Correspondence
The Use of Placebo Controls
N Engl J Med 1995; 332:60-62January 5, 1995
- Article
To the Editor:
Rothman and Michels (Aug. 11 issue)1 object to the practice of giving “individual investigators and . . . institutional review boards the right to determine how much discomfort or temporary disability patients should endure for the purpose of research.” Regardless of what controls are used, precisely such a determination must be made concerning the foreseeable adverse effects of the treatment under study and the observation procedures. Is it really worse to ask an informed patient to volunteer to forgo treatment of mild hypertension for a few weeks than to ask a research subject to undergo a radiologic procedure or a series of phlebotomies that are not clinically necessary? Informed consent is admittedly an imperfect device for protecting subjects from unreasonable risk, but this problem applies equally to all aspects of medical research.
1 ReferencesClyde Schechter, M.D
Mt. Sinai School of Medicine, New York, NY 100291
Rothman KJ ,Michels KB . The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398
Full Text | Web of Science | Medline
To the Editor:
In their excellent article about the unethical use of placebos, Rothman and Michels mention some trials in which new treatments were compared with placebos instead of with standard treatments. Similar ethical problems arise in the case of a trial that compares a new vaccine with a placebo rather than with an older, useful vaccine. Such a trial is being conducted in Italy and Sweden to evaluate a new acellular vaccine against pertussis.
From September 1992 to September 1993, 15,550 infants in Italy were enrolled in the trial: 30 percent received the conventional diphtheria, tetanus, and pertussis (DPT) vaccine, 30 percent received the combination of diphtheria and tetanus (DT) vaccine with a new acellular recombinant pertussis vaccine, 30 percent received the combination of DT vaccine with a new acellular nonrecombinant vaccine, and 10 percent (1550) received a placebo with DT vaccine. From March 1992 to April 1993, 9829 infants in Sweden were enrolled, and 2600 of them received placebo with DT vaccine. It is estimated that 5 percent of the infants in the placebo group will have become ill with pertussis during the follow-up period, which ends in September 1995.
According to the National Institute of Allergy and Infectious Diseases, which contributed $11.5 million to the Italian Istituto Superiore di Sanità for the trial, it was important to include a placebo group in order to evaluate the absolute efficacy of a new acellular vaccine against pertussis.1 Such a trial would not be permissible in the United States; the use of a placebo group would be considered unethical, since pertussis vaccine is recommended by the Centers for Disease Control and Prevention and by the American Academy of Pediatrics.
The trial has been controversial.2,3 The Italian Istituto Superiore di Sanità defended itself by stating that “90 percent of children enrolled were vaccinated against pertussis, whereas the national percentage is . . . 40 percent.” 4 This statement appears to be misleading, since there is no mention that in the Italian areas where the vaccine is being tested, the proportion is up to 95 percent. But the essential ethical problem is that 1550 children have been given a placebo instead of a useful vaccine.
4 ReferencesStefano Cagliano, M.D.
Giuseppe Traversa, M.D.
Federconsumatori, 00185 Rome, Italy1
Greenberg DS . Dubious ethics in NIH's foreign vaccine trials. Sci Gov Rep 1994;24:1-62
Leary WE. Critics question ethics of US sponsored vaccine test in Italy and Sweden. New York Times. March 13, 1994:26-7.
3
Press release of the Istituto Superiore di Sanità, Rome, Italy, March 4, 1994.
4
Greenberg DS . NIH, Italian partner defend placebo in vaccine trial. Sci Gov Rep 1994;24:5-5
To the Editor:
The assertion that the ivermectin trial by Greene et al.1 was inappropriate may appear reasonable on the basis of the synopsis that Rothman and Michels provide. However, two important points are misconstrued. First, the authors suggest that the use of a placebo denied “illiterate” Liberians safe and effective treatment with diethylcarbamazine. In their report, however, Greene et al. refer to six articles that describe diethylcarbamazine's severe side effects. The drug was widely used until the early 1980s, when its adverse effects in the treatment of onchocerciasis were recognized. For this reason the World Health Organization recommended withholding treatment with diethylcarbamazine except in the case of “severe sight-threatening or debilitating disease.”2
The criticism of the enrollment of illiterate Africans misses the important points that over 99 percent of those with onchocerciasis are African and most are illiterate. Furthermore, consent was obtained by staff members fluent in the local dialects. As indicated in the report by Greene et al., this study had received ethical approval from three separate bodies: an American institutional review board, the Liberian Institute for Biomedical Research, and the World Health Organization's Secretariat Committee on Research Involving Human Subjects.
It is misleading, even mischievous, to imply that this study, which had been explicitly approved by the World Health Organization, did not meet its requirements. In this case, at least, Rothman and Michels have chosen badly in their attempt to find an unethical study to discredit the use of placebo treatment.
2 ReferencesHugh R. Taylor, M.D.
University of Melbourne, East Melbourne, Victoria 3002, Australia1
Greene BM ,Taylor HR ,Cupp EW , et al. Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis. N Engl J Med 1985;313:133-138
Full Text | Web of Science | Medline2
WHO Expert Committee on Onchocerciasis
To the Editor:
As a practicing cardiologist involved in clinical trials, I agree that there are legitimate concerns whenever a placebo is used. However, just as the Food and Drug Administration (FDA) may be unreasonable in demanding that clinical drug research include placebo controls, Rothman and Michels are unreasonable in categorically condemning the practice.
Stephen D. Nash, M.D.
SUNY Health Science Center at Syracuse, Syracuse, NY 13210To the Editor:
Rothman and Michels contend that placebo-controlled studies are unethical because they necessarily deprive patients of effective therapy. The authors incorrectly assume that patients in placebo groups are not permitted to receive established drugs for their conditions. Controlled clinical trials of drugs for the treatment of heart failure allow (and usually require) the use of established drugs as background therapy. Patients are then randomly assigned to receive a new drug or a placebo, which is added to the existing treatment. Thus, patients in both the placebo and active-treatment groups receive all medications that would normally be prescribed. With such a study design, it is possible to determine whether the new drug is more effective than placebo, no different from placebo, or worse than placebo.
Rothman and Michels believe that new drugs should be directly compared with established drugs, but such an approach may raise ethical questions. The use of a study design with an active control necessarily deprives one group of access to established therapy and instead treats them with a drug of unknown efficacy and safety. Furthermore, if the new drug is inferior to the established drug, then the study cannot determine whether the new drug is harmful, ineffective, or simply inferior. Hence, the use of a study design with an active control raises precisely the ethical issues that Rothman and Michels consider problematic.
The experience with the use of flosequinan for the treatment of heart failure illustrates the flaws in their arguments. Rothman and Michels indicate that the usefulness of this drug should have been evaluated by comparing patients receiving flosequinan with those receiving a converting-enzyme inhibitor. Such a trial was carried out and showed that flosequinan was similar in efficacy to a converting-enzyme inhibitor.1 In the view of Rothman and Michels, this should have led to the acceptance of flosequinan. Fortunately, their approach was not taken, and an additional study was performed to compare flosequinan with placebo in patients receiving established therapy for heart failure, including a converting-enzyme inhibitor. The study found that flosequinan therapy increased the risk of death.2 This effect could not have been detected without the use of a placebo control.
2 ReferencesEdward M. Gilbert, M.D.
University of Utah School of Medicine, Salt Lake City, UT 84132Milton Packer, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 100321
Cowley AJ ,Wynne RD ,Swami A ,Birkhead J ,Skene A ,Hampton JR . A comparison of the effects of captopril and flosequinan in patients with severe heart failure. Cardiovasc Drugs Ther 1992;6:465-470
CrossRef | Web of Science | Medline2
Packer M ,Rouleau J ,Swedberg K , et al. Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE Study. Circulation 1993;88:Suppl I:I-301 abstract.
To the Editor:
Some of us have ethical problems with all controlled clinical trials in which investigators provide treatment according to strict criteria, irrespective of the individual responses of the subjects to the treatment. Although this rigor makes it possible to draw stronger conclusions — which is the main reason for clinical trials — we may ask whether it is ethically justifiable to perform such trials with human subjects. Humans ought not to be treated merely as means to an end: they must also be treated as ends in themselves. This is what makes biomedical research so special. It also sets the limits for the use of placebos.
Ton J.M. Cleophas, M.D., Ph.D.
3360 AB Sliedrecht, the NetherlandsTo the Editor:
Ethical choices must take foreseeable consequences into account. In the case of new antidepressant drugs, researchers ask a few hundred nonsuicidal patients to consent voluntarily to possible treatment with a placebo. The alternative would be to risk the acceptance of a worthless drug. Then hundreds of thousands of patients would unknowingly receive an ineffective drug each year, some for long periods of time and some while they were suicidal. Would that be ethical?
Robert Pohl, M.D.
Richard Balon, M.D.
Wayne State University School of Medicine, Detroit, MI 48207To the Editor:
The ethics of placebo use is the issue most frequently debated by the University of Arizona Institutional Review Board. The routine inclusion of a placebo control group in most treatment protocols is neither scientifically necessary nor ethically sound. Investigators invariably contend that the FDA requires the use of a placebo control. Although the FDA is careful to defer technically to the judgment of local review boards, in practical terms the agency's attitude is coercive. The institutional review board's rejection of placebo controls in a protocol would most likely result in loss of the grant to the investigator, not an alteration of the protocol to substitute another control mechanism. The sponsor (and the FDA) would simply complete the project elsewhere.
William F. Denny, M.D.
University of Arizona, Tucson, AZ 85724To the Editor:
Rothman and Michels argue that the use of placebos in trials of antidepressant drugs is unethical because patients are denied treatment with compounds that have proved efficacy. Effective antidepressant drugs do exist, at least by statistical standards, but how clinically meaningful is a 50 percent response rate for a drug as compared with a 40 percent response rate for placebo? Of the 14 efficacy studies conducted before the FDA approved the use of Prozac (fluoxetine), only 5 showed Prozac to be statistically superior to placebo.1
Because differences in efficacy between drug and placebo are small with currently available agents, the chances are slim indeed that one could be proved more effective than another. With continued research, we hope that in the future new treatments can be compared with established drugs instead of placebo, but until then, placebo-controlled trials remain the best means of assessing the efficacy of new antidepressant compounds.
1 ReferencesJohn J. Sramek, Pharm.D.
Neal R. Cutler, M.D.
California Clinical Trials Medical Group, Los Angeles, CA 90211To the Editor:
Rothman and Michels take the position that “the essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing.” On the contrary, it is more important to know “whether the new treatment is better than nothing” and will therefore offer an alternative for patients who do not have a response to the conventional treatment or cannot tolerate its adverse effects. The population of patients with medical disorders is often heterogeneous, and much of our work consists of trying to identify subgroups and differential treatment responses. The availability of treatment options is crucial to clinical work, and proof that a new treatment is superior to placebo represents an advance, even if the new treatment is inferior to the old one.
David A. Solomon, M.D.
Butler Hospital, Providence, RI 02906-4829Author/Editor Response
The authors reply:
To the Editor: Some of our critics inappropriately weigh scientific concerns against ethical ones. Others, such as Drs. Schechter and Nash, seem unhappy with the Declaration of Helsinki1 itself. The proposition that it is unethical to use placebos when accepted treatments exist did not originate with us.
As we noted in our article, we expected some of our examples to be challenged. Regarding the ivermectin trial,2 Dr. Taylor's argument that diethylcarbamazine may be no better than placebo does allay some concerns. On the other hand, his point that the study was approved by several review boards is not reassuring by itself, as evinced by Dr. Denny's revealing comments about pressure on review boards.
Dr. Solomon implies that placebo comparisons are important for the approval of alternative treatments for heterogeneous subgroups of patients. But the discovery of alternative treatments does not depend on the use of placebos. For example, a range of effective therapies for cancer now exists, despite the fact that placebos are seldom used in cancer trials.
Drs. Gilbert and Packer incorrectly claim that we failed to consider that placebos are sometimes given as supplements to effective drugs. In fact, we discussed studies in which patients were denied effective therapy, whether supplementary or not. They also apparently believe that it is unethical to offer patients an accepted treatment, because the magnitude of its efficacy may be unknown, when one can instead offer them a placebo, which has a known efficacy (of zero). But why would patients be better off with certain inefficacy?
Drs. Pohl and Balon have missed our point. We nowhere suggest, as Dr. Cleophas does, that human experimentation should be abandoned because it cannot be ethical. We merely propose greater vigilance.
The clandestine research conducted to meet FDA requirements for drug approval merits particular vigilance. As we noted, the requirement of placebo controls violates the Declaration of Helsinki. Furthermore, the FDA's misguided focus on statistical significance, rather than estimation, encourages small studies that are inadequate for estimating the efficacy and safety of drugs with precision. Thus, contrary to Sramek and Cutler's assertion, the failure of many preapproval studies to find Prozac more effective than placebo is not an argument in favor of using placebo but an indictment of the scientifically inadequate studies that the current FDA policy favors. Uncertainty about the efficacy and safety of approved treatments could be averted if the FDA required larger, ethical studies for drug approval in the first place. We still hope that the FDA, which to date has not responded to these concerns, will initiate an ethical review of studies conducted to gain approval of new drugs.
2 ReferencesKenneth J. Rothman, Dr.P.H.
Boston University Medical School, Boston, MA 02215Karin B. Michels, M.S., M.P.H.
Harvard School of Public Health, Boston, MA 021151
Declaration of Helsinki IV, World Medical Association, 41st World Medical Assembly, Hong Kong, September 1989. In: Annas GJ, Grodin MA, eds. The Nazi doctors and the Nuremberg Code: human rights in human experimentation. New York: Oxford University Press, 1992:339-42.
2
Greene BM ,Taylor HR ,Cupp EW , et al. Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis. N Engl J Med 1985;313:133-138
Full Text | Web of Science | Medline
- Citing Articles (8)
Citing Articles
1
Nicolino Ruperto, Alberto Martini. (2008) Network in pediatric rheumatology: the example of the Pediatric Rheumatology International Trials Organization. World Journal of Pediatrics 4:3, 186-191
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Charles N. Bernstein. (2006) The Placebo Effect for Gastroenterology: Tool or Torment. Clinical Gastroenterology and Hepatology 4:11, 1302-1308
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Nicolino Ruperto, Alberto Martini. (2004) International research networks in pediatric rheumatology: the PRINTO perspective. Current Opinion in Rheumatology 16:5, 566-570
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ARIF KHAN, MICHAEL DETKE, SHIRIN R. F. KHAN, CRAIG MALLINCKRODT. (2003) Placebo Response and Antidepressant Clinical Trial Outcome. The Journal of Nervous and Mental Disease 191:4, 211-218
CrossRef5
Charles W. Lidz, Paul S. Appelbaum. (2002) The Therapeutic Misconception : Problems and Solutions. Medical Care 40:9, V
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Olivier Chassany, Martin Duracinský. (1999) Ethics and clinical trials. Fundamental & Clinical Pharmacology 13:4, 437-444
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A. Hillary Steinhart. (1997) Randomized controlled trials in inflammatory bowel diseases: The case for the positive control. Inflammatory Bowel Diseases 2:4, 260-264
CrossRef8
LEONARD H. GLANTZ. (1996) Conducting Research with Children: Legal and Ethical Issues. Journal of the American Academy of Child & Adolescent Psychiatry 35:10, 1283-1291
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