Clinical trials with subjects unable to give consent: some ethical-legal paradoxes

The problem and the existing legal framework

The substantial ethical and legal problems associated with clinical trials with subjects unable to give consent are amply addressed in the literature. ¹

They can be broadly classified as involving minors, ² persons suffering from neurological or psychiatric diseases ³ and older subjects with cognitive impairment, ⁴ with each category posing particular types of problem.

For European Union member countries the legislation dealing with clinical trials is based on use of Directive 2001/20, ⁵ Article 5 of which concerns “Clinical trials on incapacitated adults not able to give informed legal consent” and lists a series of requirements that must be met before trials can be conducted. The first requirement is that “the informed consent of the legal representative has been obtained; consent must represent the subject’s presumed will and may be revoked at any time, without detriment to the subject”.

The principal differences in the various laws governing legal representation for incapacitated subjects in EU countries concern the categories of persons who may assume legal representation, the authorities delegated to appoint representatives and the scope of the legal representative's mandate.⁶ The differing degrees of complexity involved affect the chances of conducting clinical trials in these countries.

In many countries (e.g. Belgium, Denmark, Germany, Italy, the Netherlands, Spain, Sweden and the UK) the legal representative is generally a family member. Italy and the Netherlands assign priority ranking to family members and those with affective ties to patients. In Italy, for instance, guardianship (see below) is preferentially entrusted to “a spouse who is not legally separated, a stable cohabitee, the father, mother, son, brother or sister or relative within the fourth degree of the patient, or the person named by a surviving parent in a will, public deed or notorial act”.^7,8

Some countries (e.g. Austria, Germany, Italy, Sweden) require the intervention of a judge to appoint a legal representative, while others (Belgium, Denmark, Spain, the UK) follow simpler procedures.⁶

Belgium has a pragmatic arrangement that envisages a cascade of alternatives focused on the presumed wishes of the individual and involves various figures from a hierarchy of family members to a legal representative.⁹

The Italian decree incorporating the Directive is “Legislative Decree no. 211 of 24 June 2003: Transposition of Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for clinical use”. ¹⁰ Under the same heading as Article 5 of the Directive, Article 5 of the Decree establishes that “inclusion in clinical trials of incapacitated adults who have neither given nor refused informed consent prior to the onset of their incapacity shall be allowed only” if a series of requirements are met: the first of these requirements again reproduces the exact wording of the Directive.

In Italy, the legal principles for the legal representation of adults are proscription (in Italian: “interdizione”), disqualification (in Italian: “inabilitazione”) and guardianship (in Italian: “amministrazione di sostegno”).

In the case of proscription ⁷ of a person who is decisionally incapacitated the guardian stands in for the person debarred in the performance of all routine and extraordinary acts. In cases of disqualification, which is usually invoked in less serious cases, the disabled person is assisted by a guardian in the performance of extraordinary acts. ⁷ Both proscription and disqualification can be excessive and disproportionate measures and are used very infrequently. For this reason Law no. 6 of 9 January 2004 introduced assistant guardianship. ⁸ The order issued by the supervising judge to establish a guardianship must include precise and explicit indications of the acts with which the beneficiary is to be assisted by the guardian: the beneficiary is thus recognised as being capable of performing all acts not expressly attributed to the guardian. In the case of assistant guardianship the law stresses assistance for the beneficiary not only in matters relating to his/her estate, but above all in matters of “cura personae”, care of the whole person. The institution of assistant guardianship has been used only infrequently as it is generally unpopular with families and even the supervising judges are often loath to resort to it.

There are consequently very few so-called “incapacitated” individuals in Italy assisted by a legal representative, a state of affairs that further complicates the enrolment of these subjects in trials in accordance with statutory requirements.

Assuming that the protection of those involved in clinical trials is the principal concern, greater flexibility in defining the limits to the validity of informed consent expressed through a representative would help. Increased flexibility should not lower the level of protection for subjects, but improve their chances of access to beneficial treatment. Various attempts have been made in the past to amend Article 5 of Legislative Decree no.211/2003¹⁰ to enable specific categories of persons to give legally valid consent to participation in clinical trials by incapacitated individuals with no legal representation.¹¹ Leaving such considerations aside, the case described below is an example of how discrepancies between provisions in Italy can be an additional obstacle to research.

The case

On 25 October 2012 the Italian Data Protection Authority authorised a Californian pharmaceutical company and an Italian hospital to “process the personal data of patients enrolled in the ‘Multi-centre double-blind randomised trial to evaluate the safety and efficacy of MP4OX plus standard care in trauma patients with lactic acidosis due to severe haemaorragic shock’ without their consent. The authorisation is limited to such data and operations that are absolutely essential and relevant for the conduct of the trial; the provisions indicated in the present authorisation in regard to alternative procedures for compliance with the obligations relating to information and consent, as well as to suitable measures to be adopted in recording the trial data so as to safeguard the identity of the subjects, must be complied with”. ¹² The authorisation provides for consent to “be obtained from the legal guardian, a near relative, a family member, a co-habiting partner or, if none of the above is available, the person in charge of the hospital facility. Consent to the continuation of the trial must in any case be sought directly from the patient as soon as his/her health allows”. ¹³

The situation

A comparison between the authorisation granted by the Data Protection Authority ¹² and the Legislative Decree 211/2003, ¹⁰ and the paradoxical situation thus created led to a number of considerations. Four are particularly evident:

According to the authorisation, ¹² consent to the use of personal data for the purposes of the clinical trial can be validly obtained not only from the legal guardian but also from anybody with close familial or affective ties to patients or who is responsible for their care. However, Legislative Decree 2011/2003, ¹⁰ allows only the consent of a legal representative. This renders the authorisation virtually useless: permission for the researcher to use the personal data of an “incapacitated” subject who is not legally represented within the ambit of a trial is of little use if the law prohibits him or her from administering the treatment being evaluated.