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Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths

Published online by Cambridge University Press:  01 January 2021

Benjamin Freedman ,
Charles Weijer  and
Kathleen Cranley Glass
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Extract

The use of statistics in medical research has been compared to a religion: it has its high priests (statisticians), supplicants (journal editors and researchers), and orthodoxy (for example, p <.05 is significant). Although the comparison may be more unfair to religion than to research, a useful lesson can nonetheless be drawn: the practice of clinical research may benefit—as does the spirit—from critical self-examination. Arguably, no aspect of the conduct of clinical trials is currently more controversial—and thus in as dire need of critical examination—than the use of placebo controls. The ethical and scientific controversies associated with placebo-controlled trials, never far below the surface, have once again seized public attention. Clearly, concern about these issues within the professional community runs deep and wide, as evidenced by the volume of response generated by Kenneth Rothman and Karin Michels's recent Critique. Criticisms of the use of placebo controls in clinical research are scattered through the literatureo; our objective is to present the case against placebos in a compendious form that takes account of scientific and statistical as well as normative issues.

Type
Article
Information
Journal of Law, Medicine & Ethics , Volume 24 , Issue 3 , Fall 1996 , pp. 243 - 251
Copyright
Copyright © American Society of Law, Medicine and Ethics 1996

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References

Salsburg, D.S., “The Religion of Statistics as Practiced in Medical Journals,” American Statistician, 39 (1985): 220–23.Google Scholar
Rothman, K.J. Michels, K.B., “The Continuing Unethical Use of Placebo Controls,” N. Engl. J. Med., 331 (1994): 394–98.CrossRefGoogle Scholar
Sramek, J.J. Cutler, N.R., letter; comment, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 62; Denny, W.F., letter; comment, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 61–62; Pohl, R. Balon, R., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 61–62; Nash, S.D., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 61–62; Gilbert, E.M. Packer, M., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 61–62; Cleophas, T.J., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 61–62; Taylor, H.R., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 60–62; Schecter, C., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 60–62; Cagliano, S. Traversa, G., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 60–62; and Solomon, D.A., letter; comment; discussion, “The Use of Placebo Controls,” N. Engl. J. Med., 332 (1995): 60–62.Google Scholar
Markman, M., “When Regulatory Requirements Conflict with Ethical Study Design: The Case of Oral Ondansetron,” Cancer Investigation, 12 (1994): 654–56; Peterson, W.L. Elashoff, J., “Placebos in Clinical Trials of Duodenal Ulcer: The End of an Era?,” Gastroenterology, 79 (1980): 585–88; Levine, R.J., “The Use of Placebos in Randomized Clinical Trials,” IRB: A Review of Human Subjects Research, 17, no. 2 (1985): 1–4; and Freedman, B., “Placebo-Controlled Trials and the Logic of Clinical Purpose,” IRB: A Review of Human Subjects Research, 12, no. 6 (1990): 1–6.Google Scholar
Bok, S., Lying: Moral Choice in Public and Private Life (New York: Vintage Books, 1978): At 61–68.Google Scholar
Levine, R.J., Ethics and Regulation of Clinical Research (Baltimore: Urban & Schwarzenberg, 2nd ed., 1986): At 229–30.Google Scholar
Temple, R., “Difficulties in Evaluating Positive Control Trials,” Proceedings of the American Statistical Association, (1983): 1–7.Google Scholar
Bailar, J.C., “Introduction,” in Shapiro, S.H. Louis, T.A., eds., Clinical Trials: Issues and Approaches (New York: Marcel Dekker, 1983): 1–12; and Friedman, L.M. Furberg, C.D. DeMets, D.L., Fundamentals of Clinical Trials (Littleton: PSG Publishing, 2nd ed., 1985): 1–10.Google Scholar
Peruck, S.B. Hinkle, L.E., “The Effect of Expectation on Response to Phenmetrazine,” Psychosomatic Medicine, 26 (1964): 369–73.Google Scholar
Dinnerstein, A.J. Haim, J., “Modification of Placebo Effects by Means of Drugs,” Journal of Abnormal and Sociological Psychology, 75 (1970): 308–14.CrossRefGoogle Scholar
Lasagna, L. Laties, V.G. Dohan, J.L., “Further Studies on the ‘Pharmacology’ of Placebo Administration,” journal of Clinical Investigation, 37 (1958): 533–37.CrossRefGoogle Scholar
Schapira, K.et al., “Study on the Effects of Tablet Colour in the Treatment of Anxiety States,” British Medical journal, 1 (1970): 446–49; Huskisson, E.C., “Simple Analgesics for Arthritis,” British Medical Journal, 4 (1974): 196–200; Lucchelli, P.E. Cuttaneo, A.D. Zattoni, J., “Effect of Capsule Colour and Order of Administration of Hypnotic Treatments,” European Journal of Clinical Pharmacology, 13 (1978): 153–55; and Buckalew, L.W. Coffield, K.E., “An Investigation of Drug Expectancy as a Function of Capsule Color and Size and Preparation Form,” Journal of Clinical Psychopharmacology, 2 (1982): 245–48.CrossRefGoogle Scholar
Schindel, S., “The Placebo Dilemma,” European Journal of Clinical Pharmacology, 13 (1978): 231–35.Google Scholar
Ney, P.G. Collines, C. Spensor, C., “Double Blind: Double Talk or Are There Ways to Do Better Research,” Medical Hypotheses, 21 (1986): 119–26.CrossRefGoogle Scholar
Id.Google Scholar
White, K.et al., reply to letter, “Side Effects and the ‘Blindability’ of Clinical Drug Trials,” American Journal of Psychiatry, 150 (1993): 1760-61.Google Scholar
Fisher, S. Greenberg, R.P., “How Sound is the Double-Blind Design for Evaluating Psychotropic Drugs?,” Journal of Nervous and Mental Disease, 181 (1993): 345–50.CrossRefGoogle Scholar
Kuhn, T.S., The Structure of Scientific Revolutions (Chicago: University of Chicago Press, 2nd ed., 1970).Google Scholar
Curson, D.A.et al., “Does Short Term Placebo Treatment of Chronic Schizophrenia Produce Long Term Harm?,” British Medical Journal (Clinical Research Edition), 293 (1986): 726–28.CrossRefGoogle Scholar
Ross, S. Buckalew, L.W., “Placebo Agentry: Assessment of Drug and Placebo Effects,” in White, L. Tursky, B. Schwartz, G.E., eds., Placebo: Theory, Research, and Mechanisms (New York: Guilford Press, 1985): 67–82.Google Scholar
Friedman, A.S., “Interaction of Drug Therapy with Marital Therapy in Depressive Patients,” Archives of General Psychiatry, 32 (1975): 19–37.CrossRefGoogle Scholar
Fisher, Greenberg, , supra note 17.Google Scholar
Friedman, Furberg, DeMets, , supra note 8, at 84–88.Google Scholar
Lasagna, L., “The Helsinki Declaration: Timeless Guide or Irrelevant Anachronism?,” Journal of Clinical Psychopharmacology, 15 (1995): 96–98.CrossRefGoogle Scholar
Pohl, Balon, , supra note 3.Google Scholar
Grunbaum, A., “Explication and Implications of the Placebo Concept,” in White, L. Tursky, B. Schwartz, G.E., eds., Placebo: Theory, Research, and Mechanisms (New York: Guilford Press, 1985): 9–36.Google Scholar
Yusuf, S. Collins, R. Peto, R., “Why Do We Need Large, Simple Randomized Trials?,” Statistics and Medicine, 3 (1984): 409–20.CrossRefGoogle Scholar
Solomon, , supra note 3.Google Scholar
Henry, D. Hill, S., “Comparing Treatments,” British Medical Journal, 310 (1995): 1279.Google Scholar
Freedman, B. Glass, K.C. Weijer, C., “Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths,” Journal of Law, Medicine & Ethics, 24 (1996): 252–59.CrossRefGoogle Scholar
Belchetz, P.E., “Drug Therapy: Hormonal Treatment of Postmenopausal Women,” N. Engl. J. Med., 330 (1994): 1062-71.Google Scholar
Liberman, U.A.et al., “Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis,” N. Engl. J. Med., 333 (1995): 1437-43.CrossRefGoogle Scholar
Sambrook, P.N., “The Treatment of Postmenopausal Osteoporosis,” N. Engl. J. Med., 333 (1995): 1495-96.CrossRefGoogle Scholar
Temple, R., “Government Viewpoint of Clinical Trials,” Drug Information Journal, Jan./Feb. (1982): 10–17.CrossRefGoogle Scholar
Id.Google Scholar
Id.Google Scholar
Id.Google Scholar
Leber, P., “The Placebo Control in Clinical Trials (A View from the FDA),” Psychopharmacology Bulletin, 22 (1986): 30–32; and Addington, D., “The Use of Placebos in Clinical Trials for Acute Schizophrenia,” Canadian Journal of Psychiatry, 40 (1995): 171–76.Google Scholar
Blackwelder, W.C., “‘Proving the Null Hypothesis’ in Clinical Trials,” Controlled Clinical Trials, 3 (1982): 345–53.CrossRefGoogle Scholar
Fleming, T.R., “Evaluation of Active Control Trials in AIDS,” Journal of Acquired Immune Deficiency Syndromes, 3 (1990): S82–S87.Google Scholar
Lee, M.L. Lusher, J.M., “The Problem of Therapeutic Equivalence with Paired Qualitative Data: An Example from a Clinical Trial Using Hemophiliacs with an Inhibitor to Factor VIII,” Statistics in Medicine, 10 (1991): 433–41.CrossRefGoogle Scholar
Rodary, C. Com-Nougue, C. Tournade, M.F., “How to Establish Equivalence Between Treatments: A One-Sided Clinical Trial in Pediatric Oncology,” Statistics in Medicine, 8 (1989): 593–98.CrossRefGoogle Scholar
Makuch, R. Johnson, M., “Issues in Planning and Interpreting Active Control Equivalence Studies,” Journal of Clinical Epidemiology, 42 (1989): 503–11; and Blackwelder, , supra note 39.CrossRefGoogle Scholar
Blackwelder, , supra note 39.Google Scholar
Shapiro, A.K. Morris, L.A., “The Placebo Effect in Medical and Psychological Therapies,” in Garfield, S.L. Bergin, A.E., eds., Handbook of Psychotherapy and Behavior Change (New York: Wiley, 1978): 369–410.Google Scholar
Friedman, Furberg, DeMets, , supra note 8, at 88–93.Google Scholar
Makuch, R. Simon, R., “Sample Size Requirements for Evaluating Conservative Therapy,” Cancer Treatment Reports, 62 (1978): 1037-40.Google Scholar
Young, S.N. Annable, L., “The Use of Placebos in Psychiatry: A Response to the Draft Document Prepared by the Tri-Council Working Group,” Journal of Psychiatry and Neuro-science, 21 (1996): 235–38.Google Scholar
Makuch, Johnson, , supra note 43.Google Scholar