Questioning the methodologic superiority of 'Placebo' over 'Active' controlled trials

American Journal of Bioethics

Volumn 9, Issue 9, 2009, Pages 34-48

  Howick, Jeremy ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

'Active' controlled trial; Absolute effect size; Assay sensitivity; Clinical ethics; Clinical trial; Equivalence; Methodology; Non inferiority; Placebo; Randomized trial; RCT; Research ethics

Indexed keywords

NICOTINE; PLACEBO;

ARTICLE; CHEWING GUM; CONTROLLED CLINICAL TRIAL; DOCTOR PATIENT RELATION; DOUBLE BLIND PROCEDURE; DRUG POTENTIATION; ETHICS; HUMAN; HUMAN RELATION; MEDICAL ETHICS; METHODOLOGY; MORALITY; PERSONNEL; PLACEBO EFFECT; PSYCHOLOGICAL ASPECT; RANDOMIZED CONTROLLED TRIAL; RESEARCH ETHICS; RESEARCH SUBJECT; SAMPLE SIZE; SENSITIVITY AND SPECIFICITY; SMOKING CESSATION; STATISTICAL ANALYSIS;

CHEWING GUM; CONTROLLED CLINICAL TRIALS AS TOPIC; DATA INTERPRETATION, STATISTICAL; DOUBLE-BLIND METHOD; DRUG SYNERGISM; ETHICS, CLINICAL; ETHICS, MEDICAL; ETHICS, RESEARCH; HIPPOCRATIC OATH; HUMANS; MORAL OBLIGATIONS; NICOTINE; PHYSICIAN-PATIENT RELATIONS; PLACEBO EFFECT; PLACEBOS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RESEARCH DESIGN; RESEARCH PERSONNEL; RESEARCH SUBJECTS; RESEARCHER-SUBJECT RELATIONS; SAMPLE SIZE; SENSITIVITY AND SPECIFICITY; SMOKING CESSATION;

EID: 70449589963     PISSN: 15265161     EISSN: 15360075     Source Type: Journal    
DOI: 10.1080/15265160903090041     Document Type: Article

References (92)

1. Altman, D. G. 1980. Statistics and ethics in medical research. Misuse of statistics is unethical. British Medical Journal 281(6249): 1182-1184.
2. Anderson, J. A. 2006. The ethics and science of placebo-controlled trials: Assay sensitivity and the Duhem-Quine thesis. Journal of Medicine and Philosophy 31: 65-81.
3. Antihypertensive and Lipid-Lowering Heart Attack Trial (ALL- HAT) Collaborative Research Group. 2000. Major cardiovascu-lar events in hypertensive patients randomized to doxazosin vs chlorthalidone: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Journal of American Medical Association 283(15): 1967-1975.
4. Armitage, P., Berry, G., and Matthews, J. N. S. 2002. Statistical Methods in Medical Research. Oxford, UK: Blackwell Science.
5. Aronson, J. K. 2007. Concentration-effect and dose-response relations in clinical pharmacology. British Journal of Clinical Pharmacol- ogy 63(3): 255-257.
6. Ashcroft, R., and ter Meulen, R. 2004. Ethics, philosophy, and evi- dence based medicine. Journal of Medical Ethics 30(2): 119.
7. Benedetti, F., and Amanzio, M. 1997. The neurobiology of placebo analgesia: From endogenous opioids to cholecystokinin. Progress in Neurobiology 52(2): 109-125.
8. Berguer, A., Kovacs, F., Abraira, V., Mufraggi, N., Royuela, A., Muriel, A., et al. 2008. Neuro-reflexotherapy for the management of myofascial temporomandibular joint pain: A double-blind, placebo-controlled, randomized clinical trial. Journal of Oral Max-illofacial Surgery 66(8): 1664-1677.
9. Bingel, U., Lorenz, J., Schoell, E., Weiller, C., and Buchel, C. 2006. Mechanisms of placebo analgesia: RACC recruitment of a subcor- tical antinociceptive network. Pain 120(1-2): 8-15.
10. Blackwelder, W. C. 1982. Proving the null hypothesis in clinical trials. Controlled Clinical Trials 3: 345-353.
11. Boutron, I., Moher, D., Tugwell, P., Giraudeau, B., Poiraudeau, S., Nizard, R., et al. 2005. A checklist to evaluate a report of a nonphar- macological trial (CLEAR NPT) was developed using consensus. Journal Clinical Epidemiology 58(12): 1233-1240.
12. CIOMS. 1993. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: World Health Organization.
13. Craggs, J. G., Price, D. D., Verne, G. N., Perlstein, W. M., and Robinson, M. M. 2007. Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. Neuroimage 38(4): 720-729.
14. Davidson, R. A. 1986. Source of funding and outcome of clinical trials. Journal General Internal Medicine 1(3): 155-158.
15. Dickersin, K. 1990. The existence of publication bias and risk factors for its occurrence. Journal of American Medical Association 263(10): 1385-1389.
16. Dunn, A. L., Trivedi, M. H., Kampert, J. B., Clark, C. G., and Chambliss, H. O. 2005. Exercise treatment for depression: Efficacy and dose response. American Journal of Preventive Medicine 28(1): 1-8.
17. Dunnett, C. W., and Gent, M. 1977. Significance testing to establish equivalence between treatments, with special reference to data in the form of 2×2 tables. Biometrics 33(4): 593-602.
18. Dwyer, T., and Ponsonby, A. L. 1996. Sudden infant death syndrome: After the back to sleep campaign. BioMedical Journal 313(7051): 180-181.
19. Ebell, M. H., Siwek, J., Weiss, B. D., Woolf, S. H., Susman, J., Ewigman, B., et al. 2004. Strength of recommendation taxon- omy (SORT): A patient-centered approach to grading evidence in the medical literature. American Family Physician 69(3): 548-556.
20. Echt, D. S., Liebson, P. R., Mitchell, L. B., Peters, R. W., Obias-Manno, D., Barker, A. H., et al. 1991. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac ar-rhythmia suppression trial. New England Journal of Medicine 324(12): 781-788.
21. Edward, S. J., Stevens, A. J., Braunholtz, D. A., Lilford, R. J., and Swift, T. 2005. The ethics of placebo-controlled trials: A comparison of inert and active placebo controls. World Journal of Surgery 29(5): 610-614.
22. Ellenberg, S. S., and Temple, R. 2000. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments. Part 2: Practical issues and specific cases. Annals of Internal Medicine 133(6): 464-470.
23. Ellis, J., Mulligan, I., Rowe, J., and Sackett, D. L. 1995. Inpatient general medicine is evidence based. A-Team, Nuffield Department of Clinical Medicine. Lancet 346(8972): 407-410.
24. Emanuel, E. J., Wendler, D., and Grady, C. 2000. What makes clini- cal research ethical? Journal of American Medical Association 283(20): 2701-2711.
25. Evans, I., Thornton, H., and Chalmers, I. 2007. Testing Treatments: Better Research for Better Healthcare. London, UK: British Library.
26. Extracranial-Intracranial Bypass Study Group. 1985. Failure of extracranial-intracranial arterial bypass to reduce the risk of is chemic stroke. Results of an international randomized trial. New England Journal of Medicine 313(19): 1191-1200.
27. Fergusson, D., Glass, K. C., Waring, D., and Shapiro, S. 2004.Turning a blind eye: The success of blinding reported in a random sample of randomized, placebo controlled trials. BioMedical Journal 328(7437): 432.
28. Freud, S., Strachey, J., Freud, A., and Richards, A. [1913] 2001. The Standard Edition of the Complete Psychological Works of Sigmund Freud, vol. 24, indexes and bibliographies. London, UK: Vintage.
29. Garattini, S. and Bertele, V. 2007. Non-inferioritytrialsare unethical because they disregard patients' interest. Lancet 370(9602): 1875-1877.
30. Gill, P., Dowell, A. C., Neal, R. D., Smith, N., Heywood, P., Wilson, A.E.1996. Evidence based general practice: A retrospective study of interventions in one training practice. BioMedical Journal 312(7034): 819-821.
31. General Medical Council (GMC). 2006. Good medical practice. The Duties of a Doctor Registered with the General Medical Council. London, UK: GMC.
32. Golomb, B. A. 1995. Paradox of placebo effect. Nature 375(6532): 530.
33. Gomberg-Maitland, M., Frison, L., and Halperin, J. L. 2003. Active-control clinical trials to establish equivalence or noninferiority: Methodological and statistical concepts linked to quality. American Heart Journal 146(3): 398-403.
34. Grünbaum, A. 1986. The placebo concept in medicine and psychiatry. Psychological Medicine 16(1): 19-38.
35. Halpern, S. D., Karlawish, J. H., and Berlin, J. A. 2002. The contin- uing unethical conduct of underpowered clinical trials. Journal of American Medical Association 288(3): 358-362.
36. Hayes, M. A., Timmins, A. C., Yau, E. H., Palazzo, M., Hinds, C. J., and Watson, D. 1994. Elevation of systemic oxygen delivery in the treatment of critically ill patients. New England Journal of Medicine 330(24): 1717-1722.
37. Healy, D. 2004. Let Them Eat Prozac. New York, NY: New York University Press.
38. Healy, D. 2006. Did regulators fail over selective serotonin reuptake inhibitors? BioMedical Journal 333(7558): 92-95.
39. Herbert, P. C., Wells, G., and Blajchman, M. A. 1999. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators, Canadian Critical Care Trials Group. New England Journal of Medicine 340(6): 409-417.
40. Howick, J., Golomb, B., Dieppe, P., and Enkin, M. 2009. Unpublished data.
41. Hróbjartsson, A. 2002. What are the main methodological problems in the estimation of placebo effects? Journal of Clinical Epidemiology 55(5): 430-435.
42. Hróbjartsson, A., Forfang, E., Haahr, M. T., Als-Nielsen, B., and Brorson, S. 2007. Blinded trials taken to the test: An analysis of ran- domized clinical trials that report tests for the success of blinding. International Journal of Epidemiology 36(3): 654-663.
43. Hughes, J. R., Gulliver, S. B., Amori, G., Mireault, G. C., and Fenwick, J. F. 1989. Effect of instructions and nicotine on smok- ing cessation, withdrawal symptoms and self-administration of nicotine gum. Psychopharmacology Berlin 99(4): 486-491.
44. Hwang, I. K. and Morikawa, T. 1999. Design issues in noninferiority/equivalence trials. Drug Information Journal 33: 1205-1218.
45. International Conference on Harmonization (ICH). 2000. Harmonized tripartite guideline. Choice of control group and related issues in clinical trials. International Conference on Harmonization, E 10. San Diego, CA: Centre for Biologics Evaluation and Research.
46. Imrie, R., and Ramey, D. W. 2000. The evidence for evidence-based medicine. Complement Therapeutic Medicine 8(2): 123-126.
47. Kaptchuk, T. J. 2001. The double-blind, randomized, placebo- controlled trial: Gold standard or golden calf? Journal of Clinical Epidemiology 54(6): 541-549.
48. Kemp A. S., Schooler, N. R., Kalali A. H., Alphs L., Anand R., Awad G., et al. 2008. What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophrenia Bulletin, e-pub a head of print; 1-6.
49. Kirsch, I. 2000. Are drug and placebo effects in depression additive? Biological Psychiatry 47(8): 733-735.
50. Kirsch, I., Deacon, B. J., Huedo-Medina, T. B., Scoboria, A., Moore, T. J., and Johnson, B. T. 2008. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 5(2): e45.
51. Kirsch, I., and Moore, T. 2002. The Emperor's new drugs: An analysis of antidepressant medication data submitted to the U. S. Food and Drug Administration. Prevention & Treatment, 5.
52. Kirsch, I., and Sapirstein, G. 1998. Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment, I.
53. Kleijnen, J., de Craen, A. J., van Everdingen, J., and Krol, L. 1994. Placebo effect in double-blind clinical trials: A review of interactions with medications. Lancet 344(8933): 1347-1349.
54. Kong, J., Gollub, R. L., Polich, G., Kirsch, I., Laviolette, P., Vangel, M., et al. 2008. A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. Journal of Neuroscience 28(49): 13354-13362.
55. Kong, J., Kaptchuk, T. J., Polich, G., Kirsch, I., and Gollub, R. L. 2007. Placebo analgesia: Findings from brain imaging studies and emerging hypotheses. Reviews of Neuroscience 18(3-4): 173-190.
56. Lasagna, L. 1955. The controlled clinical trial: Theory and practice. Journal of Chronic Disease 1(4): 353-367.
57. Lasagna, L. 1964. Hippocratic oath-Modern version. Available at: http://www.pbs.org/wgbh/nova/doctors/oathmodern.html (accessed February 9, 2009).
58. Levine, J. D. and Gordon, N. C. 1984. Influence of the method of drug administration on analgesic response. Nature 312(5996):755-756.
59. McCann, I. L., and Holmes, D. S. 1984. Influence of aerobic exer- cise on depression. Journal of Personality and Social Psychology 46(5): 1142-1147.
60. Mill, J. S. [1843] 1973. A System of Logic, Ratiocinative, and Inductive: Being a Connected View of the Principles of Evidence and the Methods of Scientific Investigation. Toronto, Canada: University of Toronto Press.
61. Miller, F. G., and Brody, H. 2002. What makes placebo-controlled trials unethical? American Journal of Bioethics 2(2): 3-9.
62. Mitchell, S. H., Laurent, C. L., de Wit, H. 1996. Interaction of ex-pectancy and the pharmacological effects of d-amphetamine: Sub- jective effects and self-administration. Psychopharmacology Berlin 125(4): 371-378.
63. Moerman, D. E. 1983. General medical effectiveness and human biology: Placebo effects in the treatment of ulcer disease. Medical Anthropology Quarterly 14(4): 3, 13-16.
64. Moerman, D. E. 2000. Cultural variations in the placebo effect: Ul- cers, anxiety, and blood pressure. Medical Anthropology Quarterly 14(1): 51-72.
65. Moncrieff, J. 2003. A comparison of antidepressant trials using ac- tive and inert placebos. International Journal of Methods in Psychiatric Research 12(3): 117-127.
66. Moncrieff, J., and Kirsch, I. 2005. Efficacy of antidepressants in adults. BioMedical Journal 331(7509): 155-157.
67. Moncrieff, J. and Wessely, S. 1998. Active placebos in antidepressant trials. British Journal of Psychiatry 173: 88.
68. Moncrieff, J., Wessely, S., and Hardy, R. 2004. Active placebos versus antidepressants for depression. Cochrane Database Systems Review (1): CD003012.
69. Morgan, S. G., Bassett, K. L., Wright, J. M., Evans, R. G., Barer, M. L., Caetano, P. A., et al. 2005. Breakthrough drugs and growth in expenditure on prescription drugs in Canada. BioMedical Journal 331(7520): 815-816.
70. Oken, B. S. 2008. Placebo effects: Clinical aspects and neurobiology. Brain 131(Pt 11): 2812-2823.
71. Patel, S. M., Stason, W. B., Legedza, A., Ock, S. M., Kaptchuk, T. J., Conboy, L., et al. 2005. The placebo effect in irritable bowel syndrome trials: A meta-analysis. Neurogastroenterol Motility 17(3): 332-340.
72. Petrovic, P., Kalso, E., Petersson, K. M., and Ingvar, M. 2002. Placebo and opioid analgesia-imaging a shared neuronal network. Science 295(5560): 1737-1740.
73. Piaggio, G., Elbourne, D. R., Altman, D. G., Pocock, S. J., and Evans, S. J. 2006. Reporting of noninferiority and equivalence randomized trials: An extension of the CONSORT statement. Journal of American Medical Association 295(10): 1152-1160.
74. Ross, D. F., Krugman, A. D., Lyerly, S. B., and Clyde, D. J. 1962. Drugs and placebos: A model design. Psychological Reports 10: 383-392.
75. Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., et al. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. Journal of American Medical Association 288(3): 321-333.
76. Sackett, D. L., Spitzer, W. O., Gent, M., and Roberts, R. S. 1974. The Burlington randomized trial of the nurse practitioner: Health outcomes of patients. Annals of Internal Medicine 80(2): 137-142.
77. Senn, S. J. 2005. Active control equivalence studies. In Encyclopaedic Companion to Medical Statistics, eds. B. S. Everett, C. R. Palmer, and H. Arnold, 19-22.
78. Senn, S. J. 2007. Statistical Issues in Drug Development. Hoboken, NJ: Wiley.
79. Shapiro, A., and Shapiro, E. 1997. The placebo. Is it much ado about nothing? In The Placebo Effect: An Interdisciplinary Exploration, ed. A. Harrington.
80. Shapiro, A. and Morris, L. A. 1978. The Placebo Effect in Medical and Psychological Therapies. Handbook of Psychotherapy and Behavioural Change: An Empirical Analysis. S. L. Garfield and A. E. Bergin, Eds. New York, John Wiley & Sons, 369-410.
81. Smith, G. C., and Pell, J. P. 2003. Parachute use to prevent death and major trauma related to gravitational challenge: Systematic review of randomized controlled trials. British Medical Journal 327(7429): 1459-1461.
82. Smith, R. 1991. Where is the wisdom... ? British Medical Journal 303(6806): 798-799.
83. Takala, J., Roukonen, E., Webster, N. R. Nielsen, M. S., Zandstra, D. F., Vundelinckx, G., et al. 1999. Increased mortality associated with growth hormone treatment in critically ill adults. New England Journal of Medicine 341(11): 785-792.
84. Temple, R., and Ellenberg, S. 2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments: Part 1: Ethical and scientific issues. Annals of Internal Medicine 133(6): 455-463.
85. ter Riet, G., de Craen, A. J., de Boer, A., and Kessels, A. G. 1998. Is placebo analgesia mediated by endogenous opioids? A systematic review. Pain 76(3): 273-275.
86. Trivedi, M.H.,Greer, T.L., Grannemann, B. D., Church, T. S., Galper, D. I., Sunderajan, P., et al. 2006. TREAD: Treatment with Exercise Augmentation for Depression: Study rationale and design. Clinical Trials 3(3): 291-305.
87. Tuteur, W. 1958. The double blind method: Its pitfalls and fallacies. American Journal Psychiatry 114(10): 921-922.
88. Wager, T. D., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J., et al. 2004. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 303(5661): 1162-1167.
89. World Medical Association (WMA). 1949. World Medical Association International Code of Medical Ethics. Policy, WMA. Ferney-Voltaire: WMA.
90. World Medical Association (WMA). 2008, October. The Declaration of Helsinki. Geneva, Switzerland: World Medical Association. Available at www.wma.net/e/policy/63.htm (accessed July 7,2009).
91. Wootton, D. 2006. Bad Medicine: Doctors Doing Harm Since Hip-pocrates. Oxford, UK: Oxford University Press.
92. Worrall, J. 2007. Evidence in medicine. Compass, 2(6): 981-1022.