The implementation of the Trials Information System (CTIS) by the European Union (EU) and the European Economic Area (EEA) represents a fundamental shift in the management and oversight of clinical trials within the EU and EEA. The goal of the CTIS was to streamline the application process for clinical trials, increasing efficiency and transparency. As the Linical’s Regulatory Team navigates this new system, several lessons have emerged, highlighting the challenges and strategies for effective use. This article outlines our observations, key lessons learned and best practices for submissions of clinical trial applications under this new EU clinical trials regulation.
Lesson 1: The necessity of training and knowledge
One of the most significant lessons from the early days of CTIS implementation is the crucial need for comprehensive training, and the acquisition of specialized knowledge within organizations. The transition to a centralized system forced a rethink of how to structure Regulatory operations. Recognizing the complexity of CTIS, Linical created an internal team of CTIS experts, and initiated an extensive training program for Regulatory individuals, including both general orientation sessions and role-specific workshops combining theoretical knowledge with practical exercises in CTIS Sandbox. This proactive approach helped streamline our first series of applications, reducing submission timelines and errors.
What is more, another vital lesson is the importance of continuous learning. As Regulatory requirements and guidelines evolve, and the CTIS undergoes updates and improvements, users must stay informed about new features and challenges. Ongoing education, through webinars, online resources is essential for maintaining proficiency.
Finally, establishing a community of practice (e.g. with other CROs operating within a given country) can facilitate knowledge sharing and problem-solving among users, enhancing collective expertise.
Lesson 2: Adapting to new timelines
On one hand, Clinical Trials Regulation (CTR) and CTIS brought the predictability of the submission-approval timelines. Due to the features of the platform the applicant always knows when to expect request for information (RFI), by when to reply to RFIs, and when the approval for both parts is expected. On the other hand, the introduced timelines are stricter, especially in responding to queries from authorities. Sponsors now have a narrow window of 10 days to respond to RFIs raised during validation of an application, and 12 days to respond to RFIs raised during assessment. This shift represents a departure from previous practices, emphasizing the need for upfront preparedness, and strategic planning of the internal processes. Experience shows that if the applicant possesses a process on managing RFIs in place, the split of roles and responsibilities between the applicant and vendors (e.g. translation agencies) is clear, these short responses windows are achievable.
Lesson 3: More administrative work
The increased transparency facilitated by the CTIS, while beneficial for public access to trial information, has also created a notable increase in administrative duties for sponsors and stakeholders. Transparency rules require more detailed documents preparation and formatting, the need for diligent data entry, and above all, the need for meticulous attention to protecting confidential information. Consequently, submission preparation time may extend in most cases. To facilitate a smoother process, it is advisable to create a study in CTIS at the earliest opportunity to allow enough time for preparing the whole application. Less experienced sponsors may also consult with regulatory experts to ensure their redaction methods meet the transparency criteria without exposing proprietary data. However, this challenge is not going to be an issue soon. The European Medicines Agency (EMA) has recognized that the complexity of the transparency rules may be perceived by sponsors and applicants as an obstacle. Thus, EMA aims to simplify the transparency rules to make the CTIS more effective and user-friendly, lowering burden for the users and at the same time maintaining public access to clinical trials information. The revised transparency rules are expected to be effective in the second quarter of 2024.[1]
Lesson 4: Technical hurdles and system bugs
Linical’s early experience with CTIS has also been marked by technical challenges. The platform has encountered several issues, ranging from limitations on documents upload sizes, notifications not being received on time, incorrect notifications being delivered, performance problems, and unexpected system downtimes. Continuous communication and reporting the issues to the CTIS helpdesk technicians were vital for us for navigating and resolving these challenges. The representatives of the respective Reporting Members States (RMSs) were simultaneously contacted by email and updated on the status of the application, which was especially important when a due date for responses to RFIs was approaching. This experience has also shown that in case of known technical issues, EMA is eager to extend the submission deadlines to respond to RFIs.
It is important to highlight that the EMA has documented plenty of issues reported by users and, where possible, provided workarounds or noted the fixes are in the works for future system releases.
Lesson 5: Navigating national requirements
Despite the harmonization efforts, individual countries’ requirements can still apply. This flexibility is especially visible in terms of language requirements. There is a general recommendation for English in non-patient-facing documents, while patient-facing documents and specific national Part II documents must be carefully adhered to Member States Concerned’ s (MSC) guidelines. Each MSC has their own linguistic preferences, which have been a point of learning for the Linical Regulatory team. This variability required open communication lines with the MSC contact points to address study-specific issues efficiently. Engaging with forums and country networks to share experiences with the community of other users to navigate the system more efficiently was also a common practice in case of few countries. As a result, Linical decided to prepare a centralized set of documents in English for Part I of the application, while creating tailored, translated documents for Part II submissions as required by each MSC. This approach, while resource-intensive, facilitated smoother submissions across the board.
Conclusions
The journey of adapting to the CTIS has been a learning curve for all stakeholders involved in clinical trials within the EU/EEA. From the importance of specialized training to navigating the complexities of language requirements and rigorous timelines, the experiences shared by all CTIS users offer valuable insight into making the most of this new system. As the CTIS continues to evolve, staying informed and engaged with the broader use community will be key to navigating future challenges and leveraging the system to its full potential.
Authors:
Jowita Wojciechowska, Director of Regulatory Affairs
Monica Borraz, Regulatory Affairs Lead
Originally established in Japan, Linical is global Contract Research Organization (CRO) for full-service drug development with the experience, resources, and know-how to successfully conducting clinical trials throughout the Asia-Pacific (APAC) region, including China.
Linical provides a full spectrum of drug development services from early stage to large-scale, multinational studies. Our areas of focus include Phase I-IV studies in oncology, neurology & psychiatry, immunology & vaccine, and endocrinology & metabolic diseases.
Our regulatory support services are based on a clear understanding of the clinical trial objectives and their relationship to regulatory requirements leading to the development of ad-hoc solutions with well-defined priorities and detailed timelines, always with transparency and fluid collaboration with regulatory authorities.
We combine in-depth knowledge of local and international regulations with a proactive approach to risk management to help you navigate the regulatory process efficiently and effectively, avoiding unnecessary delays and improving the chances of successful approval.
Learn more about Linical’s strategy and consulting solutions.
[1] https://health.ec.europa.eu/latest-updates/clinical-trials-eu-survey-implementation-clinical-trial-regulation-2023-01-23_en.