On 16 April 2014, the European Parliament and the European Union (EU) Council released the Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use, repealing EU Directive 2001/20/ EC. The primary goal of this new regulation was to protect the rights, safety, dignity and well-being of the trial participants and to generate reliable and robust clinical trial data. The regulation was intended to facilitate harmonisation of the assessment on medicinal products, inspection and supervision of processes and publication of relevant documents for the general public and substantial trial updates over time, throughout the EU using a centralised Clinical Trials Information System (CTIS).1,2 The highlights of EU Directive 2001/20/EC and EudraCT (CTR) 536/2014 are presented in Figure 1.
The 2014 regulation will be fully implemented after the publication of the notice, confirming the full functionality of the EU portal and the EU database by the European Commission.2
Figure 1: Comparison of 2001 Directive With the New 2014 EU-CTR Regulations
New EU-CTR 536/2014
■Multiple application submission for each MS approval
■Single integrated EC (central/local) application/opinion
■Review timeline differs in each MS
■Electronic communication via CTIS only
■Individual MS assessment and decision
■12 calendar days for RFI response
■Access to limited data for public
■ Access to important CT information for public
■Varied response timelines to RFI
■Uniform review timelines
■Single application, evaluation and decision per MS, based on:
■Core scientific data dossier
■Country specific documents
CT, clinical trial; CTD, common technical document; CTIS, Clinical Trials Information System; CTR, Clinical Trials Regulation; EC, Ethics Committees; EU, European Union; MS, Member States; RA, Regulatory Authority; RFI, request further information.
The key highlight of EU Clinical Trials Regulation (CTR) 536/2014 is to provide a single, unified portal and database called CTIS, available for both trial sponsors and regulatory authorities of each Member State. The CTIS will be a centralised, paperless, integrated single-entry point for submission, evaluation of data, authorising, supervising and reporting any trial-related information between the relevant Member States. The European Medicines Agency (EMA) in collaboration with the Member States and the European Commission will manage the CTIS.3 The new system is expected to considerably facilitate the process of clinical trial conduct across EU, starting from the initial submission to authorisation, providing corrective measures, inspection information and publication of the relevant documents for the general public and substantial updates over time.1,2
CTIS will provide different user workspaces to enable sponsors, regulatory authorities and the public to access a suite of functionality (Figure 2). The various workspaces within CTIS include:
Sponsors, academia or small and medium-sized enterprises (SMEs) including Regulatory Project Managers, In-Country Specialists, and CTIS Submission Managers will use the Sponsor Workspace on the tool, which enables them to apply for their trial authorisation using a single application for up to 30 EU/European Economic Area (EEA) countries.
Member States from different participating countries, national competent authorities and ethics committees can coordinate and promote harmonisation of clinical trial assessment decisions and administrative processes.
The general public will be able to access clinical trial data available on the portal in compliance with the disclosure policies. This public website also provides access to detailed information on all clinical trials conducted across the EU, in all official EU languages.
Figure 2: Functions of Clinical Trials Information System for User Workspaces
CT, clinical trial; CTIS, Clinical Trials Information System; EU, European Union; EOT, end of trial; GCP, Good Clinical Practice; MS, Member States; RFI, request for information.
Dedicated workspaces with restricted access to multiple stakeholders are expected to enhance the support in daily business processes throughout the life cycle of a clinical trial. Business experts are focused on the continuous development of the CTIS to ensure whether it is fit for its purpose. Since June 2019, the areas of consideration have included document management, enhanced submission and facilitating overall scientific and regulatory review and monitoring4. On 21 April 2021, following a successful independent audit, the EMA's Management Board confirmed that CTIS is fully functional and meets the specifications as stated in Article 82, paragraph 2 of the Clinical Trial Regulation. The European Commission will further publish a notice in the Official Journal of the EU, 6 months before the planned CTIS launch date.
The CTIS is intended to provide an improved and more collaborative environment for the user community. Some of the key benefits of the system include efficiency, increased transparency, protection to patients and better capability to facilitate effective submission processes.
Key Benefits of the Clinical Trials Information System
Electronic safety reporting by sponsors to the member states and single decision making provisions
Access to clinical trial or investigational medical product information in lay language for patients, healthcare professionals and general public
Harmonised submission, digitally secure information-sharing, simplified end-to-end application over the life cycle of clinical trials
Unique tool facilitating submissions, efficient reporting, enhanced recruitment without reassessment of trial applications
The new clinical trial system is planned to be fully functional after the 3-year transition period (2022–2025) for all clinical trials to go through CTIS.5 The EMA announced the CTIS go-live date as 31 January 2022. During the first year, new trial applications can be submitted either under the old directive or new regulation (via the EU portal and database) or under Directive 2001/20/EC. In the second and third years (from 31 January 2023 onwards), all initial clinical trial applications will be submitted through CTIS; however, old trials will continue to be governed by the Directive. From 31 January 2025 onwards, all clinical trials ongoing will be governed by the Regulation and must go through CTIS.6
A well-planned CTIS training programme is already underway to provide the users with the required skills, capabilities and knowledge for the successful adoption of CTIS.3 EMA's training materials are tailored for clinical trial sponsors and staff of the EU Member States, European Commission and other organisations who will use the system. Presentations, quick guides, frequently asked question sheets, e-learning, webinars and short videos are available online, which will help in the preparedness for CTIS end users. The training is scheduled in 3 main programme streams for the sponsors:
1. Sponsor Master Trainersconceptualized with the train-the-trainer approach for the Member State users aimed at CTIS functions applicable for commercial sponsors and Contract Research Organisations (CROs), which are likely to submit several clinical trial applications and have multiple CTIS users across various organisation models.
2. A 2-day webinarfor SMEs, academia and other non-commercial clinical trial sponsors to disseminate the knowledge on applicable CTIS functions.
3. Training catered on specific CTIS functionsfor end users from all sponsor groups, which is planned to be initiated in the fourth quarter of 2021.7
More information on the CTIS training programme is available at: https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trials-information-system-training-support
An overview and a high-level illustration on the possible life cycle of a clinical trial via the new portal, supporting various user groups including sponsors, Member States, European Commission and the public are presented in Figure 4.8
Figure 4: Life Cycle of Clinical Trials in Clinical Trials Information Systemu
ASR, Annual Safety Report; CT, clinical trial; CTA, Clinical Trial Application; CSR, Clinical Study Report; RFI, request for information.
Source: Guide to CTIS Training Material Catalogue.8
Currently, separate clinical trial applications and submissions are globally initiated and updated locally by the in-country personnel for the multiple Member States. With the introduction of CTIS, sponsors need to assess change in the processes across the lifecycle of a clinical trial. Most of the sponsors, SMEs and academia are now involved in allocating time and resources to align with the transition to the new system. Many of the sponsors and SMEs with limited resources are also dependent on the CROs, making it a huge responsibility to decide on the user management for each trial, especially for those complex trials with more than 1 vendor. Nevertheless, the transition to a new system is leading to increased risks on trust accuracy, costs and workload. Whilst the SMEs are planning to train the available resources, the large sponsors are preparing to manage several hundreds and thousands of resources to align with the new processes.9 Some of the possible common challenges faced by sponsors are listed below:
1. Administrative burden for new user access:
To configure their 'Administrative user' accounts that will be obtained only upon EMA's validation of certain documents to perform their responsibilities and meet the business needs. Administrative sponsors will be responsible for user management by assigning, amending, revoking or approving user roles; controlling an increased number of users could be challenging. It is therefore critical for sponsors to maintain the right balance in assigning roles to their resources within the CTIS.
2. Training for end-users:
Sponsors need to carefully identify the resources (or vendors) who will undergo the EMA training programme and in turn develop training materials and train other resources within the organisation. The training programme should be aligned with the roles assigned in CTIS to ensure that employees efficiently perform their activities within the stipulated timelines.
3. Revealing sensitive data:
As CTIS has open access for the general public, it is critical for the sponsors and/or any end users to ensure that no personal or sensitive information is used within the CTIS whilst considering the transparency guidelines wherever appropriate. Coordinating with translations and redaction of trial-related documents in multiple languages could possibly burden the trial timelines.
4. Increased cost and administrative burdens:
Sponsors and institutions were accustomed to their company-specific standard operating procedures and workflows in preparing submission documents as per country-specific requirements, which may need to be revised to cater to the new requirements. In addition, essential training sessions for individuals and upgrades in the Information Technology (IT) infrastructure could lead to increased cost and administrative burden.
5. Tight submission timelines:
Upon the implementation of CTIS, sponsors need to closely coordinate with regulators for initial applications and for all subsequent clinical trial modifications. Any lapse in timeline might result in legal consequences, such as lapsed application; therefore, sponsors defined for all studies of the same product. Ongoing assessment in one Member State will hold any substantial modifications for the other Member States.
1. Planning in advance:
Sponsors planning to conduct any new trials within the EU should be mindful of the transition period and ensure compliance either with the old directives or new regulations, based on the duration of the planned clinical trials. In addition, it is important to plan timelines and trial-related activities, well in advance.
2. Adapt to new user system:
As CTIS will have dedicated Sponsor workspaces, all sponsors (including institutions, academia or organisations) should develop the expertise to adapt and compile clinical trial application dossiers in compliance with regulations for any new or ongoing trials on the new secure workspace.
3. Invest in your IT infrastructure:
Sponsors would require to upgrade IT infrastructure to gain access to the new secure workspace for preparing and compiling data to be submitted for assessments by the Member States for new and updated trials, avoiding any delay.
4. Define your workflows:
Sponsors may need to create new or revise the existing standard procedures and workflows for dossier preparation, a compilation of all clinical trial application authorisation and related documents for multiple member states assessments through the CTIS.