Informed consent in clinical trials

by Margherita Barletta

In Italy, informed consent is regulated by Legislative Decree no. 211/2003, which establishes the procedures and conditions for obtaining informed consent and the methods of informing participants in clinical trials.

In 2020, the National Coordination Center for Ethics Committees released a document containing guidelines for obtaining informed consent for participation in clinical trials.

The document aims to provide useful guidance to promote methods of obtaining informed consent that are functional to ensuring that a person's decision to participate or not in a trial is truly free and informed.

Article 32 of the Constitution establishes the principle of the freedom of each individual to decide whether to undergo a specific medical treatment.

Regulation EU 536/2014 defines informed consent as the "free and voluntary expression of a subject of their willingness to participate in a specific clinical trial, after being informed of all the relevant aspects of the clinical trial for the subject's decision to participate or, in the case of minors and incapable subjects, the authorization or agreement of their legally designated representatives to include them in the clinical trial".

The provisions of Chapter V of the Regulation respond to the fundamental ethical requirements in studies involving human subjects derived from the Convention on Human Rights and Biomedicine and the Declaration of Helsinki.

The obligation to obtain informed consent from participants in a clinical trial is first and foremost a measure that guarantees the protection of the right to human dignity and the right to personal integrity, as provided in Articles 1 and 3 of the Charter of Fundamental Rights of the European Union.

The fundamental requirements for informed consent are:

• The provision of detailed information;

• The care of the relationship between research personnel and potential participant;

• The understanding of the information;

• The freedom of choice and decision-making capacity.

Informed consent should be a process that begins with the first contact with the potential participant and continues throughout the study until its completion. The goal is to provide potential participants with adequate information about the study and procedures so that they can continue to be involved.

According to Regulation 536/2014, information must be provided during a preliminary interview with a suitably qualified member of the study group. In addition, the subject or their legal representative is given an adequate period of time to weigh their decision to participate in the study.

The information is aimed at understanding:

• Nature, objectives, benefits, implications, risks, and disadvantages of clinical trials;

• The subject's rights and guarantees (e.g., the right to refuse to participate or withdraw from the study);

• Conditions and duration of the trial;

• Alternative treatments and follow-up measures.

The participant must also be informed of the possibility of unexpected or incidental results (e.g., the presence of other illnesses). In this case, the subject has a right to "not know." This right has a limit in the presence of relatives or descendants who may be affected by the same illness (In this sense, the National Bioethics Committee also).

At the heart of informed consent is respect for a person's autonomy, so the information must be concise, clear, relevant, and understandable. Communication between the study staff and the participant must be ongoing, the language must not be ambiguous, and it must be personalized (e.g., language, culture, etc. are elements to take into account). The location of discussions with the research team must be appropriate and private (unless the participant wishes to involve their family or friends).

The participant must be asked questions to ensure that they have understood the key elements of the study. The participant must be given adequate time to make a decision.

If the participant is unable to sign the consent, it can be recorded using alternative means in the presence of an impartial witness. The witness will then sign and date the informed document.

Informed consent in specific areas or vulnerable populations

1- Biological samples

If the study involves the collection of biological samples, even greater attention must be paid to the participant to enable them to fully and consciously allow their data to be stored in a biobank.

For this purpose, it is important that specialized biobanking staff are involved in the information process.

The Ethics Committee ensures the correctness of the research biobanking process by verifying and enforcing ELSI principles (ethical, legal, social implications) and by verifying the quality of the scientific data.

2- Clinical trials involving minors

Before requesting consent for a minor's participation in a clinical trial, it is necessary to verify that certain basic conditions are met:

• The clinical trial aims to study treatments for a clinical condition that affects only minors, or the trial is essential in relation to minors to validate data obtained from trials on persons capable of providing consent;

• The clinical trial is directly associated with a clinical condition affecting the minor concerned or is of such a nature that it can only be carried out on minors;

• There are scientific reasons to believe that participation in the clinical trial will bring the minor concerned a direct benefit greater than the associated risks and burdens;

• The trials have been designed to minimize pain, discomfort, and fear.

Regarding informed consent:

• According to the Italian Civil Code, parental responsibility is exercised by both parents unless one of them is deceased, dismissed or suspended from parental responsibility. Therefore, consent must be obtained from both parents (even if separated, divorced, or not cohabiting) or from the designated legal representative. In the event that one of the parents is absent due to distance, impediment, or incapacity, consent will be expressed by means of a delegation with an attached copy of an identity card (or by means of a self-certification). This documentation must be kept with the informed consent.

• In the event of disagreement between parents, the decision is referred to the judge. Therefore, the doctor cannot proceed with the medical procedure until the judge's ruling arrives, unless there is a state of necessity.

• In the event of opposition from both parents, the doctor assesses whether the medical procedure is essential and reports the case to the Public Prosecutor's Office for evaluation by the juvenile court.

• The minor, adequately informed, with language/format appropriate to their age, must give consent.

• The information provided is differentiated based on age group (0-11; 12-18). However, the maturity of the minor must be assessed in concrete terms, not just based on their chronological age.

• If the minor wishes to withdraw from the trial or refuse to participate, their wishes must be respected.

• In the case of a mature minor (12-18 years old), they must be involved in the discussions from the outset in order to form their own opinion.

• If the minor reaches the age of majority during the trial, their written consent must be obtained.

3- Capacity to give consent

The capacity to give informed consent is based on demonstrated abilities in four main domains:

1. The ability to express one's choice: this can be considered an essential prerequisite; if it is lacking, other capacities need not be considered;

2. Understanding of the information provided: the information to be understood concerns the nature of the patient's illness, the type, goals, possible risks and benefits of the proposed treatment, and the benefits and risks of alternative approaches, including the possibility of not seeking treatment;

3. The ability to give appropriate weight to the situation and its possible consequences: this differs from understanding in that, for example, a subject may understand the characteristics and consequences of the disease, but may not adequately evaluate the fact that they themselves are ill and that the information is relevant to their condition;

4. The ability to use the information provided rationally to make a decision: the subject should be able to develop a logical process including the following steps: 1) focus on the problem; 2) consider options; 3) imagine consequences; 4) estimate the likelihood of consequences occurring; 5) evaluate the desirability of consequences based on their own value scale; 6) decide. Choices must be free and informed.

Experimentation on disabled individuals

Regulation 536/2014, in compliance with the principles of Oviedo, provides that the conduct of a clinical trial is legitimate only if all of the following conditions are satisfied:

a) The clinical trial is directly associated with a clinical condition from which the subject is suffering;

b) It is essential that the clinical trial be carried out on such disabled subjects and it is not possible to obtain data of similar validity from individuals who are able to provide their informed consent or through other research methods;

c) There are scientific reasons to believe that participation in the trial will provide:

• The disabled subject with a direct benefit that outweighs the associated risks and burdens

or

• To the population represented by the disabled subjects concerned, certain benefits if the clinical trial is directly associated with a potentially lethal or debilitating clinical condition from which the subject is suffering and if such trial entails only minimal risk and burden to the disabled subject.

d) No financial incentives or benefits are provided to the subjects or their legally designated representatives, except for a compensatory indemnity for expenses and lost earnings directly related to participation in the clinical trial.

Who can give consent?

All major guidance documents identify the legally designated representative as the person who should be involved in the informed consent process and from whom informed consent should be obtained.

In emergency situations, it is possible to obtain consent after the decision to include the subject in the trial, based on certain conditions indicated in article 35

Informazioni di contatto

Margherita Barletta
m.barletta@bmvinternational.com