
The three-year transition (2022–2025) allows all stakeholders to organize themselves, as this will be resource-intensive for both sponsors and MS in terms of managing the transition itself and also complying with EU CTR rules. Therefore, an assessment of the current trial portfolio is required to define which trials fall under the transition requirement and which may be left under the past regulatory framework of the clinical trial directive. On a portfolio level, this also means that sponsors must maintain two quality management systems and two sets of reporting requirements/results posting for their trials, depending on which regulatory framework the trial is authorized under.
For those trials that will be transitioned, Part I documents (e.g., protocol, Investigator’s Brochure, Investigational Medicinal Product Dossier) are required to be fully aligned between the different MS before starting the transition. This means substantial amendments may have to be performed before initiating the transition (assessment timelines to be accounted for). Therefore, it is critical to complete the trial portfolio assessment sooner rather than later so that any pre-transition amendment activity can be identified and managed by mid-2024, giving enough time to complete the transition itself before January 2025. Transitions may be planned from 2023–2025, with a recommendation not to process too many in the first half of 2023, considering the uptake of new initial CTAs from January 31, 2023.
In conclusion, EU CTR significantly affects multiple components of clinical trial-related activities, whether directly (e.g., CTIS, new management rules, and transparency) or indirectly (e.g., master data sources to be completed prior to CTIS use for new development products, etc.). It is worth mentioning that those changes are not yet fully stabilized, as we’re still waiting for guidance on certain points, such as:
- CCI/PPD management (coming in Q1 2023)
- Updates to CTIS functionalities (e.g., bug fixes, further improvements, and new functionalities expected through 2025)
- Clarifications on the legal interpretation of the EU CTR regularly by the EU Commission via their Q&A document
This dynamic environment means that the initial EU CTR readiness exercise needs to be maintained beyond January 2023, as some of these evolutions will require additional implementation strategies and additional training for the affected teams.
Whether your EU CTR readiness initiative is ongoing or completed, now is a good time to review what you’ve achieved or still need to address as well as lessons learned in order to adjust your implementation strategy and further optimize your processes.