Brief Introduction to the CT Regulation

Several years after enactment of the Regulation EU/536/2014 (CT Regulation) governing clinical trials with medicinal products in the EU, the CT Regulation eventually became applicable on 31 January 2022. After a certain transition period, the CT Regulation will fully replace the former Clinical Trials Directive (2001/20/EC) (“CT Directive”) and the implementing laws in the member states. The CT Regulation aims to create a harmonized regulatory environment favourable for conducting clinical trials in the European Union by also using a centralised and harmonised platform - the CTIS.

What is the CTIS?

The Clinical Trials Information System (“CTIS”) is the centralised EU online portal and database for regulatory submissions, authorisations and supervision of clinical trials across the EU/EEA. It will gradually replace the European clinical trial registry (”EudraCT”). The CTIS – accessible via euclinicaltrials.eu – went live on 31 January 2022 and the CT Regulation became applicable.

The CTIS brings together previously fragmented formal processes (inter alia, for approval or oversight of clinical trials) which varied widely across EU countries under the CT Directive, because processes and requirements for clinical trials were subject to regulation on a Member State level. The CTIS goes beyond the former platform EudraCT as it provides harmonised and simplified end-to-end electronic application procedures over the entire lifecycle of clinical trials across the EU/EEA, by also allowing coordination and collaboration of the different actors involved. Now, under the CT Regulation, all clinical trial applications must be submitted through the CTIS as one single portal for multiple Member States Concerned (“MSC”) at once. Clinical trial sponsors can apply for clinical trial authorisation for up to 30 European countries with one application. While such applications remain subject to decisions by each MSC (Art. 8 CT Regulation), the CTIS facilitates the formal process. Inter alia, it allows national authorities to collaboratively process such clinical trial applications in more than one country, request further information, authorise or refuse a clinical trial. Also, the exchange of information between sponsors and Member States will be fully electronic in CTIS.

What does the CTIS?

The CTIS includes workspaces for clinical trial sponsors and authorities as well as a public website. These are the main functionalities:

For clinical trial sponsors: The secured access workspace for sponsors serves in preparing and compiling the clinical trial application and to submitting related documentation for evaluation. The CTIS also allows for submission of information to monitor clinical trials during their entire lifecycle. Inter alia, clinical trial sponsors have to use the CTIS to:

For authorities: The secured access workspace for authorities supports the activities of the EU/EEA as well as the European Commission to evaluate and monitor clinical trials. Inter alia, authorities have to use the CTIS to:

For the public: Through the public website, everyone can, subject to certain confidentiality redactions, access detailed information on all clinical trials conducted in the EU/EEA, e.g. by searching for a particular clinical trial or for treatment-related details. The public may access the CTIS to look for an overview of clinical trial statistics or to download certain data and documents, such as clinical trial reports or decisions on the clinical trial.

For more information on the functions of CTIS, refer to Clinical Trials Information System | European Medicines Agency (europa.eu).

Data transparency and CTIS

The CTIS serves as key instrument to increase transparency of clinical trials by offering searchable clinical trial information to patients, health care professionals and the general public. Clinical trial results will be available as a technical summary and also in lay language.

There are already various transparency initiatives on an European level. Inter alia, transparency requirements are already set out in the EMA Policy 0070, as official policy for EU clinical data publication and the promotion of transparency of clinical data. However, whereas EMA Policy 0070 only applies for centrally authorised products, the CT Regulation applies to all clinical trials conducted in the EU (Art. 1 CT Regulation).

The CT Regulation requires all information stored in the CTIS database to be publicly available as default, unless confidentiality for certain information is justified on one of the following grounds (Article 81 (4) CT Regulation):

• personal data;

• commercially confidential information (in particular the marketing authorisation status of a medicinal product, unless there is an overriding public interest);

• confidential communication between EU Member States during evaluations;

• supervision of clinical trials by EU Member States.

Further, only applications on which a decision (either authorisation or rejection) has been reached by the MSC will be made public (unless there is an overriding public interest to do so earlier for a particular clinical trial).

Sponsors have the possibility to defer the publication of specific data/documents to, e.g., protect commercial confidential information or personal data. Deferral rules and maximum timelines to defer publication of data and documents depend on the trial category as defined in the Appendix, on disclosure rules, to the Functional specifications for the EU portal and EU database to be audited. To balance the need for protection of certain data, while also allowing MSC to access all required information within their secured access workspace, sponsor may upload documents in a placeholder not subject to publication or a document meant ‘for publication’ (with publicly disclosable information) alongside a version ‘not for publication’ (with further personal/confidential information).

Sponsors are recommended to introduce or adapt respective transparency programs within their organizations (e.g., respective digital tools or SOPs) in order to prepare for the data transparency requirements under the CT Regulation and to safeguard personal protective data and commercial confidential information in information made publicly in CTIS. In this regard, sponsors may also consider to involve data protection officers or other experts to implement data anonymization and de-identification mechanisms. Also potential future initiatives by industry associations such as the European Federation of Pharmaceutical Industries and Associations (EFPIA) or other associations, such as the European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) may help to balance the need for protection of certain information by sponsors and the call for increased transparency under the CT Regulation.

For more information and illustrative examples on the publication of clinical trial information contained in CTIS, refer to: Transparency publication of clinical trial information contained in CTIS (europa.eu).

How to use the CTIS?

Before using the CTIS, users must select their user management approach which best fits their organizations: The organization-centric approach is meant for larger organizations and/or sponsors that run multiple clinical trials on a regular basis. It allows the management of access and roles across trials within one organization; i.e., user management is done at organisation level. By contrast, the trial-centric approach intends to serve the needs of smaller organizations and specifically of academic sponsors, which may initiate trials on an ad hoc basis. This approach supports an easy way of submitting a limited number of clinical trial applications and straightforward management of a small number of users at trial level.

In order to access the CTIS Sponsor workspace, users need an active EMA account (either by using an existing EMA account as the user has already other EMA applications (e.g. Eudralink, EudraVigilance) or by self-registration). Further, the users need to register their organization and trials via the Organisation Management Service (OMS) from which CTIS retrieves its data. In addition, before completing the clinical trial application in CTIS, the sponsors should ensure that the details of the medicinal products used in the clinical trials are already registered in the eXtended EudraVigilance Medicinal Product Dictionary (xEVMPD). A placebo can be added manually in CTIS directly. Further, the active substance for the developed medicinal product must be available in EMA SMS (Substance Management Service).

For more information on the use of CTIS, refer to: Getting started with CTIS – Sponsor quickguide and the Handbook for clinical trial sponsors. Training for clinical trial sponsors on how to enter and maintain product information into the xEVMPD is available on euclinicaltrials.eu/training.

Transitional period for the CTIS

Whereas authorities in the EU Member States and EEA countries have to use CTIS from 31 January 2022, clinical trial sponsors may profit from a transitional period and not need to use CTIS yet. If you want to learn more on the transitional period, please refer to our first article on this CT Regulation series. In short:

• Where the sponsor decides to submit a clinical trial under the CT Regulation, the clinical trial application and all future changes to this trial and communication will need to be done in the CTIS.

• Clinical trials under the CT Directive will be able to run and be completed by using EudraCT: Either as they have been ongoing under the CT Directive at 31 January 2022, their application has been submitted by 31 January, or the sponsor chose to make use of the transitional period in Article 98 CT Regulation and submitted still under the CT Directive until 30 January 2023.

EudraCT will remain active after the end of the transition period for sponsors to notify the global end of the clinical trial and to submit the summary results of clinical trials completed under the former CT Directive. Clinical trial applications submitted from 31 January 2023 on will need to be submitted under the CT Regulation using the CTIS.

• All clinical trials still ongoing under the CT Directive with at least one active site on 30 January 2025, will have to be transitioned to the CT Regulation until then. In order to transfer clinical trials to the CT Regulation, clinical trial sponsors will need to ensure that all documentation is available in electronic format for submission via CTIS.

For further information on details on the CTIS and the transition period, please refer to the Questions & Answers document of the EMA (version 5).

Authored by Joerg Schickert, Arne Thiermann, Tina Welter-Birk and Daniela Tröppner.