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CTIS, year 2023: a critical moment for clinical trial management in Europe

What changes to expect in January of 2023 regarding the management of clinical trials in Europe? What have we learned in this first year with CTR 536/2014 in force and CTIS in operation? How much time is left until the transition period ends? How much time have the sponsors of clinical trials to adapt to the new situation?
By Lidya Domínguez
Clinical Research Manager at Sermes CRO and member of the EMA CTIS working group since 2017

Now that almost a year has passed since the go-live of the new European portal for clinical trials (CTIS), it is time to assess what has happened in this time and the lessons learned for those who, like us, are involved in the management of clinical trials in Europe. Above all, it is important to know that January 2023 will see a new change of scenery, as the first of the three-year transition period will have passed (according to Clinical Trial Regulation 536/2014). This has the direct consequence that any new clinical trial submitted after that date will have to be managed entirely through CTIS.

But before going into this analysis and understanding the framework in which we will move in the years 2024 and 2025 (in which the transition period continues), let’s make a brief summary of CTIS (what it is and why it is important to start using it immediately) and our activity within the platform.

What is CTIS?

CTIS (Clinical Trial Information System) is the new European portal that centralizes the management of all clinical trial documentation. With its implementation, the previous European directive regulating clinical trials (CTD 2001/20/EC) has been superseded. The regulation calls for a three-year transition period (of which one year has already passed), which will be discussed further on.

These are the highlights to keep in mind about CTIS:

It is the single entry point for all information related to clinical trials in Europe.
The submission process becomes exclusively telematic.
Submission and communication between the different stakeholders: Ethics Committees, Member States and sponsors. The exchange of information between trial sponsors and member states will be carried out entirely through CTIS.
Information accessible to the public: improving the availability of public data on clinical trials, both from applications and results. CTIS will offer clinical trial data to patients (facilitating their search), as well as to health professionals and the general public. Clinical trial results will be provided in both technical and layman’s terms.

What is our experience working with CTIS?

We were the first Spanish CRO to submit a clinical trial through CTIS, in March of 2022.
In total, in the nine months that the CTIS platform has been operational, we have already submitted three new clinical trials and have managed the transition to CTIS of three more trials.
We have been working within the platform and contributing to its development since 2017, thanks to our participation in the CTIS Working Group sponsored by the European Medicines Agency (EMA).

A gradual and effective adaptation to the CTIS environment

Clinical Trial Regulation 536/2014 implementation entails a structural adaptation process that requires redefining the business model by sponsors and CROs, as well as modifying standard operating procedures.

Since its entry into force (in January 2022), the new regulation provided for 3 years of transition, the first of which is about to expire. In this regard, the most important thing to know is that, as of January 2023, any application for authorization of a new clinical trial must be submitted through CTIS.

During the next two years of the transition period, 2023 and 2024, clinical trials authorized under the old directive may continue to be managed under that standard, but as of January 2025 all clinical trials submitted via EudraCT will have to have been migrated (transitioned) to CTIS, provided that the completion of such trials is scheduled after January 31, 2025.

For this reason, it is vital to plan for the transition of these trials. Firstly, by identifying the trials that need to be transitioned, and secondly, by identifying whether the Part I documents are harmonized/consolidated in all Member States, as only trials where the protocol is harmonized (recommended) or consolidated (accepted) can be transitioned. But what is the difference between harmonized and consolidated?

A harmonized protocol is an identical protocol that includes identical trial procedures in all countries, and which has been approved in all EU Member States.
A consolidated protocol is one in which there are differences in procedures in the various Member States, but the protocol document itself is identical (meaning that, issues specific to the Member States are described within the protocol or in an appendix to the protocol).

When scheduling this transition process, the following should be taken into account:

Making the necessary amendments under Directive 2001/20/EC to harmonize documentation prior to the transition.
Take into consideration the deadline for the subsequent application for authorization under the Regulation. From our experience and the timelines that are being managed within CTIS, we consider that the maximum date would be mid 2024, since the authorizations under the Directive have to be obtained.

Be very careful at this point because the time it takes to make the transition is almost the same as the time it takes to apply for a new trial in CTIS.

It should also be noted that the transition of studies from the Directive to the Clinical Trials Regulation can be made without completing the entire application dossier specified in Annex I of the Regulation.

Minimum information and documents for transitioning a clinical trial to CTIS

A cover letter for the application under the Regulation
The application form (Parts I and II)
The following information regarding Part I:
- The latest approved version of the protocol
- IB
- The relevant documents for good manufacturing standards
- IMPD
- Documents related to auxiliary medicinal products (if applicable).
The documents which must be submitted in relation to Part II are: the latest version of the information sheet of the subjects and the informed consent

The rest of the mandatory documents required to carry out the application through CTIS are to be attached in blank. For example, the following comment can be included in CTIS: “not required – transition trial“.

If the transition is made only with the minimum documents and information, we must subsequently perform the following tasks:

The application dossier must be completed, in accordance with Annex I of the Clinical Trials Regulations at the time the first application is submitted after the clinical trial has already migrated, this being the following substantial modification.
In principle, the application dossier should be completed at least for the part of the application dossier to be assessed in the procedure (e.g., in case of a substantial amendment of Part II, all elements related to Part II of the dossier relevant for the Member State(s) affected by the substantial modification should be completed).

Some unresolved issues

By unifying in a single point all clinical trial documentation management in Europe, the CTIS project represents an important challenge of coordination between all the parties involved: Member States (and their regulatory agencies, as well as research ethics committees), sponsors and CROs. That being the case, there are still some pending issues to be resolved, such as the clarification of national requirements by the different Member States; or the implementation of new functionalities in CTIS that adapt to the needs of the sponsors.

On the other hand, the correct planning of the transition of the trials is essential, since the approval periods of the amendments within the framework of the Directive are taking longer than expected according to local legislation, which prevents the transition to the Regulation, being the slowest country the one that limits the process. Because of this, there is a tendency for trials to accumulate, both for Member States and sponsors.