A Look Back as the EU Clinical Trial Regulation Moves Forward

The EU CTR kicked off in January 2022, heralding a new era for EU clinical trials. Read on for lessons learned and tips for future success.

On Jan. 31, 2022, the EU Clinical Trial Regulation (EU CTR) 536/2014 became applicable, heralding a new era for clinical trials in the European Union (EU). But with the promise of streamlining and harmonizing processes across member states, has it lived up to expectations? In this blog, our PPD FSP Regulatory Affairs solutions experts share lessons learned, along with tips for success.

Insight to industry CTR experience

During the first year of the voluntary implementation of the EU CTR, sponsors were hesitant to adopt the new process. Fewer trials were submitted or transitioned via the CTR as compared to the established clinical trials directive (CTD) due to uncertainties, the restrictive publication policy and a lack of experience around the new processes. As requirements evolved, this changed considerably, resulting in a leaner experience with more submissions and transitions. This evolution revealed a critical mass of lessons learned, enabling the industry to be more confident with the new process.

Lessons learned & challenges

Changing country and regional requirements

Despite the EU CTR’s promise of harmonization, conflict of country/site documentation requirements are still visible between the European Medicines Agency (EMA) and member states.

Although patient-facing documents other than informed consent forms (ICFs), patient questionnaires and recruiting materials are not expected to be submitted, member states concerned (MSCs) have released country specific recommendations to include several additional documents into the initial clinical trial application.

Having up-to-date knowledge of changing local requirements has proven to be pivotal – to prevent those documents from becoming a rate-limiting step for the application submission, and to ensure the documents are available, translated and properly redacted in a timely fashion.

In addition, the constant evolution of EMA and Clinical Trials Coordination Group (CTCG) guidelines requires constant attention. Thus, maintaining CTR regulatory intelligence is a worthwhile investment that can help the industry accelerate study execution and avoid regulatory pitfalls. Our PPD FSP Regulatory Affairs solutions teams, part of the PPD clinical research business of Thermo Fisher Scientific, regularly gather, assess and determine the impact of CTR intelligence. Our team carefully monitors incoming requests for information (RFIs) at a central level to anticipate trends and generate a cross-study set of best practices used to minimize the number of RFIs received in subsequent submissions. Various proprietary regulatory intelligence platforms play an important role in regulatory intelligence management.

To keep up to date with evolving, country-specific requirements and to gain knowledge from previous submissions’ experience, it is critical to constantly monitor the recurrent requests coming from local authorities for additional submission documents not mentioned in EU CTR Annex I.

Navigating transparency and disclosure processes

The publication policy and the need for redaction of submitted documents to protect personal and commercially confidential information (CCI) has proven to be a labor-intensive activity. It has also complicated the implementation of the EU CTR by creating additional costs and longer submission preparation timelines as compared to the EU CTD.

In response, the EMA has released an updated publication policy significantly reducing the number of documents to be submitted for publication, thus substantially limiting the redaction burden for sponsors, while removing the deferral mechanism. Further, the concern with the publication of copyrighted patient questionnaires has become less stringent after the release of the updated Q&A on the protection of CCI in January 2024, allowing the submission of a placeholder in CTIS in place of the copyrighted patient material.

Despite these simplification efforts, key documents, like the protocol and the ICFs, still require publication. Therefore, the redaction process remains a critical path step and must be planned and implemented early on with cooperation and collaboration between a sponsor’s key stakeholders, including regulatory, clinical, transparency, legal and local team representatives for data protection, intellectual property, business development and marketing functions. These essential team members must come together with detailed processes that minimize the number of review cycles and impact to study timelines, while ensuring adequate protection of the sensitive information. As such, our well-trained team of individuals redact Part I and II documents effectively and rapidly, to limit the impact of redaction on the overall dossier preparation.

Managing requests for information timelines

Although an application can be complete and correct at the time of submission, MSCs may still request additional information, clarifications or changes to the application by issuing a request for information (RFI) to the sponsor.

RFIs must be addressed in the clinical trial information system (CTIS) within 10 calendar days for validation and 12 calendar days for assessment. After more than two years of EU CTR implementation, encompassing 130 initial submissions and over 45 transition submissions, the limited RFI turnaround time has never caused the lapse of any clinical trial application.

One way these tight turnaround timelines can be managed is by leveraging experience from previous submissions, country intelligence and accurate analysis of historical RFIs. Limiting the number of RFIs received in similar applications can prevent critical and time consuming RFIs, therefore shortening the overall turnaround timelines and reducing the risk of an application lapsing. The intelligence collected allows clients to make informed decisions about document content/formats and plan risk mitigation solutions to complete responses to RFIs within the allotted time.

Among the RFI connected risks, translations represent a major critical path item on the way to a timely RFI reply. An accelerated translation process is necessary for existing translations to be updated quickly (preferably a maximum of two business days).

Leveraging an optimal approach to parallel submissions

The EU CTR provides different submission models to support sponsor strategies concerning complexity, country specific timelines, resource allocation and risk management. However, some of the options can restrict other submission activity. Adding new sites or member states will require careful planning in relation to the overall global trial activity.

If a mixed submission strategy is chosen, the part II dossiers of the countries that are not included with the initial application will cause delays in starting in those countries and a block on substantial modifications to the previously approved countries. Under EU CTR article 11 or 14, new countries can only be submitted after all countries in the first wave have been approved, potentially leading to an increase in startup costs and substantial delays in second wave activations.

A fully parallel submission strategy, with all countries included from the beginning, is the optimal approach in terms of cost and time savings. Currently, most clinical trials submitted by our team opted for a fully parallel submission approach, with a negligible number of studies opting for additional countries being submitted at a later stage.

Compiling a successful EU CTR submission

Successful EU CTR submissions are achieved through extensive and coordinated collaboration. Our EU CTR subject matter experts, study teams and clients work together under the internal oversight of the regulatory affairs lead to navigate the ever-evolving EU regulatory environment. To facilitate the understanding of the EU CTR process, our teams have developed various client-facing guidelines, including helpful tips and lessons learned, requirements and alignment of roles and responsibilities.

Submitting an application that is fully compliant with the EU CTR Annex I requirements, CTCG recommendations, country-specific guidance and lessons learned results in a lower number of RFIs being raised and a smoother approval process. Constant review of historical RFIs helps identify critical trends and lessons learned to be implemented in the future, further streamlining the trial assessment process.

Transitioning to EU CTR requirements for existing studies

Under the regulation, clinical trial applications submitted before Jan. 31, 2023, under the CTD can continue to be governed by the CTD until Jan. 30, 2025. The trials that plan to have at least one EU country active after Jan. 30, 2025, will need to transition to EU CTR requirements by that date.

Despite the efforts to transition well before the deadline, making the decision has proven to be tricky for sponsors, particularly those with multiple investigational products who may find it difficult to identify a suitable time for submission – a time when no amendment is under review under the EU CTD. Allocating a 60-day window to get the transition approved is causing a constant shift in submission planning. Similar considerations are causing a shift to the transition submissions close to the end of the expedited process period. This increases the risk of not having the transition approved before Jan. 30, 2025.

To facilitate the transition, the EMA launched an expedited transition process in July 2023 based on a minimum dossier that promised a transition approval within 23 calendar days. Though we’ve yet to see this come to fruition, the transition cycle time was reduced following the implementation of the expedited process, from an average 74 calendar days to the current 60 days for approval. The expedited transition process will be available for clinical trial applications submitted by Oct. 16, 2024. It is essential for the industry to target transition applications before that date to ensure their trials can still be run after the end of the transition period.

Partner with a CRO skilled at navigating shifting regulatory environments

Many sponsors will benefit from navigating these current and upcoming changes through a functional service provider (FSP) model, as an augmentation to an existing FSP or full-service outsourcing (FSO) engagement. Our PPD FSP Regulatory Affairs solutions team offers an in-depth, end-to-end experience in managing EU CTR transition applications and supports our clients in all aspects of the process, from planning, submission dossiers setup, redactions, CTIS management and more.

Implementation of EU CTR has proven to be a challenge for many sponsors. The EMA has reacted by simplifying some of the related processes (e.g. publication and transition), thus making implementation easier and more attractive for the industry.

Nevertheless, pharmaceutical companies may not have a specialized team available to coordinate and deliver projects in line with the ever-changing regulatory requirements and in a timely fashion. Finding a competent FSP partner with deep knowledge in strategic planning to handle all aspects of each initial application and transition requirement is essential to navigate significant regulatory challenges, especially in countries with specific local requirements. Our PPD FSP Regulatory Affairs solutions team provides significant EU CTR experience, in-depth intelligence, clear communication paths and knowledge transfer (consulting) to help you successfully navigate the new environment for EU trials.