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This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.
While EU Clinical Trial Regulation 536/2014 (EU-CTR) became mandatory for all new trials earlier this year, sponsors were given additional time to transition existing studies into the Clinical Trial Information System (CTIS) — the data/documents-submission platform required by EU-CTR. All studies authorized under previous regulation EU-CTD with last patient last visit after 31 January 2025 must be transitioned before this date, otherwise they will become non-compliant and must cease.
EU-CTR aims to simplify and harmonize the clinical trial application (CTA) approval and management process — a transformational change that can benefit every stakeholder in pharmaceutical development. But this shift will also require the creation and implementation of new operational and IT systems, and sponsors report steep learning curves as they work to bring studies into EU-CTR compliance.
As of November 2023, Parexel has submitted more than 100 EU-CTR trial applications, including more than 30 transition applications. Thanks to this experience, we’re able to share insights that will support robust planning and can expedite submissions during the transition period. We’re urging sponsors to begin the transition process as soon as possible.
Under the new regulation, stakeholders must use CTIS as a single-entry point to submit, evaluate, and authorize CTAs across all 30 countries in the European Economic Area (EEA). As of September 2023, we’ve seen average CTIS application approval times of 109 calendar days for trials including up to five EEA countries. Because thousands of trials must transition in the next 13 months, we expect those timelines to increase as demand for regulatory resources surges. We recommend that sponsors plan for a six-month transition process, particularly for studies that require harmonization or substantial amendments.
When transitioning trials, sponsors should expect to face a significant number of administrative requirements, many with associated deliverables. In our experience, the initial CTA for a five-country, 50-site trial could require the submission of more than 500 documents. Sponsors should also be prepared to adapt internal processes to meet request for information (RFI) response deadlines, allowing adequate time for information translation and redaction.
Because CTIS is not fully interoperable with other systems, sponsors will need extra time and resources to complete workarounds to link different systems. Another complicated factor: While clinical development often calls for concurrent activities, CTIS assumes a process with sequential steps. Sponsors will need to be flexible, finding ways to align with the new regulation while also following study protocol requirements and protecting the well-being of patients.
Based on our experience in the EU, Parexel has four recommendations.
1. Be aware of accelerated timelines.
Several EEA countries have accelerated assessment for either phase 1 or mono-national trials.
In Belgium, the timeline for mono-national phase I trials is 66 calendar days, plus an additional 50 days for advanced therapy medicinal products (ATMPs), which includes validation and content RFIs.
In Germany, the earliest decision on a mono-national phase I trial is day 30 following successful validation. For mono-national and single-center trials, validation may be reduced.
In Romania, the ethics committee shares Part I comments by day 21 following successful validation of a phase I trial. The Part II conclusion will be shared by day 38 following successful validation.
In Denmark, content RFIs for phase I trials will be raised on day 26 if coordination with the ethics committee is complete.
Assuming the availability of resources and ethics committee decisions, other countries have indicated a willingness to reduce mono-national trial timelines, including Estonia, Finland, Hungary, Latvia, Lithuania, Netherlands, Norway, and Portugal.
2. Understand dossier requirements and plan for updated content.
When transitioning to CTIS, we recommend that sponsors submit a slim dossier first, which will include redacted versions of the protocol, subject information sheet(s), and informed consent form(s). Sponsors must also include any non-redacted documents already approved by the Member States Concerned (MSCs).
Before adding any additional MSCs to a transitioned trial with an initial slim dossier, a sponsor must submit a substantial modification application.
For the investigational medicinal product and any auxiliary medicinal products used in the trial, sponsors will need an updated label for any products produced after EU-CTR authorization. Pre-transition products will not need to be relabeled.
Trial notifications and reports issued prior to EU-CTR authorization are not subject to transparency requirements and do not need to be introduced into CTIS.
3. Take a future-focused approach to in-progress trials.
When developing dossiers for in-progress trials that have not yet started transitioning to CTIS, sponsors should still conform to EU-CTR requirements as much as possible to minimize the need for rework during eventual transition.
Whenever possible, sponsors should:
4. Maintain momentum during application review.
While the slim dossier is a sponsor’s first step, it’s advisable to prepare as much of the full dossier as possible while initial approval is pending. This allows for the quick submission of the next substantial amendment as soon as initial approval is granted. Sponsors should also know that they cannot implement non-substantial changes during the transition procedure; updates may be made with the first substantial modification after transition. If sponsors have non-substantial amendments that can´t be submitted to all member states under EU-CTD, Parexel recommends that sponsors list these versions in the transition cover letter. For any documents that require an EU-CTR number, we strongly recommend including the number at time of submission.
EU-CTR aims to streamline the CTA process — but before sponsors can benefit from the changes, they must first manage change within their own organizations. Being unprepared for or late to the CTIS transition will result in higher costs, slower development, and needless frustration. With the right plan in place, however, stakeholders can keep their trials on track. And as part of that plan, sponsors might enlist the help of a partner.
At Parexel, we have more than 200 trained regulatory leads in all time zones, backed by more than 4,000 regulatory professionals, including CTIS submission specialists. And we can support sponsors until we meet the EU-CTR deadline and through all the milestones along the way. For additional insights and in-depth analysis on the impact of the new requirements, watch our recent webinar, now available on demand.
Ready to shape your EU-CTR transition strategy? Our regulatory experts can help. Contact us to learn more.
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