Introduction

Clinical research in critically ill patients is a particularly complex issue, due to the frequent incompetence of such patients and their consequent inability to give valid consent. Under the European Parliamentary Directive 2001/20/EC, informed consent may be granted either by the patient or by the legal representative of the incompetent patient [1]. In Italy, a legislative decree gave implementation to such directive; yet, it failed to specify who should be identified as legal guardian [2]. Concerns have been expressed that such a directive would bring research to a halt in critically ill incompetent patients [3], i.e., the majority of ICU patients [4].

Research studies in cancer patients have demonstrated an unacceptably low patients' comprehension of the protocols they had consented to enter [5, 6]. The competence of critically ill patients is much less adequate. This is an even more troubling issue in patients declining recommended life-saving treatments. In a well-documented case report by Grande et al. in Italy [7], the patient underwent cardiac transplantation despite that he had “firmly” refused surgery; at follow-up examination, the patient denied that he had refused consent. The need “for building and evaluating simple and robust scales of competency for seriously ill patients,” expressed almost 10 years ago [8], remains largely unanswered [9].

Research is mandatory for testing and improving the process of care for both emergency and non-emergency critical situations. Patients' competence can be questionable in both cases. In emergency critical situations (i.e., acute myocardial infarction, severe trauma, respiratory failure, septic shock, ischemic stroke), in which time pressure forces to initiate treatment at an early stage of the disease process before irreversible changes are established, patients can be awake, yet their competence can be questionable because of stress, pain, or anxiety. On the other hand, objectively incompetent critically ill patients (because of either brain injury or sedation) can be candidates for research on non-emergency potentially life-saving treatments (i.e., nutrition, setting of ventilator, antibiotics). These two different situations require a different solution. Legislation in many European countries (not in Italy) recognize waiver of consent as an adequate solution in emergency research, whereas proxy consent is used for research in non-emergency research in incompetent patients.

Legally incompetent patients

A small minority of ICU patients are legally incompetent because of age or previous mental incapacity. A legal representative is already identified (the parents or a guardian appointed by the court). Such representative should be involved in any decision regarding the incompetent patient and is the only person who may give valid consent for both therapy and research. In case the clinicians believe that the decision made by the legal guardian is contrary to the patient's interests, they can ask the court to weaken or limit the legal guardianship in order to treat the patient. This is usually done if the Jehovah witness parents refuse the permission for a life-saving blood transfusion for their child. In theory, such situation could happen also for a potentially life-saving therapeutic research, in case the clinicians believe that the patient should not be deprived of the potential benefits of an experimental approach which is likely to be beneficial. Yet, we have no notice of clinicians' appeal to the court against the legal guardian's negated consent for clinical research in incapacitated ICU patients in Italy.

Naturally incompetent patients: the role of relatives

The vast majority of ICU patients are not legally incapacitated, yet they are usually naturally incapacitated, i.e., incompetent [4]. The problem is to decide who is entitled to decide for them. The definition of the legal representative, or surrogate, of adult (temporarily) incapacitated ICU patients varies across European countries [10] and is absent in Italy. As for therapy, the common situation in Italy is to inform the relatives of what is being done, asking for a general assent and not a real consent. The relatives have a legal role of “natural defenders,” which is usually considered too weak by the Ethics Committee for Research (ECR) in Italy. In the Netherlands, in the absence of a legal representative, spouse, or life companion, the law presently permits also parents, children, and siblings to give surrogate informed consent [11]. In a recent large multicenter randomized controlled trial in UK, informed consent was given by relatives in 81.2% of cases [12]; however, a recent study in France showed that the accuracy with which surrogates reflect the wishes of patients regarding consent to intensive care is far from being optimal, highlighting the need for improving communication skills in the area of informed consent to intensive care research [13].

Naturally incompetent patients: the Support Administrator

A glimmer of hope seemed to shine in Italy few years ago, with the approval of a law which recognizes the Support Administrator (SA, Aministratore di Sostegno) [14]. The SA, appointed by the court (Family Division) within 60 days of the request (but even earlier if necessary, with an urgent provision), should assist/replace a person who cannot take care of his/her own interests, even partially or temporarily, because of a disease or physical/mental impairment. In theory, the SA could give valid consent for the patient's enrollment in a clinical trial if participating in that specific trial could be considered potentially beneficial for the patient. Yet, this solution will not solve the problem of emergency research, as at least some hours are necessary in order to have the SA appointed by the court. In fact, the precise role of the SA in the management of personal goods (health) is still debated by lawyers. As far as we know, the recourse to a court in order to have a SA appointed to obtain valid consent for clinical research has never happened in Italy and does not seem to have good chances for the future.

Naturally incompetent patients: waiver of consent

Introduction of a waiver of consent in clinical trials has shown to increase patients' recruitment [15] and to reduce the time needed to achieve satisfactory research end points [16]. Nevertheless, the possibility of using waived consent also for non-emergency research in the incompetent patient in the ICU is still debated [17].

Waiver of consent has been used only occasionally in Italy in recent years, because Italy has translated and closely applied the European Directive, without regard to the emergency situation [10]. Yet, in the multicenter COMPACT study by GiViTI (Gruppo Italiano per la valutazione degli Interventi in Terapia Intensiva) (http://www.giviti.marionegri.it/COMPACT.asp), the ECR of one of the involved centers (Brescia) waived the consent recognizing that septic shock, the essential entry criterion, impaired patients' competence. Curiously, deferred consent, and not waived consent, had been proposed by the committee which acted as the coordinating ERC for that study. In fact, one of the major problems currently faced by intensive care research in Italy is that ECRs are independent from each other, do not consider the decision of another ECR as binding, nor have any form of coordinating activity to share experience. A national, regional, or scientific society ECR, as in other European countries, is lacking, making it impossible to even trace a prevalent attitude toward challenging ethical situations.

Naturally incompetent patients: deferred consent

In Italy deferred consent has been applied with good results since the GISSI trial dating back to 1986 [18]. In that protocol, recognizing both the particularly vulnerable psychological state of enrolled patients (frightened, anxious, confused, with pain) which could invalidate a reliable comprehension of information and their right to trustfulness and quietness in hyperacute and particularly stressful situations, information and consent were explicitly deferred to a more untroubled phase. A similar approach has been subsequently applied in Italy for other fundamental studies in incompetent ICU patients [19–24]. It is also currently being applied for trials of the GiViTI group, the NUTRI, and the COMPACT trials (G. Bertolini, pers. commun.).

It must be remembered that deferred consent is admitted in the article 19 of the Additional Protocol to the Oviedo Convention concerning Biomedical Research (http://conventions.coe.int/treaty/en/Treaties/Html/195.htm) [25]. Unfortunately, such an additional protocol has not been approved yet in Italy, even though the Oviedo Convention has been ratified (but the implemental decrees – the ratification instrument – are not yet registered).

Conclusion

The situation of clinical research in critically ill patients is very complex in Italy because of the official requirement of the consent of a legal representative which is not legally identified. In practice, as the legal and social admissibility of clinical research depends on the indispensable approval of the specific protocol by an EC for research, the destiny of a protocol of research in ICU depends on the decision of the local ECR regarding the possibility of entitling someone as representative of the incompetent patient.

Waived consent in case of emergency research, family members as patient's surrogates in case of research in naturally incompetent patients, and a national coordinating center for ECRs would represent major advancements for research in critically ill patients in Italy.