A reflection on the EU Clinical Trials Regulation and future prospects

Historical perspective:

Before 2001, the EU faced a fragmented regulatory environment for clinical trials, as each Member State had its own laws, complicating multinational research. To standardise the process, the EU introduced the Clinical Trials Directive 2001/20/EC (CTD) in 2001, which was integrated into each Member State’s national law by 2004. However, the Directive’s varied interpretation by each Member State resulted in inconsistent enforcement, limited data transparency and increased costs. Addressing these issues, the EU embarked on a major overhaul leading to the inception of the CTR in 2014, which mandates uniform application across all Member States, unlike its predecessor.

The CTR which came into effect on 31January 2022, aims to streamline and harmonise the complex process of conducting clinical trials across EU Member States, fostering a more efficient and consistent approach to clinical trials.

With a focus on patient safety, data transparency and simplifying regulatory procedures, the regulation has presented both opportunities and challenges for stakeholders in the clinical trials ecosystem.

Advantages

1. A streamlined application process

One of the main characteristics of the CTR is the establishment of the Clinical Trials Information System (CTIS), a single submission portal accessible to sponsors and all the EU Member States alike, which facilitates a streamlined and harmonised application process for clinical trials. The CTIS offers an end-to-end fully electronic and secured process throughout the life cycle of a clinical trial. This centralised approach reduces the duplication of efforts and in the long run aims to reduce administrative burdens for sponsors enabling faster initiation of trials. This is particularly beneficial for the sponsors seeking to conduct clinical trials across multiple EU Member States through the unified submission process expediting regulatory approvals.

2. Collaboration and harmonisation

One of the commendable aspects of the CTR is its commitment to harmonising regulatory processes across Member States mitigating inconsistencies and disparities in trial conduct and oversight. The increased collaboration between national regulatory authorities via the shared platform, CTIS enables real-time exchange of information and joint decision making of the common dossier (Part I), which streamlines the approval timelines and facilitates muti-country trials. Furthermore, the regular engagement through the Clinical Trials Coordination and Advisory Group (CTAG) promotes knowledge sharing and collaboration among the Member States. This collaborative approach is the key factor in ensuring the efficiency and success of future clinical research endeavours. The CTR also enhances collaboration between ethics committees (ECs) and national competent authorities (NCAs) with a single decision per Member State.

3. Data transparency and patient-centric approach

The CTR places a strong emphasis on data transparency, promoting open access to clinical trial information through the publicly accessible EU Clinical Trials Database. This shift towards increased transparency not only enhances public trust but also fosters a patient-centric approach to research. For instance, a patient diagnosed with a rare disease can now easily identify ongoing clinical trials investigating potential treatments, empowering them to participate in research and access experimental therapies. As professionals, we have witnessed the positive impact of these changes on participant engagement and overall trial outcomes.

4. Simplified safety reporting requirements

The regulation brings significant simplifications for safety reporting procedures, making them easier to follow and enabling increased efficiency which allows researchers to focus on critical safety data while reducing administrative burden. This in turn is expected to expedite the development of medicines.

The regulation now allows for greater flexibility in safety reporting based on risk adaptations by permitting trial protocols to specify selective recording and reporting for adverse events and serious adverse events. This provision empowers researchers to focus resources on capturing pertinent safety data, thereby optimising trial process while ensuring adherence to safety standards.

In the context of trials involving multiple investigational medicinal products (IMPs), sponsors can now submit a single annual safety report covering all the IMPs used in that trial via CTIS. This consolidation has shown to streamline the reporting process, eliminating the need for separate reports for each IMP and reducing the administrative overhead.

The rules mandate that all suspected unexpected serious adverse reactions (SUSARs) are reported via the Eudravigilance database, serving as a centralised system for collection and analysis of suspected adverse reactions to medicinal products in the EU. This is in contrast to the CTD, which obliges sponsors to review applicable national legislations for SUSAR reporting requirements. The centralised reporting under the CTR facilitates efficient communication of safety concerns and enable comprehensive pharmacovigilance monitoring across Member States.

Challenges encountered

While the intentions behind the CTR are commendable, its implementation has not been without challenges. Delay in adoption of necessary IT infrastructure, variations in Member States readiness and adapting to new reporting requirements have presented hurdles for both sponsors and regulatory authorities.

1. CTR preparedness and high initial administrative burden

Among the challenges faced during the transition to the new regulation was the need for a comprehensive understanding of the updated requirements. Adapting existing processes to comply with the new standards demanded meticulous attention to detail, coordination with regulatory authorities and robust communication within cross-functional teams.

Notably, the primary challenges involved the high initial administrative burden and costs related to enforcing the regulation. Although staff proficiency and system improvements may gradually alleviate this burden, stricter transparency rules under the regulation have resulted in a significant increase in the number of documents needed for submissions, adding to the overall complexity.

Navigating the complexities of the CTR required a concerted effort from sponsors, investigators, NCAs and ECs alike. During the initial years of the CTR implementation, as highlighted in the CTIS Key Performance Indicators (KPIs) published by the European Medicines Agency (EMA), it is noted that organisations exhibited caution when submitting new clinical trial applications in CTIS.

2. Compliance with transparency standards

The application of the CTR transparency rules allow access to the information in the public domain of CTIS, promoting public health and fostering the innovation capacity of European medical research. Concurrently, these rules prioritise protection of personal data (PD) and commercially confidential information (CCI).

Key challenges for organisations include balancing compliance with the transparency standards at the same time as protecting PD and CCI. To address these hurdles effectively, organisations must implement robust strategies and processes ensuring that all documents and data submitted to CTIS undergo review and redaction according to the transparency principles. Under the current transparency rules, the majority of trial information within CTIS is made publicly accessible although publication can be deferred for up to seven years post-trial. Based on our experience with the prevailing publication rules, the significant redaction of documents coupled with deferral functionalities has presented complexities both from an information management and data security standpoint. Moreover, the extensive publication of data and documents duplicating information already captured in the structured data fields combined with lack of focus on documents relevant to patients and clinical researchers along with complex system functionalities, has had an impact on the use of the system.

The EMA recognised this complexity created by the current transparency rules and the necessity for the changes. As a result, in response to user’s feedback, revised transparency rules adopted by the EMA on 5 October 2023, will come into effect on 18 June 2024, coinciding with the launch of the new CTIS public portal. The updated rules have been designed to simplify the system functionalities by publishing only key documents which are relevant to patients and researchers, use of redaction methods to protect CCI and PD and eliminating the deferral requests option. Given this evolving transparency landscape, proactive preparation is essential for organisations to navigate this significant change effectively.

3. Shorter response times to requests for information (RFIs)

When regulatory authorities issue RFI notifications in CTIS, the sponsors must respond promptly. The volume of RFIs can be substantial, particularly in the case of multinational trials, adding to the complexity of the task. The deadlines for RFI responses can fluctuate, typically being set at a 12-day limit for the assessment phase. However, our experience suggests that these deadlines can often be unreasonably short, imposing a significant burden on stakeholders to compile and submit the requisite information. The short response times increase the risk of lapsed RFIs, particularly when they necessitate comprehensive amendments including need for redaction to a large array of documents. To add another layer of urgency, based on the RFIs, the documents may require translation which can be time consuming. Furthermore, the system does not alert the sponsor when RFIs are issued, requiring close monitoring of CTIS to ensure questions are noted and responded to in a timely manner.

Moreover, when inconsistencies are flagged by regulatory authorities via RFIs, there is presently no established channels for contacting the responsible regulatory authorities to obtain necessary clarifications. These clarifications are often vital, considering the nature of requests which are typically concise. This can lead to delays in regulatory review process and potentially impact the timeline for initiating or continuing the clinical trials.

Striking a balance between quality and speed is the key to manage the RFIs, as rushed responses may lead to inaccuracies, while overly cautious one can delay the approval process.

4. Disparity in documents requirement between Member States

While a harmonised assessment procedure for the common dossier (Part I) has been instituted through the establishment of the Reporting Member State (RMS), the evaluation of the Part II dossier and the granting of authorisations for trials within their respective territories remain the responsibility of each nation.

The new system was designed with the intention of simplifying the process and alleviating the administrative load by offering a centralised platform. This platform allows regulators, investigators, and the public to have unrestricted access to trial information, thereby reducing the time spent on addressing individual requests. However, practical experience suggests that the lack of EU harmonisation is frequently reported, especially regarding fees, patient-facing materials, and Part II application content. In a bid to achieve harmonisation, the EMA has made available templates for Part II documents. However, the decision to adopt these templates for their national documents remains at the discretion of each Member State.

Furthermore, additional national requirements, such as informal requests from ECs, IMP import permits, separate payment of fees for NCAs and ECs, executed site agreements, and documents on the deputy principal investigator, contribute to the complexity.

Moreover, stakeholders have called for a harmonised document naming convention, as outlined on the Clinical Trials Coordination Group (CTCG) website. Additionally, they have expressed lack of understanding on reasons for challenging the duration of the deferral period.

Currently, Annex III of the CTR Q&A document under the EudraLex-Volume 10 is a resource where sponsors can find links to national requirements and contact information of each Member State. However, the development of a central repository that consolidates all the national requirements (national legislation, languages requirements, ECs requirements) applied in the context of the CTR would be highly beneficial.

5. Technical challenges with the use of CTIS

The ‘one-stop shop’ feature offered by CTIS and the responsiveness of the helpdesk have been positively received, demonstrating the system’s potential. However, like any complex system, CTIS has faced its share of challenges. These include issues when answering RFIs, no access to uploaded documents, and inability to update applications. There have also been instances of deferral requests disappearing after submission, incorrect timetable calculations, and premature publication of documents such as RFIs and assessment reports. Some of these are significant issues that should ideally have been identified and rectified prior to the system’s deployment. It is important to note that despite these challenges, CTIS continues to serve its users and facilitate study approvals. The lessons learned from these experiences are invaluable in guiding the ongoing development and enhancement of CTIS, with the ultimate goal of minimising delays, reducing the generation of unnecessary RFIs, and avoiding duplication of work.

6. System inflexibility for modifications

Managing modifications presents a significant hurdle for sponsors due to the inflexibility of the system, especially when it comes to changes previously considered minor, such as adding a site or changing the principal investigator (PI). Any substantial modification (SM) cannot be submitted while any other application related to that clinical trial is still in progress. This includes an initial application, a request to include a Member State Concerned (MSC), or another SM. For multinational applications, all MSCs must have made their decision on the previous application before a new application on Part I can be submitted. The only exception is for Part II SMs for different MSCs, which can be submitted concurrently. This can cause delays in implementing vital changes to the clinical trial.

When planning for a major modification, it is essential for a sponsor to determine whether the changes impact just one part (either Part I or Part II) or both. This is because the nature of the modification dictates which sections need to be chosen when creating the SMs in CTIS. For instance, if a modification solely impacts the investigational medicinal product dossier (IMPD) (which is under Part I), then the sponsor would only need to choose and modify the relevant sections in Part I in CTIS. Conversely, if a modification impacts both the trial design (Part I) and the informed consent forms (Part II), then the sponsor would need to choose and modify the relevant sections in both Part I and Part II in CTIS.

By accurately identifying which parts are impacted by the modification, sponsors can ensure they are providing the correct information to the regulatory authorities, thereby preventing potential delays or problems in the approval process. It also aids in preserving the integrity and accuracy of the trial data. Additionally, given that each SM may require 50–95 days to process, prompt identification and submission of modifications are critical to avoid significant delays in implementing essential changes.

7. CTD to CTR transition

All clinical trials authorised under the CTD and still ongoing with at least one active site in the EU/EEA after 30 January 2025 should be transitioned to the CTR in time. These so-called transition trials should be registered in CTIS and should be approved by all MSC before the end of the transition period. This means a timely submission to CTIS and a submission date preferably not later than 16 October 2024. For submission beyond this date, Member States cannot guarantee a prompt approval.

The decision to transition has proven to be tricky for sponsors, especially those conducting multinational trials. These sponsors may encounter difficulties in pinpointing a suitable submission window, specifically a period when no amendment is being evaluated under the CTD. Moreover, the sponsors must assess if clinical trials conducted under across different Member States, necessitate the harmonisation or consolidation of key documents. If such harmonisation is required, sponsors must also account for the time needed to achieve this through substantial amendments under the CTD.

Navigating the transition from the CTD to the CTR also presents challenges in relation to reporting and compliance activities. As per the European Commission transition guidance, post transition, sponsors are required to update their dossier related to the clinical trial in line with the CTR requirements at the first SM. It is crucial to note that the update is not confined to the directly affected document. Rather, the entire sections of the dossier that form either Part I or Part II must be upgraded to meet the CTR standards. However, there are exceptions to this requirement. The site suitability statement and recruitment details, if concluded prior to the transition, are not required to be retrospectively created. Additionally, the introduction of a new MSC is not permissible unless all documentation per the CTR on Part I has been comprehensively updated via a SM.

These challenges require careful planning and coordination among all stakeholders to ensure a smooth transition from the CTD to the CTR.

Looking ahead: Future prospects in EU clinical trials

The future of clinical trials in Europe is significantly enhanced by the CTR and the Accelerating Clinical Trials in the EU (ACT EU) initiatives. The CTR, effective from January 2022, has established a unified framework to uphold safety and transparency in EU conducted clinical trials. Despite ongoing challenges with the CTR, the trajectory suggests a positive shift towards a more streamlined and collaborative future for EU clinical research.

The ACT EU initiative complements this regulation, aiming to further streamline the clinical trial process and foster innovation and collaboration among stakeholders. Its key focus areas include modernising clinical practice, adopting new methodologies and establishing a multi-stakeholder platform for dialogue and cooperation. Collectively, these initiatives are anticipated to boost the EU’s competitiveness as a hub for clinical research, enhance the integration of clinical trials into the European health system, and ultimately facilitate the development of high-quality, safe, and effective medicines.

If you need advice or support to ensure you comply with the CTR, or for help with the CTIS, get in touch with a member of the team today.

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