Informed consent and placebo effects: a content analysis of information leaflets to identify what clinical trial participants are told about placebos

Felicity L Bishop, Alison E M Adams, Ted J Kaptchuk, George T Lewith, Felicity L Bishop, Alison E M Adams, Ted J Kaptchuk, George T Lewith

Abstract

Background: Placebo groups are used in randomised clinical trials (RCTs) to control for placebo effects, which can be large. Participants in trials can misunderstand written information particularly regarding technical aspects of trial design such as randomisation; the adequacy of written information about placebos has not been explored. We aimed to identify what participants in major RCTs in the UK are told about placebos and their effects.

Methods and findings: We conducted a content analysis of 45 Participant Information Leaflets (PILs) using quantitative and qualitative methodologies. PILs were obtained from trials on a major registry of current UK clinical trials (the UKCRN database). Eligible leaflets were received from 44 non-commercial trials but only 1 commercial trial. The main limitation is the low response rate (13.5%), but characteristics of included trials were broadly representative of all non-commercial trials on the database. 84% of PILs were for trials with 50:50 randomisation ratios yet in almost every comparison the target treatments were prioritized over the placebos. Placebos were referred to significantly less frequently than target treatments (7 vs. 27 mentions, p<001) and were significantly less likely than target treatments to be described as triggering either beneficial effects (1 vs. 45, p<001) or adverse effects (4 vs. 39, p<001). 8 PILs (18%) explicitly stated that the placebo treatment was either undesirable or ineffective.

Conclusions: PILs from recent high quality clinical trials emphasise the benefits and adverse effects of the target treatment, while largely ignoring the possible effects of the placebo. Thus they provide incomplete and at times inaccurate information about placebos. Trial participants should be more fully informed about the health changes that they might experience from a placebo. To do otherwise jeopardises informed consent and is inconsistent with not only the science of placebos but also the fundamental rationale underpinning placebo controlled trials.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Placebo treatments were referred to…
Figure 1. Placebo treatments were referred to less frequently than target treatments.
Figure 2. The effects of placebos and…
Figure 2. The effects of placebos and target treatments were described differently.

References

    1. Brody H. The placebo response. J Fam Pract. 2000;49:649–654.
    1. Moerman DE, Jonas WB. Deconstructing the Placebo Effect and Finding the Meaning Response. Ann Intern Med. 2002;136:471–476.
    1. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, et al. Placebos without deception: A randomized controlled trial in Irritable Bowel Syndrome. PLoS One. 2010;5:e15591.
    1. Patel SM, Stason WB, Legedza A, Ock SM, Kaptchuk TJ, et al. The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005;17:332–340.
    1. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67:1716–1723.
    1. de Groot FM, Voogt-Bode A, Passchier J, Berger MY, Koes BW, et al. Headache: The placebo effects in the control groups in randomized clinical trials; an analysis of systematic reviews. J Manipulative Physiol Ther. 2011;34:297–305.
    1. Kirsch I, Sapirstein G. Listening to prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment 1: Article 0002a, posted June 26, 1998. 1998.
    1. Wampold BE, Minami T, Tierney SC, Baskin TW, Bhati KS. The placebo is powerful: estimating placebo effects in medicine and psychotherapy from randomized clinical trials. J Clin Psychol. 2005;61:835–854.
    1. Benedetti F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu Rev Pharmacol Toxicol. 2008;48:33–60.
    1. Finniss DG, Kaptchuk TJ, Miller FG, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375:686–695.
    1. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: Recent advances and current thought. Annu Rev Psychol. 2008;59:565–590.
    1. Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial: Gold standard or golden calf? J Clin Epidemiol. 2001;54:541–549.
    1. Hummer M, Holzmeister R, Kemmler G, Eder U, Hofer A, et al. Attitudes of patients with schizophrenia toward placebo-controlled clinical trials. J Clin Psychiatry. 2003;64:277–281.
    1. Welton AJ, Vickers MR, Cooper JA, Meade TW, Marteau TM. Is recruitment more difficult with a placebo arm in randomised controlled trials? A quasirandomised, interview based study. BMJ. 1999;318:1114–1117.
    1. Zifferblatt SM, Wilbur CS. A psychological perspective for double-blind trials. Clin Pharmacol Ther. 1978;23:1–10.
    1. Howard J, Whittemore AS, Hoover JJ, Panos M. How blind was the patient blind in AMIS? Clin Pharmacol Ther. 1982;32:543–553.
    1. Ney PG, Collins C, Spensor C. Double blind: double talk or are there ways to do better research. Med Hypotheses. 1986;21:119–126.
    1. Kaptchuk TJ, Shaw J, Kerr CE, Conboy LA, Kelley JM, et al. “Maybe I made up the whole thing”: Placebos and patients' experiences in a randomized controlled trial. Culture Medicine and Psychiatry. 2009;33:382–411.
    1. Jüni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ. 2001;323:42–46.
    1. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008;336:601.
    1. Diener H-C, Dowson AJ, Ferrari M, Nappi G, Tfelt-Hansen P. Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia. 1999;19:699–700.
    1. Kirsch I, Weixel LJ. Double-blind versus deceptive administration of a placebo. Behav Neurosci. 1988;102:319–323.
    1. Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009;19:34–40.
    1. Sinyor M, Levitt AJ, Cheung AH, Schaffer A, Kiss A, et al. Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J Clin Psychiatry. 2010;71:270–279.
    1. Dahan R, Caulin C, Figea L, Kanis JA, Caulin F, et al. Does informed consent influence therapeutic outcome? A clinical trial of the hypnotic activity of placebo in patients admitted to hospital. Br Med J (Clin Res Ed) 1986;293:363–364.
    1. Bergmann JF, Chassany O, Gandiol J, Deblois P, Kanis JA, et al. A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994;29:41–47.
    1. Loftus EF, Fries JF. The potential perils of informed consent. MJM. 2008;11:217–218.
    1. Amanzio M, Corazzini LL, Vase L, Benedetti F. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain. 2009;146:261–269.
    1. Rief W, Nestoriuc Y, von Lilienfeld-Toal A, Dogan I, Schreiber F, et al. Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Safety. 2009;32:1041–1056.
    1. Dinnett EM, Mungall MM, Kent JA, Ronald ES, McIntyre KE, et al. Unblinding of trial participants to their treatment allocation: lessons from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Clinical Trials. 2005;2:254–259.
    1. Avins A, Bent S, Padula A, Staccone S, Badua E, et al. Initial experience with a group presentation of study results to research participants. Trials. 2008;9:16.
    1. Di Blasi Z, Crawford F, Bradley C, Kleijnen J. Reactions to treatment debriefing among the participants of a placebo controlled trial. BMC Health Serv Res. 2005;5:30.
    1. Goetz CG, Janko K, Blasucci L, Jaglin JA. Impact of placebo assignment in clinical trials of Parkinson's disease. Mov Disord. 2003;18:1146–1149.
    1. Bishop FL, Jacobson EE, Shaw J, Kaptchuk TJ. Debriefing to placebo allocation: A phenomenological study of participants' experiences in a randomized clinical trial. Qual Health Res. In press. 2012.
    1. Criscione LG, Sugarman J, Sanders L, Pisetsky DS, St Clair EW. Informed consent in a clinical trial of a novel treatment for rheumatoid arthritis. Arthritis Care Res. 2003;49:361–367.
    1. Pope JE, Tingey DP, Arnold JMO, Hong P, Ouimet JM, et al. Are subjects satisfied with the informed consent process? A survey of research participants. J Rheumatol. 2003;30:815–824.
    1. Ellis PM, Butow PN. Focus group interviews examining attitudes to randomised trials among breast cancer patients and the general community. Aust N Z J Public Health. 1998;22:528–531.
    1. Asai A, Ohnishi M, Nishigaki E, Sekimoto M, Fukuhara S, et al. Focus group interviews examining attitudes towards medical research among the Japanese: A qualitative study. Bioethics. 2004;18:448–470.
    1. Featherstone K, Donovan JL. Random allocation or allocation at random? Patients' perspectives of participation in a randomised controlled trial. BMJ. 1998;317:1177–1180.
    1. Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, et al. Lay public's understanding of equipoise and randomisation in randomised controlled trials. Health Technology Assessment 9. 2005.
    1. Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data – Consent to research and the therapeutic misconception. Hastings Cent Rep. 1987;17:20–24.
    1. Joffe S, Cook EF, Cleary PD, Clark JW, Weeks JC. Quality of informed consent in cancer clinical trials: a cross-sectional survey. Lancet. 2001;358:1772–1777.
    1. Flory J, Emanuel E. Interventions to improve research participants' understanding in informed consent for research – A systematic review. JAMA. 2004;292:1593–1601.
    1. WMA. Declaration of Helsinki – Ethical principles for medical research involving human subjects. Updated at the 59th WMA General Assembly, Seoul, Korea, October 2008. 2008.
    1. NIHR Clinical Research Network. Eligibility for inclusion of studies in the NIHR Clinical Research Network Portfolio. 2011. .
    1. Joffe H, Yardley L. Marks DF, editor. Content and thematic analysis. 2004. pp. 56–68. Research methods for clinical and health psychology. London: Sage.
    1. UK Clinical Research Collaboration. Understanding Clinical Trials. 1st Edition. 2006.
    1. Bishop FL, Jacobson EE, Shaw JR, Kaptchuk TJ. Scientific tools, fake treatments, or triggers for psychological healing: How clinical trial participants conceptualise placebos. Soc Sci Med. 2012;74:767–774.
    1. Miller FG, Colloca L, Kaptchuk TJ. The placebo effect illness and interpersonal healing. Perspect Biol Med. 2009;52:518–539.
    1. Wechsler ME, Kelley JM, Boyd IOE, Dutile S, Marigowda G, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med 365. 2011;119–126:l.

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