How Legislation on Decisional Capacity Can Negatively Affect the Feasibility of Clinical Trials in Patients with Dementia
First Online: 23 December 2012 DOI:
10.1007/BF03262277 Cite this article as: Galeotti, F., Vanacore, N., Gainotti, S. et al. Drugs Aging (2012) 29: 607. doi:10.1007/BF03262277 Abstract
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.
Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000; 54 (11 Suppl. 5): S4–9.
Cummings JL, Zhong K. Treatments for behavioural disorders in neurodegenerative diseases: drug development strategies. Nat Rev Drug Discov 2006; 5: 64–74.
Cohen-Mansfield J, Billig N. Agitated behaviors in the elderly: I. A conceptual review. J Am Geriatr Soc 1986; 34: 711–21.
Lanctôt KL, Best TS, Mittmann N, et al. Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. J Clin Psychiatry 1998; 59 (10): 550–61.
Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev 2002; 2: CD002852.
Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry 2006; 14: 191–210.
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006; 355 (15): 1525–38.
Public Health Advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Silver Spring (MD): US FDA [online]. Available from URL:
[Accessed 2012 Apr].
Health Canada advises consumers about important safety information on atypical antipsychotic drugs and dementia. Ottawa (ON): Health Canada, 2005 Jun 15 [online]. Available from URL:
[Accessed 2012 Apr].
European Agency for the Evaluation of Medicinal Products (EMEA). Cerebrovascular events and increased mortality in eldery patients with dementia. London: EMEA, 2004.
Dorsey ER, Rabbani A, Gallagher SA, et al. Impact of FDA black box advisory on antipsychotic medication use. Arch Intern Med 2010; 170: 96–103.
Valiyeva E, Herrmann N, Rochon PA, et al. Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia: a population-based time-series analysis. CMAJ 2008; 179:438–46.
Trifirò G, Sini G, Sturkenboom MC, et al. Prescribing pattern of antipsychotic drugs in the Italian general population 2000–2005: a focus on elderly with dementia. Int Clin Psychopharmacol 2010; 25: 22–8.
Paulsen JS, Salmon DP, Thal LJ, et al. Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology 2000; 54: 1965–71.
Viale D, Mereu RM, Asuni G, et al. Behave-AD-FW Behavioral Pathology in Alzheimer’s Disease Rating Scale: reliability of the Italian version of the scale. G Gerontol 2005; 53: 20–32.
Izzicupo F, Vanacore N, Galeotti F, et al. Parametri per la valutazione della capacita di esprimere consenso al trattamento e strumenti per la loro misurazione. In: Petrini C, editor. Il Consenso informato al trattamento dei soggetti affetti da demenza; aspetti etici, deontologici e giuridici. Rapporto ISTISAN 2008; 33: 14–22.
Gainotti S, Fusari Imperatori S, Spila-Alegiani S, et al. How are the interests of incapacitated research participants protected through legislation? An Italian study on legal agency for dementia patients. PLoS One 2010; 5: e11150.
Gurrera RJ, Moye J, Karel MJ, et al. Cognitive performance predicts treatment decisional abilities in mild to moderate dementia. Neurology 2006; 66: 1367–72.
Department of Veterans Affairs. Clinical assessment for competency determination: a practice guideline for psychologist. Milwaukee (WI): Department of Veterans affairs, National Centers for Cost Containment, 1997.
Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med 2007; 357: 1834–40.
Italian Medicines Agency (AIFA) Research & Development Working Group. Feasibility and challenges of independent research on drugs: the Italian medicines agency (AIFA) experience. Eur J Clin Invest 2010; 40: 69–86.
Friedman A, Robbins E, Wendler D. Which benefits of research participation count as ‘direct’? Bioethics 2012 Feb; 26 (2): 60–7.
Wall A. Including persons with Alzheimer disease in research on comorbid conditions. IRB 2009; 31 (1): 1–6.
Kim SYH, Karlawish JHT, Caine ED. Current state of research on decision-making competence of cognitively impaired elderly persons. Am J Ger Psychiatry 2002; 10: 151–65.
Dunn LB, Nowrangi MA, Palmer BW, et al. Assessing decisional capacity for clinical research or treatment: a review of instruments. Am J Psychiatry. 2006; 163: 1323–34.
Sullivan K. Neuropsychological assessment of mental capacity. Neuropsychol Rev 2004; 14: 131–42.
Stewart PM, Stears A, Tomlinson JW, et al. Regulation: the real threat to clinical research. BMJ 2008; 337: a1732. doi: 10.1136/bmj.a1732.
McMahon AD, Conway DI, Macdonald TM, et al. The unintended consequences of clinical trials regulations. PLoS Med 2009; 3: e1000131.
Traversa G, Sagliocca L, Liberati A, et al. The need to promote independent research on drugs [letter]. Ann Oncol 2010; 21: 2295.
Saks ER, Dunn LB, Wimer J, et al. Proxy consent to research: the legal landscape. Yale J Health Policy Law Ethics 2008; 8: 37–92.
Schneider LS, Tariot PN, Lyketsos CG, et al. National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. Am J Geriatr Psychiatry 2001; 9: 346–60.
Kim SY, Appelbaum PS, Jeste DV, et al. Proxy and surrogate consent in geriatric neuropsychiatric research: update and recommendations. Am J Psychiatry 2004; 161: 797–806.
National Bioethics Advisory Commission. Research involving persons with mental disorders that may affect decision-making capacity. Vol. 1. Report and recommendations of the National Bioethics Advisory Commission. Rockville (MD): US Government Printing Office, 1998.
Stocking CB, Hougham GW, Baron AR, et al. Are the rules for research with subjects with dementia changing? Views from the field. Neurology 2003; 61: 1649–51.
Landhuis E. AD research participation: informed consent complicates trials, part 2. Subject protection versus research progress: debate continues. Alzheimer Research Forum [online]. Available from URL:
[Accessed 2012 Apr].
European Parliament and the Council of the European Union. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products of human use. Official Journal of the European Communities 2001 May 1; L121: 34–44.
Dementia in Europe Yearbook 2009. Luxembourg: Alzheimer Europe, 2009.
Warner J, Nomani E. Giving consent in dementia research. Lancet 2008; 372: 183–5.
Draper B, Peisah C, Snowdon J, et al. Early dementia diagnosis and the risk of suicide and euthanasia. Alzheimers Dement 2010; 6: 75–82.
Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009; 8 (2): 151–7.
Brass EP. The gap between clinical trials and clinical practice: the use of pragmatic clinical trials to inform regulatory decision making. Clin Pharmacol Ther 2010; 87: 351–5.
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