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Charting New Horizons: Decoding the Impact and Opportunities of the EU’s Clinical Trial Regulation

Over a year has passed since the introduction of the European Union’s (EU) Clinical Trial Regulation (CTR) No 536/2014,1 and the jury is still out as to whether there has been substantial headway in meeting the principal goal of the regulation: streamlining Europe’s clinical trial process to bolster the region’s appeal for clinical research while robustly maintaining participant safety and data integrity.

The preceding 2004-era Directive 2001/20/EC undoubtedly needed substantial updating. Per the former directive, each EU Member State had to implement its legal requirements through national legislation, creating a fragmented and diverse assessment process for multinational clinical trial applications. Under this framework, the EU has consequently trailed the U.S., China, and Japan when it comes to hosting clinical trials.

The CTR promised to turn the tide in favor of Europe by streamlining workflows in multinational trials, increasing transparency, and reducing administrative burden. But the regulation also represents a sea change for clinical trialists, and many sponsors are finding its implementation to be easier said than done. With several drawbacks observed and navigated among the many gains, let’s explore how the clinical research community is taking to the new regulation.

Increased visibility and international synchronization

There’s a lot the CTR gets right. For starters, as a regulation, the CTR holds heavier weight than its directive predecessor, effectively binding all EU Member States to a single standard of conduct. Clinical trial application procedures now align national competent authorities and ethics committee approvals, consolidating them into a single decision per Member State. For multinational trials, one Member State leads the assessment process, chosen either by the sponsor or through mutual agreement with other willing states, and must notify its role within six days of application submission as the reporting member state. If we needed reminding of why such alignment is crucial, the COVID-19 pandemic brought into stark focus the indispensability of remote monitoring and multinational synergy.

The CTR also leverages the Clinical Trial Information System (CTIS) as a centralized portal and database with a single electronic submission instead of multiple submissions with different dossiers. The CTIS serves a dual purpose: it supports communication between clinical trial sponsors and EU regulatory authorities and provides public access to information on EU clinical trials via a searchable website. This centralized approach to the application process significantly reduces fragmentation, streamlines the process, and facilitates better synchronization of international clinical trials. However, one area that still requires particular attention is the current legislative framework concerning clinical trials for genetically modified organism (GMO)-based medicinal products. As with the previous directive, the process for obtaining approvals in the EU for GMO trials under the CTR requires separate submissions to a diverse array of national GMO authorities responsible for assessment under the “contained use” Directive 2009/41/EC or “deliberate release” Directive 2001/18/EC. Although progress has been made to harmonize GMO procedures across the EU, including the development of an EU-wide common application form, several Member States are yet to align and update national GMO procedures to accommodate the changes introduced with the CTR.2 Companies developing GMO-based products will need to continue to manage the required authorization steps outside of the CTR framework, potentially canceling out any gains from the harmonized CTR procedures.

Beginning in 2025, all new and ongoing trials must be entered into the CTIS. This step could lead to research being more inclusive and less divided by country, potentially resulting in medical treatments suitable for diverse patient groups across the EU.3

Navigating the transition

While the benefits are substantial, implementing the CTR and CTIS does come with challenges. The learning curve for sponsors and regulatory agencies and the resulting potential for slower activation of trial sites in the short term are significant hurdles. Companies have reported technical issues and challenges in coordinating submissions and meeting the CTR’s tight deadlines, mostly due to fragmented and time-consuming data collection processes. Disclosures are another pain point, needing to be fully integrated within the standard clinical trial process but occurring more frequently across the trial lifecycle than before.

These challenges have required sponsors and contract research organizations (CROs) to rethink how they collect and store trial data and documents for EU and non-EU studies. This paradigm shift is reshuffling organizational operations, making the transition difficult for some companies. Below are our top tips for navigating this complexity:

Set yourself up for submission success early on

One of the quirks of CTIS is that it lacks flexibility for last-minute decisions and changes in study strategy. For example, after the initial submission to CTIS, sponsors can only add new countries to an application once a decision has been reached following the standard assessment period. This puts pressure on sponsors to plan strategically well in advance to avoid delays due to technical limitations.

Engage as early as possible with internal stakeholders and external outsourcing partners, like CROs, to clearly define processes and workflows that will ensure business continuity and adhere to the CTR. To achieve efficient communication via CTIS, dedicate teams to monitor incoming communications, handle document management for trial master files, and track timelines. Consider centralizing responsibility for redactions, streamlining this process with training for new standard operating procedures within a single dedicated team.

Plan your data input strategy

Under the CTR, the success of a clinical trial application relies heavily on the initial quality of the dossier—and due to the infrastructure of CTIS, data to support that dossier must be input manually. Clinical trial applications must pass validation in all concerned Member State competent authorities before proceeding, an interdependency that demands accurate, high-quality applications from the outset.3

In an environment where even small errors can lead to various risks and challenges for sponsors, small and mid-size companies might consider leveraging expertise from an external partner for data input under the CTR. An error like an incorrect redaction of personal information or an erroneously uploaded document can cause significant delays in your approval process. Plan ahead to de-risk your data input.

Get ready for 2025

As of January 2023, the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), the previous clinical trial registry, closed its doors for new clinical trial applications, but it remains open for ongoing clinical trials. However, after January 2025, all new and ongoing studies must be managed on the CTIS platform.4 This situation demands a carefully planned strategy and a dedicated workforce to transition studies to the new CTR, which is an urgent and complex task. Any sponsors who have been taking a wait-and-see approach in the hopes they could complete their trial before the 2025 deadline should start preparing for 2025 now.

In May 2023, the European Medicines Agency (EMA) initiated a public consultation to evaluate transparency rules for publishing clinical trial data submitted via CTIS across the EU. This consultation aims to improve patient access to clinical trial information, further fulfilling the EMA’s original intent of harmonizing the process and increasing transparency.

Looking ahead

While the implementation of the new EU CTR has been challenging, it is a necessary step towards making Europe a more attractive location for clinical studies. With some dedicated energy to push through this transition period, companies will arrive at the other side with fully aligned multinational trials, streamlined processes, and less administrative burden than ever before. While this is something for the entire EU clinical research community to celebrate, the ultimate beneficiary of these changes is the patient, who will have easy access to vital clinical trial information and faster trial outcomes. The next few years will determine the long-term effects and success of these regulations, but the initial signs point to a promising future for clinical trials in Europe.

Should you find yourself in need of a CRO adept at navigating the intricacies of the new CTR, consider partnering with TFS HealthScience. We pride ourselves on our early and fully transparent discussions around the new CTR, helping you devise a robust execution plan for your trial. With our team, you will find an ally that not only embraces flexibility and adaptability, but also spearheads the integration of novel approaches and innovations such as the CTR and CTIS. As a dedicated partner, TFS HealthScience remains unwavering in its commitment to your timelines, diligently ensuring the achievement of your crucial milestones. Begin your journey with us today—let’s transform the landscape of clinical trials together.

About the Author:

TFS Regulatory Affairs Expert

Mesfin James
Vice President, Head of Regulatory Affairs

Mesfin is a seasoned regulatory affairs professional with an extensive career spanning over 17 years in the clinical research sector. His invaluable expertise has facilitated multinational, global clinical trials throughout all phases of development and across diverse therapeutic domains. His profound knowledge is particularly notable in oncology and rare diseases, and he has played a pivotal role in advancing regulatory activities across various regions, including the EU, the Americas, Asia Pacific, North Africa, and the Middle East.

His rich experience encompasses a broad spectrum, ranging from pharmaceuticals to small and large molecules, GMO-based vaccines, and Gene Therapy products. He is well-versed in the meticulous compilation, review, and collation of regulatory dossiers and adept at forging meaningful connections with regulatory authorities and external vendors. Mesfin’s collaborative spirit and keen insight extend to his pivotal role in supporting clinical development activities, providing invaluable regulatory strategy and guidance to cross-functional teams and sponsors across various product types and therapeutic areas.

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