Brief Introduction to the CT Regulation

Several years after enactment, the Regulation EU/536/2014 governing clinical trials with medicinal products in the EU 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. As specified in the summary of the CT Regulation released by EU, the “CT Regulation aims to ensure safety to those participating in clinical trials”. In order to achieve this scope, the CT Regulation puts a special focus on “vulnerable groups”.

Who are the “vulnerable groups”?

The summary of the CT Regulation and the Recitals no. 19 of the CT Regulation define as vulnerable patients “participants in emergency situations, minors, those who are incapacitated, pregnant and breast-feeding women and, where appropriate, certain other groups, such as older people or those suffering from rare and extremely rare diseases”.

According to Articles 19 and 20 of Helsinki Declaration “some groups or individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm. All vulnerable groups and individuals should receive specifically considered protection. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research.”

Protection of vulnerable groups

In accordance with the Helsinki Declaration, the CT Regulation implements the protection of vulnerable patients, first of all, by limiting such trials to cases in which the clinical trials cannot be conducted on patients who are not in vulnerable situations.

In particular, according to Article 10 of the CT Regulation:

• in case of incapacitated subjects, a clinical trial may be conducted only if it is essential with respect to the incapacitated subjects and data of comparable validity cannot be obtained in clinical trials on person able to give informed consent or by other research method;
• in case of minors, a clinical trial may be conducted only if is intended to investigate treatments for a medical condition that only occurs in minors or if the clinical trial is essential with respect to minors to validate data obtained in clinical trials on persons able to give informed consent or by other research methods. Furthermore, the clinical trial may be conducted, in this hypothesis, only if either relates directly to a medical condition from which the minor concerned suffers or is of such a nature that it can only be carried out on minors;
• in case of pregnant or breastfeeding woman, if the clinical trial has no direct benefit for the pregnant or breastfeeding women concerned (or her embryo, foetus or child after birth), it can be conducted only if a clinical trial of comparable effectiveness cannot be carried out on woman who are not pregnant or breastfeeding.

Another form of protection of the vulnerable groups is specifically represented by the assessment of applications for authorizations of clinical trials, that, according to Recital no. 19 of the CT Regulation, should be conducted on the basis of appropriate expertise. Therefore, a specific expertise should be considered when assessing clinical trials involving vulnerable groups.

In this regard, the CT Regulation, for example, states that specific consideration shall be given to the assessment of the application for authorisation of such clinical trial:

• when the subjects are minor, on the basis of paediatric expertise or after taking advice on clinical, ethical and psychosocial problems in the field of paediatrics;
• when the subjects are incapacitated, on the basis of expertise in the relevant disease and the patient population concerned or after taking advice on clinical, ethical and psychosocial questions in the field of the relevant disease and the patient population concerned;
• when the subjects are pregnant or breastfeeding women, on the basis of expertise in the relevant condition and the population represented by the subject concerned.

Consent of vulnerable subjects

The Charter of Fundamental Rights of the European Union requires that any intervention in the field of biology and medicine can only be performed based on free and informed consent of the person concerned. As specified by CT Regulation in its Recital no. 27, the protection of incapacitated subjects, minors, pregnant women and breastfeeding require specific protection measures.

In particular, the CT Regulation allows for, as far as possible, the involvement in the consent process of vulnerable subjects who are incapable of giving consent or who have not reached the legal age to be able to give consent or who are in an emergency situation.

As regards the clinical trials on incapacitated subjects, provided that the informed consent of the legally designated representative must be obtained, the general information on the clinical trials have to be communicated to the incapacitated subjects, in a way that is adequate in view of their capacity to understand it. As specified by the CT Regulation the incapacitated subject shall, as far as possible, take part in the informed consent procedure.

Concerning the clinical trials on minors, the general information on the clinical trials have to be communicated to the minors in a way adapted to their age and mental maturity, provided that, also in this hypothesis, the informed consent of the legally designated representative must be obtained. The CT Regulation also requires that this information comes from investigators or members of the investigating team who are trained or experienced in working with children.

Furthermore, the investigator has to respect the explicit wish of a minor who is capable of forming an opinion and assessing the general information on the clinical trials to refuse the participation in, or to withdraw from the clinical trial at any time. In case the minor reaches the age of legal competence to give informed consent, his or her express consent shall be obtained before the subject can continue to participate to the clinical trial.

Special provisions are provided for clinical trials in emergency situations, where, if certain conditions are fulfilled, the informed consent to participate in a clinical trial and information on the clinical trial may be given, after the decision to include the subject in the clinical trial, provided that this decision is taken at the time of the first intervention on the subjects.

Following this intervention, the CT Regulation provides that informed consent shall be sought to continue the participation of the subjects in the clinical trial. As regards incapacitated subjects and minors, the consent shall be sought by investigators from the legally designated representative without undue delay. As regards other subjects, the informed consent shall be sought by investigator with undue delay from the subject or from the legally designated representative, whichever is sooner.

Compared to the previous legal framework, there are no particular changes, except for the expansion of the definition of vulnerable individuals, which now includes pregnant and breastfeeding women.

Authored by Giuseppe Aminzade, and Chiara Perolari.