title: The ethics of placebo-controlled trials: methodological justifications.
abstract: The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling.
authors.affiliation: Department of Bioethics, Clinical Center, National Institutes of Health, 10/1C118, 10 Center Drive, Bethesda, MD 20892, United States; Fogarty International Center, National Institutes of Health, 16/210, Stone House, Bethesda, MD 20892, United States. Electronic address: joseph.millum@nih.gov.
authors.forename: Joseph
authors.initials: J
authors.lastname: Millum
authors.forename: Christine
authors.initials: C
authors.lastname: Grady
mesh_terms: D032984:Ethics, Research; D006381:Helsinki Declaration; D006801:Humans; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000941:ethics*; D012107:Research Design
chemical_list: D010919:Placebos
keywords: Ethics; Placebo control; Randomized controlled trial
references.citation: N Engl J Med. 1994 Nov 3;331(18):1173-80
references.pmid: 7935654
references.citation: Ann Intern Med. 2000 Sep 19;133(6):455-63
references.pmid: 10975964
references.citation: Lancet. 1999 Mar 6;353(9155):781-5
references.pmid: 10459958
references.citation: Hastings Cent Rep. 1998 Nov-Dec;28(6):34-8
references.pmid: 9868609
references.citation: Stat Med. 2003 Mar 30;22(6):883-99
references.pmid: 12627407
references.citation: N Engl J Med. 1997 Sep 18;337(12):847-9
references.pmid: 9295243
references.citation: Am J Med Qual. 2002 Nov-Dec;17(6):215-7
references.pmid: 12487336
references.citation: J Nerv Ment Dis. 2012 Mar;200(3):248-9
references.pmid: 22373764
references.citation: J Allergy Clin Immunol. 2014 Jan;133(1):121-9.e1-2
references.pmid: 23870670
references.citation: Bull Med Ethics. 2002 Oct;(182):17-23
references.pmid: 14983848
references.citation: Science. 2007 Dec 21;318(5858):1937-40
references.pmid: 18096809
references.citation: Clin Orthop Relat Res. 2014 May;472(5):1384-93
references.pmid: 23928707
references.citation: Br J Psychiatry. 2006 May;188:489-90; author reply 490-1; discussion 491-2
references.pmid: 16648540
references.citation: N Engl J Med. 1997 Sep 18;337(12):853-6
references.pmid: 9295246
references.citation: J Med Ethics. 2004 Apr;30(2):190-3
references.pmid: 15082816
references.citation: Br J Psychiatry. 2005 Sep;187:229-34
references.pmid: 16135859
references.citation: Am J Public Health. 2004 Jun;94(6):923-8
references.pmid: 15249290
references.citation: N Engl J Med. 1997 Oct 2;337(14):1003-5
references.pmid: 9309109
references.citation: N Engl J Med. 2013 Jul 25;369(4):341-50
references.pmid: 23883379
references.citation: J Med Ethics. 2010 Feb;36(2):116-20
references.pmid: 20133408
references.citation: N Engl J Med. 2001 Sep 20;345(12):915-9
references.pmid: 11565527
references.citation: Ann Rheum Dis. 2014 Jan;73(1):48-55
references.pmid: 23942868
references.citation: J Am Acad Dermatol. 2012 Sep;67(3):379-86
references.pmid: 22325459
references.citation: N Engl J Med. 2011 Dec 29;365(26):2473-83
references.pmid: 22204724
references.citation: J Infect Dis. 2004 Mar 1;189(5):930-7
references.pmid: 14976611
references.citation: Am J Psychiatry. 2013 Sep;170(9):1003-10
references.pmid: 23846759