How Legislation on Decisional Capacity Can Negatively Affect the Feasibility of Clinical Trials in Patients with Dementia

Antipsychotic drugs are widely used to treat behavioural and psychological disturbances associated with Alzheimer's disease (AD), although only modest evidence from randomized controlled trials supports their efficacy, and increasing evidence from post-marketing surveillance shows serious adverse events associated with their use, including increased mortality. The AdCare study, a non-profit, randomized, placebo-controlled, double-blind, multicentre, pragmatic trial coordinated by the Italian National Institute of Health, aimed to evaluate the long-term safety and efficacy profiles of three atypical antipsychotic drugs (risperidone, olanzapine and quetiapine) and one conventional antipsychotic drug (haloperidol) in treating psychosis, aggression and agitation in outpatients with AD. The study was planned to be carried out in 19 clinical centres and to enrol 1000 outpatients. According to Italian law, in the case where a patient is considered unable to give informed consent, a legal representative designated by the court has to provide it. Because of difficulties in the informed consent procedure, the study had to be prematurely interrupted. From February 2009 to April 2010, 83 patients gave informed consent to participate in the trial. Fifty-six patients (68%) were included with consent given by a legal representative, while 27 patients (32%) were considered to provide personal informed consent on the basis of the results from a specifically built procedure. Patients and caregivers were offered the opportunity to participate in the trial before the occurrence of behavioural disturbances, in order to provide them with enough time to consider their participation in the study. Twenty-three patients experienced behavioural, clinically relevant symptoms and were randomized to the study drug; all randomized patients except one had consent for inclusion in the study given by legal representatives. After trial interruption, all patients taking an active drug continued treatment with the same molecule in clinical practice. Randomized controlled trials are acknowledged as the gold standard source of evidence on drug safety and efficacy. The AdCare study showed that an excessively rigid regulation can become a major obstacle while carrying out therapeutic research with incapacitated persons.