1. What is entering into application today?
Clinical trials are scientifically controlled studies undertaken in humans to establish or confirm the safety and effectiveness of investigational medicinal products. Until now, the conduct of clinical trials in the EU was governed by a Directive dating from 2001.
Published in 2014, the Clinical Trials Regulation (CTR) is now applicable. Its main goal is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information.
The Regulation lays down consistent rules for authorising and conducting clinical trials throughout the EU. Information on the authorisation, conduct and results of each clinical trial carried out in the EU will be publicly available.
This will increase the efficiency of all trials in Europe with the greatest benefit for those conducted in multiple Member States.
2. What changes is the Regulation bringing to clinical trials in the EU?
The Clinical Trials Regulation aims to ensure a greater level of harmonisation of the rules of conducting clinical trials throughout the EU.
Key features are:
- A streamlined application procedure for all clinical trials conducted in Europe via an online portal (the “Clinical Trials Information System” or CTIS)
- A single authorisation procedure for all clinical trials, to allow a fast and thorough assessment by all concerned EU countries
- The extension of the silent agreement principle(1) to the authorisation process giving more legal certainty to the organisations or individuals that undertake clinical trials
- Transparency of clinical trial data will become the rule. Information on the approval, execution and result of a given clinical trial will be available for the general public.
- Improvement of the collaboration between Member States on the assessment of unexpected events occurring in clinical trials, thus assuring the highest standards of safety for participants in European clinical trials. Ultimately, this will lead to an even better understanding of the benefits and the risks of authorised medicinal products.
(1) In the existing legislation, the principle of silent agreement exists only for the assessment by the National Competent Authority. The explicit agreement from an ethics committee was required, even when the timelines foreseen in the legislation were not respected. This lead in practice to delays and uncertainties.
3. How will clinical trials be centralized at EU-level?
The CTIS (Clinical Trials Information System) is the single entry point for submitting applications in the EU, which will be stored and treated in the system without parallel processes.
This is a major difference with the current situation, in which the authorisation needs to be requested separately in each European Member State. Furthermore, within each Member State, a submission needs to be done to a National Competent Authority and one or multiple ethics committees. The processes for these submissions differ from one Member State to the other.
The CTIS is run by EMA (European Medicines Agency).
4. How will the Regulation ensure a greater level of harmonisation ?
The CTR defines every aspect of a clinical trial application: the submission point (CTIS), the content of the submission, the processes for validation and assessment, and the timelines.
For each clinical trial submitted in CTIS, one Reporting Member State will lead the assessment process for those elements of the clinical trial application that are common throughout the EU (“part I of the assessment report”).
Each Member State in which the trial will be run has the possibility to provide objections to the Reporting Member State on the common elements in the application (“part I”), and is in charge of the assessment of the elements with a more local or ethical component (“part II”).
In the end, each Member State takes its own decision based on the outcome of the part I and II assessment.
Each Member State needs to define the responsibilities of the National Competent Authority and ethics committee.
The assessment and exchanges between Member States are bound to strict timelines during which objections need to be formulated and resolved.
5. Why will it be easier for pharmaceutical companies to carry out clinical trials?
Under the current legislation, there is a multitude of requirements that differ slightly between Member States. For organisations that set up clinical trials, it is cumbersome to launch a clinical trial in several Member States at the same time as the requirements and timings are far from identical.
This changes with the streamlined process through CTIS which creates a “one stop shop” to obtain clear decisions from each Member State concerned at a predefined time after submission.
Furthermore, the CTR introduces administrative simplifications on the requirements for clinical trials that make it more straightforward to undertake clinical research, all this whilst maintaining the same quality of research.
6. Will the transparency on clinical trials be enhanced through this Regulation?
The starting point of the Regulation is that information submitted through the CTIS is public.
Some exceptions apply for the protection of commercially confidential information, personal data and the internal decision making processes of Member States.
As soon as the decision on a clinical trial is taken, information on this trial will be made public through the public interface of CTIS and will be searchable.
7. How many clinical trials are conducted each year in the EU?
On a yearly basis, around 3700 clinical trials are authorised each year for the whole of the EU27 (2020 figures).
This equals approximately 8,000 clinical-trial applications, with each trial involving two Member States on average.
About 80% of the clinical trial applications are submitted by a commercial organisation (e.g pharmaceutical companies), the rest concerns non-commercial entities (e.g. universities)
8. What about clinical trials conducted outside the EU?
The CTR introduces a control mechanism called “union controls” for the European Commission to verify whether countries outside of the EU have rules in place that are equivalent to those of the CTR for the protection of the safety of the participant and the reliability of the results.
The reports of those controls will be publicly available as well through CTIS.
This new control assures that data of clinical trials used in a marketing authorisation for a medicine in Europe have been obtained according to similar ethical and scientific standards.
9. When will patients fully benefit from this Regulation?
The CTR contains several measures to ensure the continuity of clinical research, some of which enter into force immediately, whilst others will take a few years to full effect.
The impact on patients will be on different levels.
First, there is the level of the authorisation of clinical trials. For the coming year, organisations are able to choose between submitting under the CTR or submitting under the old rules.
From 31 January 2023 onward, all new submissions will need to follow the CTR rules.
It is expected that this will lead to more multinational trials, especially in smaller Member States.
Second, ongoing clinical trials that have been authorised according to the old rules can continue until 31 January 2025. If a trial would still be ongoing by that time, it needs to be resubmitted according to the CTR rules, and all CTR principles will apply. For patients in these trials, there are no changes or interruptions of the treatment.
Thirdly, the new reporting and transparency rules apply only for CTR rules.
Information on authorised trials will be immediately public, allowing patients to verify which trials are ongoing in which Member States.
In the longer term, the information and results of all CTR trials will be available.
10. Why did it take so long for the CTR to become applicable?
The CTR was indeed adopted 7 years ago and it is a complex legislation, with very detailed rules on how a decision on a given clinical trial is taken.
These detailed rules needed to be translated into the CTIS. In addition, there was a legal obligation to verify that the system is fully functional on the basis of an independent audit.
Six months ago, the Commission confirmed that the CTIS is fully functional, and can therefore start to be used. A transition period of 6 months was foreseen in the CTR itself.
This does not mean that the development of CTIS is now completely finished: additional improvements and functionalities will be added over the next year, on the basis of the experience of the users and the legal requirements.
11. What are the next steps?
From today on, applications for clinical trials can be launched under the CTR.
A close follow-up of the experiences with the CTR will be put in place.
At the moment, EMA, the Heads of Medicines Agencies and the Commission are establishing a project portfolio called ACT EU that aims to make the EU more attractive for clinical research, but also to assure that the objectives for clinical trials in the Pharmaceutical Strategy (e.g. more patient-oriented research, guidance of complex trial designs, better integration of the medicines development cycle, research preparedness in public health crisis) can be achieved.