Reviews/Commentaries/Position Statements COMMENTARY

Placebo-Controlled Trials of New Drugs: Ethical Considerations

DAVID ORENTLICHER, MD, JD als, placebo controls are not appropriate when patients’ health would be placed at significant risk (8–10). A placebo- controlled study for a new hair- uch controversy exists regarding sufficiently more effective than placebo to thickening agent could be justified; a the ethics of placebo-controlled justify its use. Finally, not all established placebo-controlled study for patients M trials in which an experimental therapies have been shown to be superior with moderate or severe hypertension therapy will compete with an already es- to placebo. If newer drugs are compared would not be acceptable (11). Similarly, if tablished treatment (or treatments). In with the unproven existing therapies, an illness causes problems when it goes such cases, argue critics, patients in the then patients may continue to receive untreated for a long period of time, a 52- control arm of the study should receive an drugs that are harmful without being week study with a placebo control is accepted therapy rather than a placebo. helpful. much more difficult to justify than a By using an active and effective drug, the Moreover, say proponents of placebo 6-week study (12). control patients would not be placed at controls, patients can be protected from When David S.H. Bell (13) explains risk for deterioration of their disease, and harm by “escape” criteria, which call for why placebo controls are unacceptable the study would generate more meaning- withdrawal from the trial if the patient for new drugs to treat type 2 diabetes, he ful results for physicians. The key question, shows evidence of inadequately con- makes arguments that would resonate it is said, is not whether a new therapy is trolled disease (5). Other changes in study with proponents as well as opponents of better than nothing but whether it is bet- design can also be used to minimize the placebo controls. As he observes, patients in ter than the current standard of care (1,2). risk to patients from exposure to placebos a placebo arm of a study could go 6 months In response, say proponents of place- (7). without effective therapy and thereby suf- bo-controlled trials, critical information Yet for all of the controversy over pla- fer significant and irreversible harm. cannot always be obtained by giving con- cebo-controlled studies, the amount of Still, the very fact that Bell has written trol patients an existing therapy. For some agreement may be greater than the his letter points to a serious concern with effective therapies, the drug may perform amount of disagreement. For many stud- placebo-controlled trials. Apparently, no better than placebo in a particular trial ies, people on both sides of the issue many are conducted even though they even though other trials demonstrate the would agree that a placebo control is ei- cannot be justified in terms of widely drug’s superiority to placebo. If an exper- ther necessary or unacceptable. It is only shared views about the ethical appropri- imental agent confers the same benefit as in a fairly limited area of concern in which ateness of such trials (2). such an existing therapy in a comparative commenters part ways. There are probably multiple reasons trial, we cannot be certain that the new Thus, for example, opponents of pla- for the overuse of placebo controls. Phar- agent is any better than placebo. We cebo-controlled trials recognize that pla- maceutical companies may believe it is in might have one of the trials in which the cebo controls are justified for “first- their interest to compare new drugs with existing therapy (and therefore the new generation” drugs—drugs designed to fill placebo rather than existing therapy, even agent) does no better than placebo, per- a gap in the therapeutic armamentarium. when better information for patients and haps because of inadequate sample size, Relatedly, placebo controls are often jus- physicians would be provided by an ac- perhaps because the outcome measure tified when there is not adequate evidence tive control. There also appears to be can vary widely from one patient group to to support the efficacy of existing therapy. some misunderstanding of the U.S. Food another (3–5). In addition, some new Just as opponents of placebo controls and Drug Administration’s (FDA’s) posi- therapies are useful even if they are less accept some uses of placebos, proponents tion on the need for placebo controls effective than existing therapies. Some pa- of placebo controls support some limits and/or some overly aggressive requiring tients might choose a less effective drug if on placebo-controlled trials. Basic princi- of placebo-controlled studies by the FDA. substantial cost savings or a reduction in ples of medical ethics tell us that clinical Whether the FDA is truly at fault is not side effects would be realized (6). With- studies can go forward only if the ex- always obvious. One article, for example, out a placebo control, however, one can- pected benefits sufficiently outweigh the criticized the FDA for demanding a place- not always tell whether a new drug that is expected risks. Accordingly, acknowledge bo-controlled trial of a new anti-anginal not as effective as existing therapy is still the proponents of placebo-controlled tri- drug, despite a study demonstrating that ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● the drug was comparable to propranolol From the Center for Law and Health, Indiana University School of Law-Indianapolis, and the Indiana as an anti-anginal agent (2). According to University School of Medicine, Indianapolis, Indiana. the FDA, however, the problem with the Address correspondence and reprint requests to Dr. David Orentlicher, Indiana University School of study was not necessarily its failure to use Law-Indianapolis, 735 W. New York St. (530 W. New York St. as of 7 May 2001), Indianapolis, IN 46202. E-mail: [email protected]. a placebo arm. Rather, the study design Received and accepted for publication 23 January 2001. was defective because it left open the pos- Abbreviations: FDA, U.S. Food and Drug Administration; IRB, institutional review board. sibility that neither the new drug nor pro-

DIABETES CARE, VOLUME 24, NUMBER 4, APRIL 2001 771 Commentary pranolol was more effective than placebo ing placebo controls, that a placebo- References in that particular trial (8). controlled study can often be completed 1. Hill AB: Medical ethics and controlled tri- Where do we go from here? Undoubt- with fewer subjects and in a shorter pe- als. BMJ 1:1043–1049, 1963 edly, study sponsors and investigators riod of time (14). Costs are not irrele- 2. Rothman KJ, Michels KB: The continuing need to improve their understanding of vant—more expensive studies may mean unethical use of placebo controls. N Engl the extent to which placebo controls have fewer desirable studies—but arguments J Med 331:394–398, 1994 a role in clinical trials. Some studies with about costs cannot be accepted automat- 3. Makuch R, Johnson M: Issues in planning a placebo control should have an active ically. If an IRB is to make judgments on and interpreting active control equiva- control instead; other studies with only an cost grounds, the board would need spe- lence studies. J Clin Epidemiol 42:503– active control also need an arm with a cific information about the costs of the 511, 1989 placebo control. proposed and alternative studies. Indeed, 4. Tramer MR, Reynolds DJM, Moore RA, In addition, institutional review as a general matter, common arguments McQuay HJ: When placebo controlled tri- boards (IRBs) need to demand more of in favor of placebo controls are not ade- als are essential and equivalence trials are study investigators who submit proposals quate to justify a particular use of a pla- inadequate. BMJ 317:875–880, 1998 for trials of new drugs. If a placebo arm is cebo control. Rather, the arguments 5. Temple R, Ellenberg SS: Placebo-con- included for a drug that will compete with would have to be based on the specifics of trolled trials and active-control trials in an established treatment, the study proto- the study in question. the evaluation of new treatments. I. Ethi- col must supply a persuasive justification In deciding whether study investiga- cal and scientific issues. Ann Intern Med for using a placebo control (2). Similarly, tors have persuasive justification for in- 133:455–463, 2000 if a placebo arm is not included, there cluding or excluding a placebo control, 6. Miller FG: Placebo-controlled trials in psychiatric research: an ethical perspec- must be assurances that the study is de- IRBs should rely on one of the federal gov- tive. Biol Psychiatry 47:707–716, 2000 signed to avoid the possibility that the ernment’s basic requirements for medical 7. Amery W, Dony J: A clinical trial design new and active drugs show equal effec- research, a requirement that is too often avoiding undue placebo treatment. J Clin tiveness but that neither drug would be overlooked. According to regulations for Pharmacol 15:674–679, 1975 more effective than placebo in that study. the “Protection of Human Subjects,” not 8. Temple R: Government viewpoint of clin- IRBs, in other words, must approach only must studies have a favorable bene- ical trials. Drug Information J 16:10–17, studies of new drugs more skeptically and fit-to-risk ratio, but they must be de- 1982 approve studies only when they have signed so as to have the most favorable 9. Freedman B, Glass KC, Weijer C: Placebo enough information to make an indepen- benefit-to-risk ratio possible. In the lan- orthodoxy in clinical research. II. Ethical, dent judgment about the desirability or guage of the regulations, an IRB shall not legal, and regulatory myths. J Law Med & undesirability of a placebo control. approve a study unless it is satisfied that Ethics 24:252–259, 1996 In providing the information neces- the “[r]isks to subjects are minimized” 10. Levine RJ: Ethics and Regulation of Clinical sary to justify a placebo control, the (15). In other words, it is not sufficient to Research. 2nd ed. Baltimore, MD, Urban study’s investigators would have to ex- demonstrate relatively low risk; it is also & Schwarzenberg, 1986, p. 202–203 plain why adequate results could not be necessary to demonstrate that risks have 11. Weber MA: The ethics of using placebo in obtained by comparing the study drug been made as low as possible given the hypertension clinical trials. J Hypertens with an existing therapy in a well- potential benefits at stake. Thus, if the 17:5–8, 1999 designed study with ample subjects, or same benefits as the proposed study can 12. Ellenberg SS, Temple R: Placebo-con- trolled trials and active-control trials in why adequate results could not be ob- be obtained from a different study and the the evaluation of new treatments. II. Prac- tained by using the study drug plus exist- different study would pose less risk to the tical issues and specific cases. Ann Intern ing therapy in one arm and the existing subjects, the IRB must reject the proposed Med 133:464–470, 2000 therapy plus placebo in the other arm. study. Likewise, if two studies pose the 13. Bell DSH: Ethics in diabetic clinical trials Similarly, when a placebo arm is justified, same risks but one study offers greater (Letter). Diabetes Care 24:606, 2001 study investigators would need to explain benefit, the study with less benefit should 14. Freedman B, Weijer C, Glass KC: Placebo why the study does not also include a not be approved. With this requirement orthodoxy in clinical research. I. Empiri- third arm with existing therapy. as a guide, IRBs can further refine their cal and methodological myths. J Law Med In some cases, investigators will ob- inquiry and better distinguish acceptable & Ethics 24:243–251, 1996 serve that costs are a consideration in us- studies from those that are unacceptable. 15. 45 C.F.R. § 46:111(a)(1), 1999

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