Clinical Trials Regulation in H2020 and Horizon Europe

Clinical Trials Regulation: a common denominator for health-related projects

Privanova’s portfolio of EU-funded projects includes several innovative, interdisciplinary initiatives focusing on health-related issues and clinical trials. DigiCare4You objective is to deliver an intersectoral innovation involving digital tools for early screening, prevention and management of type 2 diabetes (T2D) and hypertension (HTN). FACILITATE balances regulatory and ethical frameworks with the need for high-quality, exploitable medical data. The aim of this project is to define clear mechanisms for data subjects to allow the re-use of their data in accordance with European data protection regulations. AI4HealthSec proposes a state-of-the-art solution that improves the detection and analysis of cyber-attacks and threats on health care information infrastructure. It increases the knowledge on the current cyber security and privacy risks.

Notwithstanding that these projects do not share the common research objective, there is one similarity for all of them – they are subjected to similar legal frameworks. All of them are regulated by the EU Law and specific regulation related to projects supported by Horizon 2020. Of course, each project has project-specific regulatory and ethical framework. Nevertheless, all frameworks have identical roots – the EU Law. Finally, all research activities must be performed in accordance with the European Code of Conduct for Research Integrity (ECCRI) and within the EC’s Ethics Appraisal Process.

Clinical Trials Regulation and its contribution to the EU Law

With the introduction of the Clinical Trial Regulation (EU) No 536/2014 (CTR), the EU Law became richer by one more regulatory source specifically relevant to medical and clinical domains. This regulation was adopted by in 2014 and entered into force on the 31 January 2022. CTR replaces Clinical Trials Directive 2001/20/EC translates the need for a harmonization of clinical trials on the EU level. Namely, the Directive sets legal requirements, that affected both clinical trials sponsors and member states with an underlying aim of ensuring better protection for clinical trial participants and optimizing the results of clinical trials at an EU level by creating harmonized mechanisms between member states.

However, the Directive required national law to be implemented and was subject to different interpretations by the EU’s member states, which resulted in a lack of harmonization of processes. The evolution that was undertaken with the CTR presents a set of legal measures and mechanisms to ensure clarity and consistency in the domain of clinical trials in all of the EU member states. The CTR came into effect on the 31st of January 2022, and it should substitute the Directive. The Directive will continue to be applied to previously authorized clinical trials under the CTR up until the 31st of January 2025; the date at which the trials need to transition to comply with the CTR.

The general ambition behind the CTR is to create an environment that is favorable to conducting clinical trials in the EU. Therefore, the highest standards of safety for participants and increased transparency of trial information are one of the crucial objectives for the adoption of the new regulation. CTR ensures a greater level of harmonization of the rules for conducting clinical trials throughout the EU. It streamlines the application procedure for all clinical trials conducted in Europe via a single EU portal and database. A single authorization procedure for all clinical trials should allow a faster and more thorough assessment by all concerned EU countries. Thus, the Regulation laid down consistent rules for conducting clinical trials throughout the EU. As a result, it is expected increase of collaboration among researchers in Europe.

Finally, the CTR empowers not only collaboration but also the transparency of clinical trials data. Information on the authorization, conduct, and results of each clinical trial carried out in the EU will be publicly available. In addition, it is expected that information sharing will be strengthened. The main actors – industry and member states will need to ensure that submission of data and related documentation should meet defined deadlines. Missing the deadlines might result in applications being considered as lapsed. In the opposite case, that application could be validated by default.

Clinical Trials Regulation: Application

The CTR applies to clinical trials that it defines as a ‘clinical study which fulfills any of the following conditions:

• the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned;
• the decision to prescribe the investigatory medicinal products is taken together with the decision to include the subject in the clinical study, or
• diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.’

The CTR imposes more requirements regarding applications for clinical trials. The application should be submitted via the new clinical trials portal (CT Portal). The portal is a part of the IT infrastructure that also includes database as a single-entry point for the submission of data and information relating to clinical trials in accordance with the CTR. European Medical Agency (EMA) shall be considered to be the controller of the processing data stored at the database. This system is composed of three components (actually workspaces) – submission workspace, authority workspace and public workspace. Each of components is serve for particular set of functionalities as presented in the table below. The application for a clinical trial should be composed of information related to the trial, product, and protocol. Also, it should contain data specific to the member states where the trial will be run. There are four application types – initial application; substantial modification application; non-substantial modification application; and Additional Member State Concerned (MSC) application.

The sponsors of clinical trials should report the progress of trials by submitting various notifications via the CT Portal and Database. Inter alias, the key trial milestones, and important safety information should be shared as well as reports for approval purposes. Transparency is promoted during the whole cycle of a clinical trial (end-to-end transparency). The exception from this concern protecting personal data; protecting commercially confidential information; protecting confidential communication between the Member States in relation to the preparation of the assessment report; ensuring effective supervision of the conduct of a clinical trial by the Member States.

Clinical Trials Regulation: relation to Horizon 2020 and Horizon Europe

The CTR deals with important bioethical issues, and thus it could be an important source for ethical assessments that are carried out before granting EU funding. The CTR forms a piece of a coherent legal and ethical structure applied to research. Therefore, it would not be wrong to claim that the CTR supplements the GDPR, the Helsinki Declaration, the Charter of fundamental rights of the EU, and various other texts to create a ground for identifying and assessing consortia’s ability to respect a set of ethical and legal rules.

The consortia are dedicated to respecting the legal and ethical requirements. The CTR regulates the concept of informed consent (Chapter V). However, the consent under the CTR should not be confused with informed consent enshrined by the GDPR. The CTR informed consent satisfies ethical requirements proclaimed by the Helsinki Declaration, and it primarily protects the human dignity and integrity of individuals. Informed consent laid down by the GDPR is one (out of several) legal ground for lawful personal data processing. Therefore, the CTR is implementable to research projects due to fact that it does not only enshrines new requirements (e.g. application of the trials through central portal) but also additionally develop already existing concepts such as informed consent. The project partners in charge of the research that will need to be based on the informed consent of the participants will adhere not only to GDPR but also CTR requirements. These project partners will need to pay attention, in particular, to the balance of power between research participants and researchers.

The CTR imposes the set of standards for improving the security of data processed within clinical trials. For instance, there is breach notification obligation that in essence is not unknown. The GDPR laid down the set of rules about notifying relevant authorities or even affected data subjects when confidentiality, integrity or availability of data is jeopardized. The CTR empowers data safety by enshrining new set of obligation concerning notifications when data related to clinical trials is breached. For this reason, project partners will need to deal with additional set of requirements whereas data subjects (clinical trials subjects) will enjoy additional layer of protection.

Clinical Trials Regulation: a new driver toward harmonized clinical trials throughout the EU

CTR is a regulation that sets out the aim of being a comprehensive text that establishes a favorable environment for conducting clinical trials in the EU. It allows for harmonization of legislation between member states in order to boost cooperation between different stakeholders while underlining high standards of protection of clinical trial subjects. The regulation can be seen as a catalyses for medical innovation as it helps build a clear framework for all stakeholders involved in clinical trials, including academia, policymakers, and industries. It also brings sufficient protection for clinical trial subjects who benefit from a robust legal structure.