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The New England Journal of Medicine February 3, 2000 -- Vol. 342, No. 5 Placebo Surgery in Trials of Therapy for Parkinson's Disease To the Editor: The Sounding Board articles by Freeman et al. (1) and Macklin (2) (Sept. 23 issue) provided an excellent discussion of sham surgery for patients with Parkinson's disease. However, Freeman et al. seem overenthusiastic about downplaying the risks of sham surgery. Their statement that these procedures are easier to perform, standardize, and reproduce than traditional surgical procedures does not do justice to the neurosurgical skills involved in performing stereotactic brain surgery. It is probable that the wide range of outcomes regarding the effectiveness of and morbidity associated with pallidotomy is related to the varying skills of the operating neurosurgeon. Freeman et al. present the cogent argument that sham surgery is the only solution for proving the validity of the neurosurgical procedures discussed in relation to Parkinson's disease. Not only are there important clinical questions that need to be answered, but society also needs to know whether any surgical therapy for Parkinson's disease provides substantial enduring benefit. Macklin is no doubt correct that the informed-consent process is less than perfect. Rather than turn our backs on objectively evaluating surgical procedures, however, we should be more diligent in obtaining consent. In the end, the patients with Parkinson's disease who give informed and valid consent to participate in trials in which sham surgery is used are truly brave pioneers who are helping to advance the frontier of research. We should not prevent such trials from taking place. William J. Weiner, M.D. University of Miami Medical School Miami, FL 33155 References 1. Freeman TB, Vawter DE, Leaverton PE, et al. Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson's disease. N Engl J Med 1999;341:988-92. 2. Macklin R. The ethical problems with sham surgery in clinical research. N Engl J Med 1999;341:992-6. ================== To the Editor: Macklin's argument against sham surgery in clinical research is fundamentally flawed in two important respects. First, there is no ethical requirement to minimize absolutely the risk of harm to research subjects. The ethical requirements are that there be a reasonable balance between the potential risks and the potential benefits to the subject or to society (1) and that the subject make a fully informed choice about participating in the research. (2) Within the context of a reasonable overall risk-benefit ratio, risks should be minimized by using medically and scientifically appropriate procedures. (1) Second, preventing subjects from deciding what risks they are willing to take is a direct violation of the principle of autonomy. We should not declare research unethical because the process of informed consent can be imperfect; instead, we should concentrate on improving that process. Medical paternalism, in which physicians decide what risks to expose patients to, is ethically unacceptable. A medical maternalism in which research subjects are protected from all risks and from the autonomous exercise of their right to choose is no better. (The opinions expressed in this letter are those of the author and do not necessarily represent the policy of the Department of Veterans Affairs.) James F. Burris, M.D. Veterans Health Administration Washington, DC 20420 References 1. 45 CFR 46.111. 2. 45 CFR 46.116. ==================== To the Editor: In 1993, when we proposed the idea of a double-blind design for fetal-cell transplantation for Parkinson's disease, our plan was met with a good deal of skepticism by members of the scientific community, including Dr. Freeman's coauthor Dr. Olanow. (1) Because no neurosurgical trial had been performed with a double-blind design, it was unclear whether such a protocol could or should be carried out. Our double-blind study of 40 patients (20 patients who received implants and 20 control subjects) has been completed. (2,3) It is particularly challenging to do a double-blind surgical study in patients with Parkinson's disease. Because it would be unethical to discontinue antiparkinsonian drugs in these patients, neurotransplants have to add substantially to the best pharmacologic treatment of each patient. It is likely, though not sure, that the effects of transplantation would be much easier to demonstrate in a placebo-controlled design in which the placebo group did not receive drug therapy. Because of the great value of levodopa and other drugs, such a placebo design could not be justified. Double-blind studies are undertaken to demonstrate the value of a treatment in a small group of patients with reasonable, but not zero, risk. In our study, the patients who received implants were exposed to more risk than the patients who had placebo surgery, because of needle penetrations of the brain. Whether the patients who received implants benefited more than the patients who underwent placebo surgery could be answered only with the double-blind design. We were not surprised that our design produced controversy seven years ago. Even as discussion continues about the role of double-blind surgical studies, review groups of the Food and Drug Administration and National Institutes of Health have embraced the concept, and several such studies are now under way. Curt R. Freed, M.D. Robert E. Breeze, M.D. University of Colorado School of Medicine Denver, CO 80262 Stanley Fahn, M.D. Columbia University New York, NY 10032 References 1. Cohen J. New fight over fetal tissue grafts. Science 1994;263:600-1. 2. Freed CR, Breeze RE, Greene PE, et al. Double-blind placebo-controlled human fetal cell transplants in advanced Parkinson's disease. Soc Neurosci 1999;1:212. abstract. 3. Fahn S, Greene PE, Tsai W-Y, et al. Double-blind controlled trial of human embryonic dopaminergic tissue transplants in advanced Parkinson's disease: clinical outcomes. Neurology 1999;52:Suppl 2:A405. ==================== To the Editor: Macklin states, "An alternative research design that did not involve sham surgery... would be less rigorous from a methodologic point of view." That a placebo procedure in a clinical trial be manifestly harmless is not only an ethical requirement but also a fundamental requirement for clinically relevant, generalizable inferences to be drawn from the trial. Even if the implanted material is found to improve the patient's condition, it may not fully counter any damage that may have occurred as a result of the surgery. In other words, a positive effect of treatment in a trial involving a potentially harmful control may result in the adoption into clinical practice of a treatment that results in more harm to patients than if they had received no intervention at all. Some may argue that a trial that compares a treatment involving surgery and implantation with conservative management and finds a beneficial effect also admits the possibility that the implantation itself added nothing to, or even detracted from, a beneficial placebo effect. If this is truly a possibility, then perhaps the three-group trial that Macklin describes at the end of her article is the only clinically informative option. However, the assumption that sham surgery is likely to have a positive effect on health requires careful examination. Jim Slattery, M.Sc. 2 Guest Rd. Cambridge CB1 2AL, United Kingdom ==================== To the Editor: The advantages of a new treatment are often vastly overestimated, in spite of the most objectively written notice of information, as a result of the combined effects of the physician-investigator's expectations and the patient's hopes. Therefore, many patients not only agree to participate but also eagerly desire participation in studies of such treatments, which represent the only hope offered to them. Under these circumstances it is likely that the consent will not really be freely given, and therefore the study may not be ethically acceptable. I suggest the following solution: when participation in a randomized study with a sham-procedure group is proposed to a patient, the patient must be offered, in addition to the alternative of agreeing or refusing to participate in the randomized study, the possibility of receiving the new experimental treatment without participating in the randomized study. Obviously, when offered this choice, fewer patients will agree to enter the study. However, if the investigator presents the possible outcome in a realistic way, with all the uncertainties about the outcome of the new treatment, some patients will agree to participate for purely altruistic reasons, and even more patients will want to participate if all the patients are offered the possibility of receiving the new treatment later if it is proved to be effective. This design will force the investigator to present the possible outcomes of the two groups of the study in a realistic and balanced way: if the investigator exaggerates the expected benefits of the new treatment, no patients will agree to participate in the randomized study. This approach would make the recruitment of patients more difficult, but there are good reasons why this type of study should not be easy to carry out. Jean-Daniel Horisberger, M.D. University of Lausanne Medical School CH-1005 Lausanne, Switzerland ==================== The authors reply: To the Editor: It is affirming to note that all the correspondents support the use of placebo-surgery controls under certain conditions. We agree with Burris that it is neither required nor reasonable to expect surgical trials to involve no risk. As with all trials, patients must be informed of the potential risks, and risks must be reasonable in relation to the possible benefits to the individual patient as well as to society. (1,2,3) We believe it is a mistake to hold surgical trials to a standard more stringent than that required for the study of nonsurgical interventions. Horisberger recommends that patients be offered access to the experimental treatment without participating in the study in order to minimize exaggerated estimates of benefit and to ensure that informed consent is freely given. Offering the patient such access to an unproved intervention implies that the investigator condones the procedure and that it is beneficial when this is not known to be the case. It would therefore serve to exaggerate benefit and to induce a less informed decision about receiving the intervention. We believe it is inappropriate for an investigator to offer an intervention as a therapy while at the same time asserting that it is necessary to perform a placebo-controlled trial to determine whether it is effective. We agree with Weiner that differences in surgical methods and skills can affect the outcome of surgical procedures. However, it is easier to standardize surgical methods used with nonablative and minimally invasive procedures, as in the case of cellular transplantation. It is because of the variability that can occur even with a single surgeon that randomized clinical trials are necessary. (4) Freed et al. assert that we were skeptical about the use of a placebo control in their trial design. Rather, we argued for multiple trials in which different variables with regard to transplantation were used, so that negative or inconclusive results with a single protocol would not adversely affect the entire field. (5) We were not opposed to the use of placebo controls. In our article, we cited numerous examples of such studies (including neurosurgical trials) that predated both of our trials. Our concern is that patients may undergo operations performed by surgeons who stand to benefit financially, academically, and by reputation but who fail to disclose that the operations have unproved benefits and undefined risks. If the safety and efficacy of a new surgical procedure are not established in controlled trials involving patients who give informed consent, thousands of future patients may be subjected to the risks and costs of an unproved operation in uncontrolled studies, without their full knowledge and consent. Thomas B. Freeman, M.D. University of South Florida Tampa, FL 33606 Dorothy E. Vawter, Ph.D. Minnesota Center for Health Care Ethics Minneapolis, MN 55454 C. Warren Olanow, M.D. Mount Sinai School of Medicine New York, NY 10029 References 1. Department of Health and Human Services, National Institutes of Health, Office for Protection from Research Risks. Protection of human subjects. 45 CFR 46 (1991). 2. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Washington, D.C.: Government Printing Office, 1978. (DHEW publication no. (OS) 78-0012.) 3. Levine RJ. The use of placebos in randomized clinical trials. IRB 1985;7(2):1-4. 4. Baum M. Reflections on randomised controlled trials in surgery. Lancet 1999;353:Suppl 1:SI6-SI8. 5. Cohen J. New fight over fetal tissue grafts. Science 1994;263:600-1. ==================== To the Editor: The claim that my argument against sham surgery in clinical research is "fundamentally flawed in two important respects" is mistaken on both counts. Burris contends that "there is no ethical requirement to minimize absolutely the risk of harm to research subjects." I do not know what he intends by "absolutely"; it is a term without meaning in this context. However, a look at the U.S. Code of Federal Regulations reveals the following as the first of the requirements that institutional review boards must determine are satisfied in order to approve research: "Risks to subjects are minimized." (1) The second alleged flaw is that "preventing subjects from deciding what risks they are willing to take is a direct violation of the principle of autonomy." But the role of the institutional review board in our system for the protection of human subjects is precisely to determine the acceptability of risks. Once the institutional review board has determined that risks to subjects are minimized and that "risks to subjects are reasonable in relation to anticipated benefits," (1) then potential subjects are asked to provide their voluntary, informed consent. If subjects' informed consent were the only ethical requirement for research, there would be no need for institutional review boards to make risk-benefit determinations before approving research protocols. Weiner endorses the view that "sham surgery is the only solution for proving the validity of the neurosurgical procedures" and concludes that we should not prevent such trials from taking place. Although I acknowledge that using sham surgery as a control may be the best way to seek proof, it is not the only "objective" way to demonstrate efficacy. There are other, albeit less rigorous, ways. Slattery questions whether it is even the best way, since harm produced in a control group of a trial prevents investigators from determining whether there is a benefit from the experimental treatment. Freed et al. note that review groups of the Food and Drug Administration and National Institutes of Health have embraced the concept of trials that involve sham surgery and that several such studies are under way. This means that the trials were approved by institutional review boards, an important procedural requirement in our system for the protection of human subjects. However, approval by an institutional review board does not make a study ethically acceptable. It is evidence only that the institutional review board found the research to be ethically acceptable, a judgment with which another institutional review board might reasonably disagree. Ruth Macklin, Ph.D. Albert Einstein College of Medicine Bronx, NY 10461 References 1. 45 CFR 46.111.